Esketamine
Esketamine hydrochloride
Brand names:Spravato, Ketanest S
The S-enantiomer of ketamine, available as an intranasal formulation in the 2026 TCCC analgesia algorithm. Esketamine binds the same NMDA receptor target as racemic ketamine with greater affinity, allowing for lower total drug exposure at equivalent analgesic effect.
Pharmacology and Actions
Esketamine is the S(+) enantiomer of ketamine, the more pharmacologically active half of the racemic ketamine molecule. It produces non-competitive antagonism at the NMDA receptor with approximately twice the potency of racemic ketamine on a milligram-per-milligram basis. The clinical effects (dissociation, analgesia, amnesia, sympathetic activation) parallel those of racemic ketamine. Like ketamine, esketamine does not significantly depress respiratory drive at standard doses and tends to maintain blood pressure.
Indications
- Analgesia for non-mission-capable casualties (TCCC 2026, intranasal route)
- Treatment-resistant depression (FDA-approved indication, separate from tactical use)
- Adjunct in pain management when intranasal delivery is preferred over IV access
Absolute Contraindications
- Known esketamine or ketamine allergy
- Active angina or unstable coronary artery disease
- Congestive heart failure (relative; varies by protocol)
- Pregnancy (relative; varies by protocol and clinical urgency)
- Aneurysmal vascular disease
Precautions and Side Effects
Same precaution profile as racemic ketamine
Transient blood pressure elevation more pronounced than with racemic ketamine
May cause emergence reaction on awakening
May cause nystagmus (expected dissociation endpoint)
May cause hypersalivation and increased airway secretions
Use with caution in patients with schizophrenia or significant psychiatric history
Dissociation may complicate neurologic assessment in TBI casualties
Adult Dosing
Repeat doses every 30 minutes as needed. Endpoints: reduction of pain or development of nystagmus.
Administer via mucosal atomizer device (MAD). Split dose between nostrils when possible.
Onset: 5 to 10 minutes
Pharmacokinetics
Peak Effect: IN: 10 to 15 minutes
Duration: IN: 60 to 90 minutes
Storage and Handling
Store at controlled room temperature. Protect from light.
Esketamine is a Schedule III controlled substance. Storage, accountability, wastage documentation, and chain of custody requirements apply per DEA regulation and agency policy.
Document AVPU mental status on the DD 1380 TCCC Casualty Card prior to administration. Disarm and consider disconnecting communications equipment for any casualty given esketamine.
Reconstitution:
Esketamine intranasal formulations are supplied as ready-to-use prefilled nasal spray devices in some forms (Spravato), or as a solution that can be drawn into a syringe and delivered via mucosal atomizer device. No reconstitution required.
The Spravato prefilled device is a single-use product designed specifically for the depression indication and may not be the formulation used for tactical analgesia. Tactical use typically involves a solution-based product administered via MAD.
TCCC and TECC Role
Esketamine appears in the 2026 TCCC analgesia algorithm as an alternative to intranasal ketamine for non-mission-capable casualties. The clinical role is identical: rapid analgesia delivered without IV access, in a casualty who cannot stay in the fight but does not yet require procedural sedation.
The same polypharmacy guidance applies. Co-administration of benzodiazepines with esketamine is not recommended outside the procedural-sedation emergence exception. If a casualty appears partially dissociated, more esketamine is safer than a benzodiazepine.
The same TBI considerations apply. Esketamine does not preclude use in TBI casualties, with caution that dissociation may complicate neurologic assessment.
Esketamine is the more pharmacologically active half of the ketamine molecule. The drug binds the same NMDA receptor target with greater affinity, which allows for lower total drug exposure at equivalent analgesic effect. The 2026 TCCC update lists intranasal esketamine as an alternative to intranasal ketamine for non-mission-capable casualties.
The clinical advantage in tactical settings is the formulation. Intranasal delivery does not require IV access, does not require a casualty to swallow, and can be administered through a mucosal atomizer device in seconds. For a casualty who needs analgesia but does not need IV resuscitation, intranasal esketamine provides a clean delivery option.
For civilian providers, esketamine is FDA-approved in the United States for treatment-resistant depression under the brand Spravato. Its tactical analgesia use mirrors the off-label intranasal ketamine practice that has been adopted in some EMS systems. State EMS scope of practice and standing orders will determine availability.
Treating esketamine and ketamine doses as interchangeable. Esketamine has greater receptor affinity, so the dosing differs from racemic ketamine. The 2026 TCCC dosing reflects this.
This drug profile is provided as educational reference material for trained medical providers. It is not medical advice, not a substitute for formal training, and not a substitute for current published guidelines or medical direction.
Drug administration is governed by your scope of practice, agency standing orders, medical director protocols, and applicable state and federal regulations. Controlled substances are subject to additional handling, accountability, and documentation requirements per DEA and state law. Always verify dosing, indications, contraindications, and route of administration against current published guidelines and your local protocols before administration.
If this content is being viewed during a medical emergency, call 911 immediately and follow the direction of your local emergency dispatch and medical control. Do not use this reference as a substitute for emergency medical services.
Drug information evolves. Last reviewed dates and source citations are provided for each entry. Confirm currency against the cited source before clinical use.
Penn Tactical Solutions publishes this reference for educational purposes. PTS does not provide medical direction and does not assume responsibility for clinical decisions made in the field. Clinical responsibility rests with the administering provider, their medical director, and their agency.
Educational reference for trained medical providers. Not medical advice. Not a substitute for formal training, current published guidelines, or medical direction. Drug administration is governed by your scope of practice, agency standing orders, medical director protocols, and applicable state and federal regulations. Controlled substances require additional storage, accountability, and documentation per DEA and state law.
In a medical emergency, call 911. This reference is not a substitute for emergency medical services.
Verify dosing, indications, and contraindications against current published guidelines and your local protocols before administration. Confirm content currency against the source citation. Penn Tactical Solutions does not provide medical direction. Clinical responsibility rests with the administering provider, their medical director, and their agency.
Esketamine
Schedule III| IN | Analgesia (TCCC 2026): 14 mg or 28 mg IN once Repeat doses every 30 minutes as needed. Endpoints: reduction of pain or development of nystagmus. Administer via mucosal atomizer device (MAD). Split dose between nostrils when possible. (5 to 10 minutes) |