Intranasal Ketamine in Adults

Intranasal ketamine is FDA-approved only as esketamine (Spravato) for treatment-resistant major depressive disorder (TRD) in combination with an SSRI/SNRI, requiring structured administration with mandatory 2-hour post-treatment monitoring in certified healthcare settings. 1

FDA-Approved Indication & Dosing

Esketamine (Spravato) for Treatment-Resistant Depression

Indication: Adults with MDD who have failed ≥2 adequate antidepressant trials 1
Dosing regimen:
- Induction phase: Twice weekly for 4 weeks
- Maintenance: Weekly to every 2 weeks based on response 1
- Dosing range established in clinical trials: typically starting doses with titration based on tolerability
Administration requirements:
- Must be combined with ongoing oral SSRI or SNRI
- Requires Risk Evaluation and Mitigation Strategy (REMS) certification for pharmacy and healthcare setting
- Mandatory 2-hour monitoring post-administration for blood pressure, dissociation, and sedation 1

Evidence Base

Meta-analysis of 5 RCTs demonstrated that twice-weekly esketamine as augmentation therapy improved depressive symptoms and remission rates at 28 days in TRD patients, but only in those with treatment-resistant disease—not as initial therapy 1. Single-dose IV ketamine (0.5 mg/kg) shows significant improvement in depressive symptoms persisting 3-7 days, with longer duration when added to ongoing antidepressants versus monotherapy 1.

Off-Label Uses (Not FDA-Approved for Intranasal Route)

Acute Pain Management

Intranasal racemic ketamine at 0.7-1.0 mg/kg provides clinically significant pain reduction in 56% of adult ED patients with moderate-to-severe pain when used as primary analgesic. 2

Dosing for Acute Pain:

Initial dose: 0.7-1.0 mg/kg intranasal 2
Secondary dose: 0.5 mg/kg at 15 minutes if inadequate response 2
Median effective total dose: ~1 mg/kg 2
Onset: Pain reduction evident by 15 minutes, maximal at 30 minutes 3

When combined with nitrous oxide in prehospital setting, intranasal ketamine 0.75 mg/kg resulted in 76% of patients achieving ≥2-point pain reduction at 30 minutes versus 41% with placebo 3.

For limb trauma specifically, intranasal ketamine 0.02 ml/kg (concentration not specified) combined with IV morphine reduced supplemental narcotic requests from 67.5% to 30% 4.

Cancer-Related Pain

Intranasal ketamine for chronic cancer pain is a double-edged sword: while it can reduce opioid requirements by up to 90%, adverse effects (fatigue, cognitive slowing, dissociation) frequently limit tolerability and warrant treatment discontinuation. 5

The 2025 NCCN guidelines acknowledge ketamine's modest analgesic potential for cancer pain but note limited data and lack of long-term safety studies 6. Case series show treatment durations of only 1-8 months with doses of 50 mg TID to 100 mg QID before adverse effects necessitate cessation 5.

Absolute Contraindications

Based on IV ketamine data (intranasal-specific contraindications not established):

Renal or hepatic insufficiency (ketamine detoxified by liver, excreted by kidneys) 7
Uncontrolled hypertension (causes cardiovascular stimulation)
Acute coronary syndrome
Increased intracranial pressure
Glaucoma
Pregnancy and breastfeeding
Known ketamine intolerance 3
Psychotic disorders (risk of exacerbation)

Monitoring Requirements

For Esketamine (FDA-Approved):

Blood pressure: Before, 40 minutes post-dose, and prior to discharge 1
Dissociative symptoms: Continuous observation during 2-hour monitoring period 1
Sedation level: Until patient safe for discharge 1
Setting: Must be administered in REMS-certified facility 1

For Off-Label Intranasal Use:

Based on IV ketamine safety data and clinical practice:

Vital signs: Baseline and every 15-30 minutes during recovery
Oxygen saturation: Continuous monitoring (respiratory depression possible at higher doses)
Mental status: Assess for dissociation, emergence reactions
Avoid stimulation: Minimize sound/handling during recovery to reduce emergence reactions 7

Adverse Effects

Common (Dose-Related):

Dissociation and psychotomimetic effects: 62% in acute pain studies 3
Nausea/vomiting: 7-19% (higher with ketamine alone vs. with midazolam) 8
Dizziness and vertigo
Fatigue and cognitive slowing 5
Increased salivation

Serious (Rare):

Respiratory depression (especially at higher doses or with concurrent sedatives)
Cardiac arrest (more frequent when combined with other anesthetics) 7
Hypertension and tachycardia
Emergence reactions (reduced by minimizing stimulation during recovery)

Critical caveat: All adverse events in acute pain studies were minor, requiring no physical or medical intervention 3. However, chronic use in cancer pain led to treatment discontinuation in all reported cases 5.

Clinical Positioning & Alternatives

For Depression:

Esketamine is reserved for patients who have failed ≥2 adequate antidepressant trials—never as initial therapy. 1 It lacks long-term efficacy and safety data beyond maintenance studies in TRD populations 1.

Alternatives:

Optimize current antidepressant therapy
Switch to different antidepressant class
Augmentation with atypical antipsychotics (aripiprazole, quetiapine)
Electroconvulsive therapy (ECT) for severe TRD
Transcranial magnetic stimulation (TMS)

For Acute Pain:

Intranasal ketamine may be considered when:

IV access difficult or unavailable (prehospital setting)
Opioid-sparing strategy desired
Rapid analgesia needed for moderate-to-severe pain