Sufentanil

# Research Output: Sufentanil

## Chemical Identity

**PubChem CID:** 41693 (api_verified via get_pubchem_compound) [Ref 1 — PubChem lookup]

**IUPAC Name:** N-[4-(methoxymethyl)-1-(2-thiophen-2-ylethyl)piperidin-4-yl]-N-phenylpropanamide
*(Confirmed match with seed data)*

**Molecular Formula:** C₂₂H₃₀N₂O₂S — confirmed [Ref 1]

**Molecular Weight:** 386.6 g/mol — confirmed [Ref 1]

**InChIKey:** GGCSSNBKKAUURC-UHFFFAOYSA-N — confirmed [Ref 1] *(absent from seed; now supplied)*

**CAS Number:** 56030-54-7 (well-established; not returned by PubChem API call — web_retrieved)

**SMILES:** CCC(=O)N(c1ccccc1)C2(COC)CCN(CCc3cccs3)CC2 *(PubChem API did not return SMILES in this call; this canonical SMILES is consistent with PubChem CID 41693 structure, web_retrieved. Flagged for API verification.)*

**Chemical Class:** Anilidopiperidine (4-anilidopiperidine with thiophene substitution); belongs to the fentanyl family of synthetic opioids. Classified as piperidine/substituted piperidine per seed data — confirmed [Ref 10].

**Seed Data Discrepancies:**
- **Characterization "emerging"**: ⚠️ FLAG — Sufentanil is not an emerging substance. It was first synthesized in 1974, published in 1976, and received FDA approval for injection in 1984. It is a well-established, extensively studied clinical drug used worldwide. The characterization field should read "established" or "well-characterized." This is likely a seed data error.
- **PubChem CID absent from seed**: Now confirmed as 41693.
- **InChIKey absent from seed**: Now confirmed as GGCSSNBKKAUURC-UHFFFAOYSA-N.
- **SMILES absent from seed**: Canonical SMILES provided above.
- **Known ROAs listed as only "intravenous"**: ⚠️ FLAG — Incomplete. Sufentanil has well-established clinical routes including IV, epidural, intrathecal, sublingual (Dsuvia, FDA-approved 2018), and intranasal. The ROA list requires expansion.

---

## Pharmacology

### Receptor Binding and Mechanism

Sufentanil is a potent, highly selective full agonist at the mu-opioid receptor (MOR). In a uniform radioligand binding assay using recombinant human MOR, sufentanil demonstrated the highest binding affinity (lowest Ki) of 19 approved opioid drugs tested, with **Ki = 0.1380 nM** (Volpe et al. 2011 [Ref 1]). This places sufentanil in the sub-nanomolar category alongside butorphanol, levorphanol, oxymorphone, hydromorphone, and buprenorphine, substantially more potent than fentanyl (Ki ~1–10 nM range) [Ref 1].

Sufentanil acts via Gi/o-protein-coupled MOR to inhibit adenylyl cyclase (reducing cAMP), activate inwardly rectifying potassium channels (GIRK channels causing membrane hyperpolarization), and inhibit voltage-gated calcium channels — collectively suppressing neuronal excitability and pain transmission (Herman et al. 2026 [Ref 2]).

Unlike meperidine, remifentanil, and tramadol, sufentanil does **not** interact with α₂-adrenoceptors at any tested concentration in mouse brain receptor autoradiography studies, demonstrating exceptionally high opioid receptor selectivity (Höcker et al. 2008 [Ref 3]).

Sufentanil has **high MOR endocytotic efficacy** — it efficiently drives receptor internalization following activation, which may counteract receptor desensitization and thereby reduce tolerance development relative to morphine. However, this same property may facilitate compensatory cellular mechanisms underlying physical dependence (Koch et al. 2005 [Ref 7]).

Following chronic opioid treatment, sufentanil can stimulate rather than inhibit cAMP production within lipid membrane microdomains (caveolae), mediated by augmented caveolin-1 scaffolding of MOR–Gsα–adenylyl cyclase complexes — a mechanism potentially underlying opioid tolerance (Chakrabarti et al. 2016 [Ref — see PMID 27726130]).

### Potency Relative to Other Opioids

- **vs. morphine (animal):** 2,304× more potent than morphine in mice (hot plate test, ED₅₀ 0.0028 mg/kg vs. 6.45 mg/kg); 4,521× more potent in rats (tail withdrawal test) (Niemegeers et al. 1976 [Ref 34]).
- **vs. morphine (clinical):** Approximately 500–1,000× more potent than morphine when used intravenously (FDA prescribing information [Ref 33]).
- **vs. fentanyl (clinical, balanced anesthesia):** Up to 10× more potent than fentanyl as an analgesic adjunct; 5–7× when used as primary anesthetic with 100% oxygen (FDA prescribing information [Ref 33]).
- **vs. fentanyl (equianalgesic infusion, human subjects):** In a double-blind, target-controlled infusion study in 41 opioid-tolerant chronic pain patients, the median equianalgesic concentration ratio was **7.5** (95% CI: 6.8–8.2), meaning sufentanil is approximately 7.5× more potent than fentanyl by continuous infusion (Reynolds et al. 2004 [Ref 25]).

### Therapeutic Index

Based on preclinical data from Niemegeers et al. 1976 [Ref 34]:
- **Mice (IV):** LD₅₀ 18.7 mg/kg; ED₅₀ 0.0028 mg/kg → safety margin **1:6,679**
- **Rats (IV):** LD₅₀ 17.9 mg/kg; ED₅₀ 0.00071 mg/kg → safety margin **1:25,211**
- **Dogs (IV):** LD₅₀ ~14.0 mg/kg; ED₅₀ ~0.00028 mg/kg → safety margin **~1:50,000**

For comparison under the same conditions: pethidine 1:7.97, morphine 1:34.9, fentanyl 1:454. Sufentanil's preclinical therapeutic index is the highest of the major opioids tested. The clinical claim that sufentanil has "the highest therapeutic index of any opioid used in clinical practice" (Sacerdote et al. 2016 [Ref 16]) derives from these data, though this applies to preclinical animal models rather than direct human measurement.

### Pharmacokinetics

**Primary route:** Intravenous. Also used epidurally, intrathecally, sublingually (Dsuvia), and intranasally.

**Compartmental model:** Three-compartment model (Bovill et al. 1984 [Ref 13]):
- Rapid distribution half-life (π): **1.4 ± 0.3 min**
- Slow distribution half-life (α): **17.7 ± 2.6 min**
- Terminal elimination half-life (β): **164 ± 22 min** (~2.7 hours)
- Volume of distribution at steady state (Vdss): **1.7 ± 0.2 L/kg**
- Volume of distribution (beta, Vdβ): **2.9 ± 0.2 L/kg**
- Total plasma clearance: **12.7 ± 0.8 mL/kg/min** (935 ± 50 mL/min)
- 98% of administered IV dose leaves plasma within 30 minutes due to rapid tissue redistribution

**Protein binding:** ~93% in healthy males; 91% in parturients; 79% in neonates — bound primarily to alpha-1-acid glycoprotein (web-retrieved, FDA label [Ref 33]).

**Metabolism:** Hepatic and intestinal biotransformation via **CYP3A4** N-dealkylation to the primary metabolite **norsufentanil** (Tateishi et al. 1996 [Ref 4]). CYP3A4 responsibility was confirmed by: (1) significant correlation with nifedipine oxidation activity (r=0.87); (2) inhibition by gestodene, troleandomycin, and anti-CYP3A4 antibody; (3) CYP3A4 expressed in E. coli shows N-dealkylation activity while CYP1A2, 2C10, and 2E1 do not [Ref 4]. Approximately 80% of administered dose is excreted within 24 hours; only ~2% is eliminated as unchanged drug (FDA label [Ref 33]).

**Norsufentanil** is the primary metabolite (Wang et al. 2025 [Ref 40]). It has substantially lower opioid activity than the parent compound.

**Pediatric/neonatal PK:** Terminal elimination half-life is shorter in infants and children (~97 ± 42 min) and significantly longer in neonates (~434 ± 160 min) vs. adults (164 min), requiring dose adjustment (Scholz et al. 1996 [Ref 14]).

**Cardiopulmonary bypass (CPB) effects:** Sufentanil plasma concentrations decrease ~25% at CPB initiation due to increased volume of distribution, then increase by ~50% post-CPB. Clearance increases 2.80-fold during CPB/warming phases; central compartment volume increases 2.74-fold (Khaowroongrueng et al. 2024 [Ref 5]; Beukers et al. 2026 [Ref 12]).

**Epidural route:** Sufentanil concentrations decline more slowly after epidural than IV administration; the "flip-flop" phenomenon has been observed, indicating absorption-rate-limited kinetics after epidural administration (Bienert et al. 2025 [Ref 6]).

**Intranasal:** Used clinically at 0.5–1 μg/kg; documented in pediatric procedural sedation (Nielsen et al. 2014 [Ref — PMID 24118506]); Phase 4 trial conducted (NCT01954368).

---

## History

Sufentanil (internal laboratory designation **R 30 730**) was first synthesized at **Janssen Pharmaceutica** in **1974** by the team of Paul Adriaan Jan Janssen (1926–2003) and colleagues. Janssen had previously synthesized fentanyl in 1959 based on structure–activity relationship studies of meperidine, and continued developing more potent and selective analogs throughout the 1960s–1970s (Stanley TH 2014 [Ref 18]; web-retrieved sources).

The foundational pharmacological characterization was published by **Niemegeers, Schellekens, Van Bever, and Janssen** in 1976 in *Arzneimittel-Forschung* under the title "Sufentanil, a very potent and extremely safe intravenous morphine-like compound in mice, rats and dogs" [Ref 34]. This paper established the exceptional potency (2,304× morphine in mice) and safety margin (1:6,679) that defined sufentanil's clinical promise.

**1984:** FDA approved sufentanil citrate injection (NDA 019050) under the brand name **Sufenta** (Janssen Pharmaceutica), for use as an analgesic adjunct and primary anesthetic in cardiac surgery. In the same year, sufentanil was reportedly used in the anesthesia protocol for the first successful artificial human heart implantation (web-retrieved).

**1984:** Sufentanil added to the UK Misuse of Drugs Act 1971 as a Class A substance via the Modification Order 1983 [Ref 30].

**Chronogesic / TRANSDUR-Sufentanil:** DURECT Corporation developed sufentanil delivery systems for chronic pain — an implantable osmotic pump (Chronogesic) in partnership with Endo Pharmaceuticals, and a transdermal patch (TRANSDUR-Sufentanil). Endo returned Chronogesic rights to DURECT in April 2008. The transdermal patch was discontinued from DURECT's pipeline by approximately 2015 [Ref 31]. Neither received FDA approval.

**2018 (November 2):** FDA approved **Dsuvia** (sufentanil sublingual tablet, 30 mcg) by **AcelRx Pharmaceuticals** for the management of acute pain severe enough to require an opioid analgesic in medically supervised settings. The approval was controversial — Public Citizen and the chair of the FDA's Anesthetic and Analgesic Drug Products Advisory Committee opposed it [Ref 22]. Dsuvia is also marketed as **Dzuveo** in Europe.

**Scheduling history:** Sufentanil has been a DEA Schedule II controlled substance (US) since its initial approval. The class-wide scheduling of fentanyl-related substances implemented February 2018 provided additional control mechanisms for novel fentanyl analogs (Weedn et al. 2021 [Ref 11]).

---

## Subjective Effects

Published descriptions of sufentanil's subjective effects derive primarily from controlled clinical studies and one case series of healthcare professional fatalities, not from recreational user reports. No formal placebo-controlled studies of subjective effects in healthy volunteers using standard psychometric instruments (OOWS, VAS, ARCI) were identified in this search.

**From controlled anesthesia studies:**

Sufentanil produces dose-dependent **sedation**, **analgesia**, and at anesthetic doses, **loss of consciousness**. In balanced anesthesia studies, sufentanil produced the lowest hemodynamic stress response (blood pressure, heart rate, plasma catecholamines) of four opioids tested (vs. meperidine, morphine, fentanyl) and required no supplemental inhalational agents for any patient in the sufentanil group (Flacke et al. 1985 [Ref 15]).

At subanesthetic doses (≥8 μg/kg IV), sufentanil produces "deep anesthesia" with dose-related attenuation of catecholamine release [Ref 33].

**Documented adverse and subjective effects from clinical literature:**

- **Sedation** — pronounced dose-dependent CNS depression [Ref 2, 15]
- **Respiratory depression** — dose-dependent; at clinical doses, most serious risk [Ref 33]
- **Euphoria** — mediated by MOR activation in limbic system, nucleus accumbens [Ref 2]; inferred from class effects, not directly measured for sufentanil specifically
- **Analgesia / pain suppression** — primary intended effect [Refs 15, 25]
- **Muscle rigidity (truncal/chest wall)** — dose-dependent skeletal muscle rigidity; particularly truncal; can compromise ventilation; prevented by neuromuscular blocking agents [Ref 33]
- **Miosis** — pupil constriction via MOR in iris [Ref 2]
- **Nausea and vomiting** — documented in clinical trials [Ref 37]
- **Pruritus** — particularly associated with epidural and intrathecal routes; high rate vs. alfentanil (Jiang et al. 2026 [Ref 37])
- **Constipation** — via gastrointestinal MOR activation [Ref 2]
- **Bradycardia / hypotension** — at higher doses; in cardiac surgery context [Refs 5, 15]
- **Opioid-induced hyperalgesia (OIH)** — demonstrated in mouse inflammatory pain model via kinin B2 receptor pathway (Grastilleur et al. 2013 [Ref 27]); clinically, substituting sufentanil for morphine resolved morphine-induced hyperalgesia in one case (Sjøgren et al. 1994 [Ref 28])

**Duration data from controlled studies:**
- IV onset: ~1–2 minutes (per seed data; consistent with PK showing rapid distribution half-life of 1.4 min [Ref 13])
- Peak effect IV: ~5–10 minutes (consistent with seed data)
- Terminal elimination: ~164 min, but clinical duration of action at standard doses is shorter due to redistribution

No controlled study data on full subjective effect duration at subtherapeutic ("recreational") doses was identified. Duration data in the DB seed is classified as from intravenous route — consistent with PK literature.

**Effect profile proposals** (from pharmacological class and clinical data, flagged as class inference):

*Body:* pain-suppression (strong), sedation (strong), respiratory-depression (strong), muscle-relaxation, constipation, nausea, vomiting, pupil-constriction, bodily-heaviness

*Feeling:* euphoria (moderate, MOR-mediated), anxiety-suppression

*Thinking:* cognitive-impairment, amnesia (at anesthetic doses)

*Self:* disinhibition

⚠️ FLAG: No controlled subjective effect studies in non-anesthetized human subjects were found. All effect attributions are inferred from clinical anesthesia/analgesia studies or pharmacological class. The generation agent should label these as class-inferred unless substance-specific data can be cited.

---

## Safety & Toxicity

### Acute Toxicity (Animal Data)

From Niemegeers et al. 1976 [Ref 34] — all IV administration:
- **Mice:** LD₅₀ = 18.7 mg/kg; safety margin 1:6,679
- **Rats:** LD₅₀ = 17.9 mg/kg; safety margin 1:25,211
- **Dogs:** LD₅₀ = ~14.0 mg/kg; safety margin ~1:50,000

For context: all morphine-like effects antagonized by nalorphine (a mixed agonist-antagonist; now superseded by naloxone) [Ref 34].

No human LD₅₀ data exist. The exceptionally high preclinical therapeutic index supports the clinical characterization of sufentanil as having the highest safety margin among tested opioids [Ref 34]; however, extrapolation to humans requires caution, and respiratory depression remains the critical cause of opioid overdose death in clinical and illicit contexts.

### Overdose and Fatal Cases

**Mechanism:** Acute sufentanil overdose causes life-threatening **respiratory depression** — suppression of respiratory drive via MOR activation in the brainstem, leading to hypoxia, hypercapnia, and death if untreated [Ref 33].

**Case data:** Hayashi et al. 2013 [Ref 26] reviewed 9 deaths from self-administered IV anesthetics in healthcare professionals (Berlin, 1998–2011). One case was attributed to sufentanil (compound undetectable due to putrefaction at autopsy, but death attributed to respiratory depressant effects without respiratory assistance). Benzodiazepines contributed to fatal respiratory depression in 4/9 cases by synergistic inhibition. This constitutes very limited published fatality data specific to sufentanil — the larger opioid overdose epidemiology is dominated by morphine, fentanyl, and heroin.

**Naloxone reversal:** Sufentanil overdose is reversible by naloxone. In a 2026 study, 4 mg intranasal naloxone (Narcan) was evaluated for reversing moderate respiratory depression from both fentanyl and sufentanil; sufentanil was selected specifically due to its higher MOR affinity than fentanyl (van Lemmen et al. 2026 [Ref 19]). Due to sufentanil's higher receptor affinity, higher or repeated naloxone doses may be required vs. morphine overdose.

**Muscle rigidity:** Rapid IV administration can produce severe truncal/chest wall rigidity, potentially preventing adequate ventilation. This is not an overdose per se but a serious dose-dependent adverse effect requiring neuromuscular blockade [Ref 33].

### Chronic Toxicity

**High** by opioid class inference (seed data note: "inferred from pharmacological class — not sourced from literature"). No sufentanil-specific long-term human toxicity studies were identified. Chronic opioid toxicity includes: immunosuppression, endocrine effects (hypogonadism, hyperprolactinemia), cardiovascular effects, and psychological dependence [Ref 2].

⚠️ FLAG: Chronic toxicity rating "high" in seed data is labeled as inferred from class. No primary sources for sufentanil-specific chronic human toxicity were found in this research. This should be noted as class-inferred.

---

## Harm Reduction

### Risk Reduction

1. **Never use outside medical supervision**: Sufentanil at anesthetic potency requires airway management equipment and trained personnel. Even small dose errors can cause fatal respiratory depression [Ref 33].

2. **Naloxone availability**: Given sufentanil's high MOR affinity, standard naloxone doses may need to be repeated. Van Lemmen et al. 2026 [Ref 19] specifically studied 4 mg intranasal naloxone against sufentanil respiratory depression. Higher affinity may require higher total naloxone doses.

3. **Respiratory monitoring**: Due to rapid redistribution, plasma levels may change quickly with positional changes after IV administration. Respiratory depression may outlast the first dose of opioid antagonist [Ref 33].

4. **Avoid combination with CNS depressants**: Benzodiazepines and other CNS depressants synergistically potentiate respiratory depression (Hayashi et al. 2013 [Ref 26]; Whitwam 1995 [Ref — PMID 8719667]).

5. **Not for community/self-use**: Sufentanil is formulated in concentrations intended for anesthesia. Diversion and misuse by healthcare workers is documented in the forensic literature [Ref 26]. Community-acquired sufentanil would represent an extreme overdose risk.

6. **Testing**: Sufentanil does not reliably appear on standard fentanyl test strips (which target fentanyl and its common analogs). Mass spectrometry confirmation is required. In forensic toxicology, sufentanil may be undetectable post-mortem due to degradation [Ref 26].

### Contraindications (from published sources)

- Known hypersensitivity to sufentanil or other opioid agonists [Ref 33]
- Patients without access to resuscitation equipment and trained personnel
- Respiratory depression or obstructive airway conditions (relative contraindication)
- Neonates (significantly prolonged elimination half-life of ~434 min vs. ~164 min in adults [Ref 14])

---

## Tolerance & Dependence

### Tolerance Development

Sufentanil's unique pharmacological profile presents a complex tolerance picture. Chronic sufentanil treatment produces **antinociceptive tolerance** associated with uncoupling of spinal MOR from G-proteins (reduced [³⁵S]GTPγS binding, reduced adenylyl cyclase inhibition) and loss of co-precipitation of Gαo, Gαi2, Gαz, and Gαq11 with MOR (Mostany et al. 2008 [Ref — PMID 18384820]).

Sufentanil's **high MOR endocytotic efficacy** counteracts receptor desensitization by promoting fast receptor recycling/reactivation, suggesting sufentanil may produce less tolerance than morphine (which induces minimal endocytosis) (Koch et al. 2005 [Ref 7]). However, this same high endocytotic efficacy can facilitate compensatory upregulation of the cAMP pathway — a cellular marker of opioid withdrawal [Ref 7].

Cross-tolerance from sufentanil to morphine and DADLE (delta agonist) is demonstrated in rats. Sufentanil-tolerant rats showed cross-tolerance to ICV morphine (tolerance index 3.6), ICV DADLE (4.3), and SC morphine (6.6) by respiratory endpoint, but not to IV morphine — highlighting the influence of pharmacokinetics on tolerance expression (Ayesta & Flórez 1990 [Ref 24]).

### Physical Dependence

Physical dependence documented following intrathecal sufentanil infusion in rats (Stevens & Yaksh 1989 [Ref 8]): dose-dependent withdrawal body shakes after naloxone challenge. Magnitude of dependence: sufentanil (25.0 shakes) < DADLE (32.8) and morphine (30.2) but > DAMGO (8.7) at highest tested doses.

**Clinical (pediatric):** In neonates and children receiving IV sufentanil for ICU analgosedation, cumulative dose and treatment duration are the strongest predictors of withdrawal syndrome. **Treatment duration >177 hours predicts withdrawal syndrome with 81% sensitivity and 94% specificity** (Hronová et al. 2016 [Ref 20]). Pharmacogenetic factors (CYP3A5, COMT, ABCB1, OPRM1, PXR polymorphisms) affected dosing requirements but were not independently associated with withdrawal syndrome development [Ref 20].

### Pharmacogenomics

OPRM1 A118G polymorphism (rs1799971) significantly affects sufentanil dose requirement and adverse event rates in epidural analgesia. Heterozygous A/G patients required ~2.3× more injections and had twice the rate of opioid-induced adverse effects compared to A/A homozygotes (Bartošová et al. 2019 [Ref 35]). ABCB1 (P-glycoprotein gene) polymorphisms also affect sufentanil transport and efficacy (Zhao et al. 2019 [Ref 38]).

---

## Interactions

### Documented/High-Priority Interactions

**CNS Depressants (additive to synergistic respiratory depression):**
- **Alcohol** — additive CNS/respiratory depression. Seed data lists as "lethal." Published evidence supports additive CNS depression for opioid+alcohol combinations; sufentanil-specific human data not found. Class inference supported.
- **Benzodiazepines** — synergistic respiratory depression documented in forensic deaths (Hayashi et al. 2013 [Ref 26]); Whitwam 1995 [Ref — PMID 8719667] documents synergistic anesthesia/respiratory depression with midazolam + opioids. ⚠️ Seed lists Nitrous as "unknown" — N₂O does not cause significant opioid-type respiratory depression and reduces opioid dose requirements; this is an additive anesthetic interaction [from general anesthesia literature; not sufentanil-specific].
- **GHB/GBL** — seed lists "lethal." Both GHB and GBL cause CNS/respiratory depression; additive respiratory depression with opioids is plausible by mechanism. No sufentanil-specific data found. ⚠️ Class inference.
- **Tramadol** — seed lists "lethal." Tramadol has both opioid and serotonergic/noradrenergic activity. Combined opioid effects may cause respiratory depression; serotonin syndrome possible with serotonergic agents. Sufentanil itself does NOT appear to interact significantly with serotonin systems (no specific data found for serotonin syndrome). ⚠️ Interaction rated based on class; severity needs primary source.
- **Ketamine** — seed lists "lethal." Ketamine and opioids used routinely together in anesthesia; at subanesthetic doses, the combination is synergistic for analgesia but both can cause respiratory depression at higher doses. Clinical concern for respiratory depression at high combined doses. ⚠️ Sufentanil-specific data not found.
- **PCP** — seed lists "unknown." PCP is a dissociative with complex pharmacology; combined with opioids, additive CNS depression is possible. No specific data found.

**Drug metabolic interactions:**
- As a CYP3A4 substrate, CYP3A4 inhibitors (e.g., ketoconazole, erythromycin, diltiazem, grapefruit juice) may increase sufentanil plasma concentrations and effects [Ref 4, 14].
- CYP3A4 inducers (e.g., rifampicin, carbamazepine, St. John's wort) may reduce sufentanil efficacy [Ref 4].

**Alpha-2 adrenoceptors:**
Sufentanil does NOT interact with α₂-adrenoceptors (Höcker et al. 2008 [Ref 3]), unlike meperidine, remifentanil, and tramadol. This means sufentanil lacks the anti-shivering and alpha-2 modulatory effects of those agents.

**MAOIs / Serotonin syndrome:**
No sufentanil-specific MAOI interaction data were found in this search. Fentanyl class is generally considered lower-risk for serotonin syndrome than meperidine or tramadol, as it lacks significant serotonin reuptake inhibition. However, combined use with MAOIs remains contraindicated for opioids as a class [from class inference; not sufentanil-specific]. ⚠️ FLAG for editorial review.

⚠️ FLAG: Multiple interaction severity ratings in seed data ("lethal" for GBL, GHB, tramadol, ketamine) are plausible by mechanism but unsupported by published sufentanil-specific evidence. These should be labeled as class-inferred interactions in the article.

---

## Legal Status

**United States:**
- DEA Schedule II controlled substance under the Controlled Substances Act (21 U.S.C. § 812)
- FDA approved: Sufentanil citrate injection (NDA 019050), 1984; Dsuvia sublingual tablets (NDA 209128), November 2, 2018 [Refs 21, 22]
- Prescription required; no OTC availability

**United Kingdom:**
- Class A controlled drug under the Misuse of Drugs Act 1971, added via the Modification Order 1983 [Ref 30]
- Schedule 2 under the Misuse of Drugs Regulations 2001 (available for medical use with strict controls)

**Australia:**
- Controlled substance under the Poisons Standard; listed by the Office of Drug Control (ODC) [Ref 29]

**European Union:**
- Sufentanil is approved for medical use in multiple EU countries (Dzuveo sublingual tablet marketed in Europe)
- Controlled under national narcotic schedules consistent with the 1961 UN Single Convention on Narcotic Drugs

**International:**
- Sufentanil is listed under international drug control treaties as a narcotic. Specific scheduling confirmation for Canada not retrieved in this research session.

---

## Clinical Trials

**Sufentanil Sublingual Tablet (SST / Dsuvia) Trials:**

| NCT ID | Phase | Status | Indication | Sponsor |
|--------|-------|--------|------------|---------|
| NCT02356588 | Phase III | Completed | Post-op pain (abdominal surgery) | Talphera, Inc |
| NCT02662556 | Phase III | Completed | Acute moderate-severe pain | Talphera, Inc |
| NCT02447848 | Phase III | Completed | Acute pain (open-label) | Talphera, Inc |
| NCT04263909 | Phase IV | Completed | Spine surgery post-op pain | Brigham and Women's Hospital |
| NCT04432428 | Phase IV | Completed | TKA post-op pain (fast track) | University Hospital Ghent |
| NCT03459404 | — | Completed | Vertebral surgery post-op pain (NanoTab) | Policlinico Gemelli IRCCS |

**Pooled Phase III safety data** (n=804): AEs in 60.5% (SST) vs 61.4% (placebo); treatment-related AEs in 43.8% vs 33.5%; no dose-dependent oxygen desaturation; well-tolerated overall (Miner et al. 2019 [Ref 17]).

**Intranasal Sufentanil Trials:**

| NCT ID | Phase | Status | Indication | Sponsor |
|--------|-------|--------|------------|---------|
| NCT01954368 | Phase IV | Completed | Acute pain in ED (traumatic limb injury) | CHU de Nice |
| NCT03224039 | Phase IV | Unknown | Acute pain (vs IV morphine) | The Brooklyn Hospital Center |
| NCT04897750 | Phase II | Completed | Pediatric analgesia (CT001) | Cessatech A/S |

**Ongoing/Recruiting:**

| NCT ID | Phase | Status | Indication | Sponsor |
|--------|-------|--------|------------|---------|
| NCT06917651 | Phase III | Recruiting | Acute moderate-severe monotraumatic pain (emergency) | CHU Clermont-Ferrand |

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## Community Feedback Analysis

No community feedback was submitted for sufentanil (Part A2 of the brief is empty). No community feedback items to assess.

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## Gaps & Flags

### Critical Flags (Safety-Critical Values)

1. ⚠️ **Seed data: Characterization "emerging"** — INCORRECT. Sufentanil is a well-established clinical drug with FDA approval since 1984. This field should read "established." This may affect how the article positions the substance.

2. ⚠️ **Seed data: Known ROAs listed as "intravenous" only** — Incomplete. Published evidence confirms epidural, intrathecal, sublingual (Dsuvia, FDA-approved), and intranasal routes are well-documented and used clinically.

3. ⚠️ **Interaction severities not confirmed by primary source:** "Lethal" ratings for GBL, GHB, tramadol, and ketamine in seed data are plausible by mechanism but no sufentanil-specific fatal interaction studies were found. These are class-inferred.

4. ⚠️ **Toxicity data (Acute/Chronic "high"):** Seed data notes these are "inferred from pharmacological class." Confirmed: the "acute high" toxicity is consistent with animal LD₅₀ data and respiratory depression risk. Chronic toxicity "high" remains class-inferred for sufentanil specifically.

5. ⚠️ **SMILES in seed data: absent** — PubChem CID 41693 identified; SMILES should be retrieved from PubChem directly. Canonical SMILES provided above is from web-retrieved source, not API-confirmed.

6. ⚠️ **No serotonin syndrome specific data found** — unlike tramadol or meperidine, sufentanil has no documented serotonin reuptake inhibition. MAOI interaction rating should be reviewed by pharmacologist.

7. ⚠️ **No recreational/subjective effect controlled studies** — all effect profile data is from anesthesia/analgesia studies or class inference. Effects at sub-anesthetic doses in non-opioid-tolerant individuals are not directly characterized by any published study found in this search.

8. ⚠️ **Stereochemistry data gap** — Sufentanil has a chiral center at C4 of the piperidine ring. The clinically used compound is the racemate. No published studies on enantiomeric potency differences for sufentanil were found in this search. The IUPAC name from PubChem does not specify stereochemistry (no @ notation), consistent with the racemate.

9. ⚠️ **Physical properties incomplete** — No primary source for melting point, aqueous solubility, or logP was retrieved. DrugBank lists sufentanil as highly lipophilic (logP ~3.9) but this was not API-verified in this session.

### Data Gaps (Non-Critical)

- No published epidemiological data on sufentanil diversion or illicit use frequency found (unlike fentanyl, sufentanil has not been prominently featured in the street drug market in published surveillance reports).
- Duration data in seed (onset 1–2 min, peak 5–10 min IV) is consistent with PK literature but not directly cited from a controlled observational study.
- No published controlled human pharmacodynamic studies characterizing sufentanil's subjective effects using validated instruments (ARCI, OOWS, etc.) were found — this represents a genuine literature gap given the substance's clinical history.
- Dose sensitivity in seed (threshold 0.1 μg, light 1–5 μg, common 5–10 μg, strong 10–25 μg, heavy 25+ μg IV) appears consistent with anesthesia dosing of 1–2 μg/kg adjunct to 8–30 μg/kg primary anesthetic [Ref 33], but these seed dose ranges describe sub-anesthetic uses and should be reviewed. The "light" range overlaps with analgesic adjunct dosing (1 μg/kg = ~70 μg for 70 kg adult), suggesting a possible unit error in the seed data (ranges are in absolute μg, not μg/kg).

### Positive Seed Verification

- ✅ Molecular formula C₂₂H₃₀N₂O₂S — confirmed
- ✅ Molecular weight 386.6 g/mol — confirmed
- ✅ IUPAC name — confirmed
- ✅ Chemical class (piperidine/substituted piperidine/anilidopiperidine) — confirmed
- ✅ Pharmacological class (opioid system, MOR agonist) — confirmed
- ✅ Psychoactive class (depressant, opioid) — confirmed
- ✅ Primary ROA intravenous — confirmed (though incomplete)
- ✅ Interactions with alcohol, GBL, GHB as lethal — plausible by class mechanism (though not sufentanil-specific citations found)
- ✅ Dose data (μg range IV) — broadly consistent with clinical data
- ✅ Onset 1–2 min, peak 5–10 min IV — consistent with PK rapid distribution phases