KETAMINE INJ,SOLN

Generic Name: KETAMINE INJ
Brand Names: KETALAR, KETAMINE HCL, KETAMINE HCL-0.9% NACL, KETAMINE HCL-NACL, KETAMINE HCL-WATER
Drug Class: GENERAL ANESTHETICS,OTHER
Formulary Status: Formulary On formulary with criteria for specific uses
Copay Tier: N/A
Last Updated: October 1, 2025

Clinical Criteria Summary

Document 411: Ketamine Infusion for the Treatment of Intractable Neuropathic Pain Update DEC 2024

Indication & Patient Population

Treatment of complex neuropathic pain disorders, specifically Complex Regional Pain Syndrome (CRPS) or centralized pain disorder
Veterans receiving care by a VHA Pain provider or Pain Management Teams (not VA Community Care)

Inclusion Criteria

Current diagnosis of CRPS or centralized pain disorder
Failed adequate trials (unless contraindicated) of: TCAs (amitriptylline, desipramine, nortriptyline), SNRIs (venlafaxine, duloxetine), alpha-2-delta calcium channel blockers (gabapentin, pregabalin)
Evaluated and qualified by a pain management or interventional pain specialist; reasoning documented in medical record
Evaluated and cleared of mental health contraindications by a Mental Health Pain Provider; documented in medical record
Verbal informed consent provided by patient or legal representative
Adult accompaniment for transportation arranged and documented, or another safe transport method arranged

Exclusion Criteria

Current or past history of schizophrenia, schizoaffective disorder, bipolar disorder, or decompensated psychiatric disorder
Dementia
Current or recent (within 7 days) delirium
Current uncontrolled hypertension (SBP >160 mm Hg or DBP >90 mm Hg)
Conditions in which an increase in blood pressure would be hazardous
Severe cardiac decompensation
Myocardial ischemia/angina, recent MI (within 3 months)
Pregnant (positive pregnancy test) or lack of birth control method in women of childbearing potential
Positive urine drug screen or current/previous abuse of ketamine (patients prescribed opioids, benzodiazepines, or barbiturates by VHA are eligible; acute intoxication or detox needs addressing first)
Allergy or previous serious adverse effects to ketamine
Recent infection or illness
Psychosis or decompensated psychiatric condition
Ketamine-related cystitis
Illicit drug use (e.g., cocaine, methamphetamine, marijuana)
Morbid obesity with BMI > 40
End-stage renal or hepatic disease
DM2 with HbA1c > 9.0 (unless improved diabetic control evidenced by most recent 2-week glucose diary recordings)
Pulmonary HTN (mod-severe)

Screening & Pre-Treatment Requirements

Screening completed no more than 30 days prior to first dose
Includes: verbal informed consent, inclusion/exclusion criteria review, physical exam with vitals (BP, HR, RR, SpO2, weight), relevant labs, urine toxicology, pregnancy screens
SBP >150 mm Hg or DBP >95 mm Hg at screening = higher risk; treat hypertension prior to infusion
Cardiopulmonary/cerebrovascular disease, recent MI, symptomatic ischemic heart disease, dyspnea (SOB/wheezing), poor exercise capacity (<6 METs), or conditions increasing risk of acute cardiac demand/BP/respiratory depression = individual case basis
Baseline HR <60 bpm or >100 bpm = case-by-case consideration for relative risks
SpO2 at screening must be >94% after mild exertion
Other physical/laboratory screening per individual risk factors (prescribing psychiatrist's responsibility)
Medical clearance/consults based on risk factors (prescribing provider's responsibility)
Screen for CNS depressant use/abuse history; length of sobriety considered when making decisions

Administration, Monitoring & Infusion Protocol

Private or semi-private location large enough to accommodate patient and required personnel
Immediate care capability with crash cart readily accessible
Monitor cardiovascular function (ECG, BP) and respiratory function (SpO2, end-tidal CO2)
Capable of administering oxygen, medications, and restraints for potentially dangerous behavioral symptoms
Plan for rapid response to sustained CV alterations (ACLS or transfer to acute care hospital)
High-risk patients treated at facilities equipped/staffed for cardiovascular/respiratory events
ACLS-certified pain physician/anesthesiologist present at initiation, intermittently during, and end; ACLS-certified nurse present during infusion
Ordering provider may leave after completion if stable; must return to evaluate and clear for discharge. ACLS provider remains until discharge
Initial dose: 0.5 mg/kg IV over 4 hours via infusion pump
For BMI >30 kg/m2, calculate dose using ideal body weight (Men: 50 kg + 2.3 kg per inch >5 ft; Women: 45.5 kg + 2.3 kg per inch >5 ft)
Pre-medication/concurrent meds (e.g., IV lorazepam for agitation) ordered by pain specialist to prevent/manage adverse effects
Timeline: T-2 days or sooner: UDS, pregnancy tests, med review, consent. T-60 min: IV line, vitals (sitting/standing BP/pulse, RR, SpO2), baseline BPI. T-0 min: Administer ketamine if acceptable vitals/negative screens. T+10, 20, 30, 40, 80, 110 min: Vitals and cognitive status check. T+240 min: Vitals, Pain NRS
Repeat infusions: Daily up to 5 days (excluding weekends) for up to 4 hours, per pain physician discretion based on response
Alternative schedule: Every other day x 3 days (M-W-F) for 1-2 weeks; failure to respond = discontinue
"Booster" sessions if necessary, no more frequently than every 3 months, individualized
Taper and discontinue in interest of patient safety; time frame undefined/individualized

Infusion Discontinuation Parameters

BP must remain <180 mm Hg systolic and <110 mm Hg diastolic at all times
SBP drop >10 mm Hg during infusion accompanied by increased HR or evidence of distress requires stopping
HR must remain below age-adjusted maximums: 20 yrs <140 bpm, 30 yrs <133, 40 yrs <126, 50 yrs <119, 60 yrs <112. For ≥65 yrs, individualize based on exercise capacity/risk factors
Stop infusion for: pallor/cyanosis/poor perfusion, respiratory symptoms (SOB/wheezing), chest/jaw/arm pain suggesting cardiac involvement, or patient desire to stop

Treatment Failure & Discontinuation Criteria

Patient wishes to stop for any reason
Infusion stopped >1 time due to exceeding BP or HR thresholds
After 4-6 infusions without adequate response (defined as ≥50% decline in NRS pain score from baseline)
Dosing cannot be spaced out to minimum of 1 dose per week by second month of treatment

Adverse Effects Requiring Monitoring

CV: hypertension, tachycardia, increased cardiac output, paradoxical direct myocardial depression, hypotension, bradycardia
CNS: tremors, tonic-clonic movements, fasciculation, increased intracranial pressure, dysphoria, amnesia, confusion, vivid dreams, delirium, sedation, dizziness
GI: hypersalivation, vomiting, nausea
Neuromuscular/skeletal: increased skeletal tone, muscular rigidity
Ocular: diplopia, nystagmus, increased intraocular pressure
Respiratory: increased airway resistance, depression of cough reflex, respiratory depression/apnea with large doses/rapid infusions, laryngospasm
Endocrine/Metabolic: increased metabolic rate, Diabetes Insipidus
Genitourinary: ulcerative/hemorrhagic cystitis (severity linked to chronicity/doses >700mg/day; resolves with cessation)
Hepatic: possible risk for increased LFTs

Outcomes Monitoring Schedule

Baseline, 1-2 weeks post-infusion, and monthly
Tools: Brief Pain Inventory (BPI), number and dosing regimens of opioid (MEDD) and non-opioid pain medications

Document 438: IM Ketamine for Acute Agitation in ED and UCC RFU Apr 2023

Indications & Patient Selection

Extremely combative patients at immediate risk of causing physical harm to medical staff, the public, or themselves
Patients who have failed de-escalation techniques and one or more rapid tranquilization medications (e.g., benzodiazepines, droperidol, haloperidol, olanzapine, ziprasidone)
Patients in whom ketamine is determined to be a preferred first-line agent
Acute behavioral agitation (non-procedural sedation)

Contraindications

Hypersensitivity to ketamine or any excipient

Precautions

Active psychosis
Pregnancy
Elevated intracranial or intraocular pressure
Severe cardiovascular disease: acute coronary syndrome, decompensated heart failure, severe valvular disease, active cardiac dysthymias
Pulmonary hypertension
Severe hepatic dysfunction

Dosing

Intramuscular: 1-3 mg/kg (Ideal Body Weight)
If administered shortly after receipt of another sedating agent, dose at the lower end of the dosing range

Monitoring, Equipment, and Personnel Requirements

Facility responsible for monitoring patient during and after injection(s)
Capability to administer oxygen, medication, and/or restraints to manage potentially dangerous behavioral symptoms
Bag Mask Valve (BVM) device and airway rescue equipment must be immediately available to the provider
Plan required to rapidly address sustained alterations in cardiovascular function, including advanced cardiac life support or transfer to a hospital capable of caring for acute cardiovascular events
Licensed Independent Practitioner (LIP) with at least Out of Operating Room Airway Management (OOORAM) Level 2 privileges must be immediately available at the bedside
Patient must be directly observed by an appropriate member of clinical staff for at least 30 minutes after receiving IM ketamine
Non-invasive blood pressure monitoring, cardiac monitoring, continuous pulse oximetry, and respiratory rate monitoring recommended as practical
ED/UCC LIP responsible for ensuring patient appropriateness, documenting risk/benefits, and alternatives in the medical record
ED/UCC RN responsible for patient monitoring activities and may administer medication under appropriate order from ED/UCC LIP per state licensure

Exclusions/Scope Limitations

Does not apply to deep sedation
Does not apply to acute pain management outside of sedation
Does not apply to use for securing an endotracheal airway (e.g., rapid sequence intubation)
Does not apply to care of mechanically ventilated patients

Pharmacokinetics

Onset: 5 minutes
Duration: Up to 60 minutes
Half-life: 2 to 3 hours
Note: IM ketamine may have significant variation in clinical effect between individuals; caution advised

Document 439: Ketamine for Acute Pain in VHA ED or UCC

Indication

Acute Pain
Intractable Pain
When conventional modes of treatment have failed or when ketamine is determined to be a more suitable agent
Adjunct to opioid therapy for acute pain; advantageous in patients on partial opioid or opioid antagonist therapy who have acute tissue trauma related pain

Contraindications

Hypersensitivity to ketamine or any excipient

Precautions

Active or history of psychosis
Patients for whom significant elevations in blood pressure would constitute a serious hazard
Myocardial ischemia
Pregnancy or lactation
Consider IVPB and lower dosing for older patients or patients with comorbidities to mitigate adverse effects

Dosing & Administration

Intravenous: Initial dose 0.1 to 0.3 mg/kg Ideal Body Weight (IBW); administer via IVPB over 10-15 minutes (preferred) or slow IV push over 5 minutes; maximum single dose 30 mg
Intramuscular: Initial dose 0.35 to 0.7 mg/kg when intravenous access not available
Additional Dosing: Repeat initial dose via IVPB, slow IV push, or IM as appropriate; OR start continuous infusion at 0.15 to 0.2 mg/kg/hr; titrate every 30 minutes until pain is relieved
Total Dose Limit: Should not exceed 1 mg/kg IBW
IV Compatibility: Dextrose 5% in Water (D5W), Normal Saline (NS), or Sterile Water for Injection

Adverse Effects (at Sub-Dissociative Doses)

Common: dizziness, sedation, sense of unreality, nausea
Rare: excess sedation, respiratory compromise
Adverse effects requiring additional management were rare in adults in ED SDK clinical trials reviewed
Dizziness and perceptual changes attenuated with 15-minute infusion vs. IV push

Monitoring, Equipment, and Personnel Requirements

Bag Mask Valve (BVM) device must be available immediately at the bedside
Licensed Independent Practitioner (LIP) with Out of Operating Room Airway Management (OOORAM) privileges must be available in ED/UC to immediately respond to the bedside
Non-invasive blood pressure monitoring, cardiac monitoring, continuous pulse oximetry, and respiratory rate monitoring recommended during and for at least 15 minutes after completion of ketamine administration
ED/UCC LIP responsible for ensuring patient appropriateness, obtaining informed consent, and immediately attending to the patient in event of adverse effect
ED/UCC RN responsible for patient monitoring activities and may administer medication under appropriate order from ED/UCC LIP consistent with applicable state licensure requirements

Pharmacokinetics

Onset IV: within 30 seconds; IM: onset variable (approximately 15 minutes)
Duration: Up to 60 minutes
Half-life: 2 to 3 hours

Scope/Exclusions

Does not apply to use for deep sedation, securing an endotracheal airway (e.g., rapid sequence intubation), or care of mechanically ventilated patients

Document 643: Ketamine for Tx Refractory Pain in VHA Hospice Palliative Care RFU AUG 2024

Indication & Patient Population

Management of treatment-refractory pain (nociceptive, neuropathic) when first-line therapies fail or are contraindicated.
For non-sedation purposes in VHA Hospice or Palliative Care under the care or direction of a palliative care team (or locally identified expert).
Applicable for inpatient or Community Living Center (CLC) settings.

Contraindications

Hypersensitivity to ketamine or any excipient.

Precautions

Active psychosis, delirium, or inability to report side effects.
Patients for whom significant elevations in blood pressure would constitute a serious hazard.
Patients with or at risk of increased intracranial pressure.
Unstable cardiovascular disease.
Consider lower dosing for older patients or patients with comorbidities to mitigate adverse effects.

Dosing & Administration

Continuous Infusion: Initial dose 0.1 to 0.2 mg/kg/hr of Ideal Body Weight (IBW) via continuous IV or SQ infusion. Titrate no sooner than every 12 hours; max titration increment 0.1 mg/kg/hr. Recommended maximum dose 0.5 mg/kg/hr IBW. Duration typically ranges from 1 to 5 days; consider titrating to effect/max tolerated dose and continuing for an additional 48 hours, then discontinue.
IVPB or SQ Bolus: Initial dose 0.1 to 0.3 mg/kg (IVPB administered over 30 minutes). Additional doses may be repeated if effective or converted to alternate route; frequency not to exceed q8hr dosing. May increase dose up to 0.5 mg/kg; maximum total daily dose not to exceed 1 mg/kg IBW.
Oral Administration: Test/initial dose 10 mg PO once, then 5-10 mg PO q8h based on response. Initial titration 5 to 10 mg per dose per 24 hours. Maximum dose 400 mg/day (e.g., 100 mg q6h). Parenteral to oral conversion: Calculate total 24-hour parenteral dose and replace at 2/3rds of that amount.
Consider using actual body weight if less than IBW to calculate dose.

Monitoring Requirements

Check vital signs, pain, affect, and psychomimetic adverse effects at baseline, at 1 hour after infusion starts or first dose/dose increase, then with each shift change.
Repeat initial monitoring process after each dose change.
Palliative care team may adjust monitoring as needed if vital signs assessment is not consistent with patient goals.
Alert provider if: Systolic BP change > 20 mmHg or HR change < or > 20 beats/min; Respiratory rate < 12 breaths/min or persistent shallow breathing/apnea; O2 saturation <90% or RASS score -2 or below.

Adverse Effects & Management

Common: Dizziness, sedation, sense of unreality, nausea. Manage with lower doses or slower routes; educate patient to report bothersome effects.
Uncommon: Increase in blood pressure.
Rare: Excess sedation, respiratory compromise.
Psychomimetic side effects: Add benzodiazepine or haloperidol (lorazepam commonly used) and decrease ketamine dose to previously tolerated dose.
Increased secretions/lacrimation/salivation: Manage with anticholinergic agent (glycopyrrolate, atropine ophthalmic drops, or scopolamine patch).
Discontinuation/Withdrawal: Hyperalgesia and allodynia reported after abrupt discontinuation after 3 weeks. If used >10 days, safely taper over 48-72 hours. Monitor for withdrawal signs including nausea, dizziness, diarrhea, depression, anxiety, and schizophrenic-type behaviors.

Additional Clinical Considerations & Scope

Consider decreasing opioids by 15-50% at initiation due to opioid-sparing effect; may need to continue taper if excessive respiratory depression or hemodynamic instability occur.
IV formulation may be drawn up directly for oral administration but is very bitter; administer with sweet liquid (e.g., fruit juice, cola).
Does not apply to primary sedation, securing an endotracheal airway (e.g., rapid sequence intubation), mechanically ventilated patients, topical-oral ketamine for mucositis, or outpatient oral use.
Dosing, duration, and route flexibility allowed per facility operational needs; must be individualized under guidance of providers experienced in palliative and hospice medicine.

Document 789: Ketamine Infusion for Treatment Resistant Depression

Indications & Patient Selection

Treatment for treatment-resistant major depressive disorder (TRD) or severe suicidal ideation
Meets one of the following:
Remission not achieved from 2 antidepressant trials (including an augmentation strategy) in the current episode of depression AND 4 total adequate antidepressant trials in the patient’s lifetime
Hospitalized with TRD with acute suicidal ideation/behavior
Must meet ALL additional criteria:
Moderate to severe depressive symptomatology (PHQ-9 > 15 within the last 30 days)
Antidepressant trials considered unsuccessful if no response to at least 6 weeks of an antidepressant at half maximum dose or greater
Evaluated and documented by a VA psychiatrist or VA licensed Mental Health care provider (CPP, NP, PA) as qualifying for ketamine treatment
Signed informed consent from patient or legal representative
Agreement to remain monitored post-administration, refrain from driving/operating machinery, and avoid making major financial/legal decisions for the remainder of the day
Adult accompaniment for transportation OR documented safe transport method arranged
For women of childbearing potential: Pregnancy excluded prior to administration; provided contraceptive counseling on risks vs. benefits

Exclusion Criteria

Current or history of schizophrenia, schizoaffective disorder, or bipolar disorder
Dementia
Current or recent (within 30 days) delirium
Current uncontrolled hypertension (SBP >140 mm Hg or DBP >90 mm Hg)
Severe cardiac decompensation (Class IV heart failure or unstable angina)
Severe hepatic impairment (Child-Pugh class C)
Uncontrolled seizures
History of non-response to ketamine or esketamine
Pregnant (positive pregnancy test) or lack of birth control method in women of childbearing potential
Breastfeeding
Current or previous abuse of ketamine or esketamine
Clinical evidence for current substance misuse (except tobacco)
Current moderate or severe substance use disorder (SUD)
Allergy or previous serious adverse effects to ketamine or esketamine

Screening & Referral Requirements

Screening completed no more than 60 days prior to first dose acceptance/administration
Required screening components: Signed informed consent, psychiatric examination (including inclusion/exclusion criteria assessment), PHQ-9 depression rating scale, cognitive status evaluation (e.g., M-ACE), suicide risk assessment (C-SSRS at intake/initial evaluation and within 24 hours of discharge/clinically indicated; CSRE if first ever or updated clinically indicated), physical examination with vitals (BP, HR), relevant laboratory measures, urine toxicology, pregnancy screens
Medical clearance/consultation based on individual risk factors is the responsibility of the prescribing provider
Concurrent psychoactive substance use/abuse history must be evaluated; patients in recovery warned of relapse risk; close monitoring/random monitored urine drug testing recommended if treatment is chosen
CNS depressants (benzodiazepines, non-benzodiazepine hypnotics, naltrexone) may attenuate antidepressant effects; allow adequate washout time prior to administration

Administration & Monitoring Parameters

Facility must provide a private setting with crash cart access, capability for immediate care, monitoring of cardiovascular (ECG, BP) and respiratory function (O2 sat or end-tidal CO2), management of dangerous behavioral symptoms (oxygen, medications, restraints), and plan for sustained CV alterations/advanced cardiac life support
High-risk patients must be treated at equipped/staffed facilities
Ordering provider: VA psychiatrist or VA licensed Mental Health care provider (CPP, NP, PA)
Required personnel during infusion: ACLS certified physician/nurse and ordering provider (ordering provider may leave once stable; must return 120 minutes after start to clear for discharge; ACLS provider remains until discharge)
Dosing: 0.5 mg/kg IV infusion over 40 minutes (range 0.5–1 mg/kg). For BMI >30 kg/m2, calculate dose using ideal body weight
Monitoring schedule during infusion: Vitals at T+10, 20, 30, 40 min; check for resolution of sedation/dissociation/adverse effects at T+80 and T+120 min
Parameters to stop infusion: BP must remain <180 mm Hg systolic and <110 mm Hg diastolic. Stop if SBP drops >10 mm Hg with increased HR or distress. Heart rate must remain below age-adjusted maximum (e.g., 20 yrs <140, 30 yrs <133, 40 yrs <126, 50 yrs <119, 60 yrs <112; ≥65 yrs individualized). Stop for pallor/cyanosis/poor perfusion, respiratory symptoms (SOB/wheezing), chest/jaw/arm pain, or patient desire to stop

Infusion Schedule & Duration

Repeat no less than 2 days apart and not more frequently than twice a week for 4 weeks
After 4 weeks: Once a week to once every 3 weeks, with goal of extending interval (usually monthly)
Long-term maintenance may be used but requires regular clinical review/re-evaluation

Discontinuation Criteria

Discontinue if patient wishes for any reason
Discontinue if infusion stopped >1 time due to exceeding BP or HR thresholds
Discontinue if no response after 4 weeks (adequate response defined as ≥50% decline in PHQ-9 from baseline)
Discontinue if pronounced or slow-to-correct cognitive impairment or repeated dissociative symptoms
Discontinue when dosing cannot be spaced to a minimum of 1 dose per week by the second month

Longitudinal Monitoring

PHQ-9 completed prior to each IV ketamine dose
PHQ-9 and cognitive evaluation (e.g., M-ACE) at end of induction phase, every 6 months, and at end of treatment course
Suicide risk monitored via CSRE and C-SSRS Screener
C-SSRS required at intake/initial evaluation and within 24 hours of discharge/discontinuation; CSRE at intake if first ever or updated clinically indicated

Source Documents

Document 411: Ketamine Infusion for the Treatment of Intractable Neuropathic Pain Update DEC 2024 Document 438: IM Ketamine for Acute Agitation in ED and UCC RFU Apr 2023 Document 439: Ketamine for Acute Pain in VHA ED or UCC Document 643: Ketamine for Tx Refractory Pain in VHA Hospice Palliative Care RFU AUG 2024 Document 789: Ketamine Infusion for Treatment Resistant Depression