What are the guidelines for using ketamine in an adult patient with treatment-resistant depression or for pain management?

Ketamine for Treatment-Resistant Depression and Pain Management

For treatment-resistant depression in adults, ketamine at 0.5 mg/kg IV over 40 minutes is the evidence-based standard, demonstrating superior efficacy to ECT with 55.4% response rates and fewer cognitive side effects, while for acute pain management, use low-dose ketamine (0.5 mg/kg IV bolus followed by 1-2 μg/kg/min infusion) as an opioid-sparing adjunct. 1, 2, 3

Treatment-Resistant Depression Protocol

Standard Dosing Regimen

• Administer 0.5 mg/kg IV over 40 minutes for acute treatment of treatment-resistant depression 4, 1
• This dose produces rapid antidepressant effects within 24 hours in approximately 67% of patients with treatment-resistant depression 4
• The 2023 ELEKT-D trial demonstrated ketamine's noninferiority to ECT, with ketamine showing 55.4% response rates versus 41.2% for ECT (14.2 percentage point difference, p<0.001) 1

Treatment Schedule Options

• Acute phase: Administer twice weekly for 3-5 weeks 5, 1
• For patients requiring more intensive treatment, high-dose protocols (0.75-1 mg/kg IV) twice weekly for 5 weeks show enhanced efficacy in multiple treatment-resistant depression 5
• Alternative prolonged infusion: 96-hour continuous infusion at 0.15-0.6 mg/kg/h produces sustained remission lasting 8 weeks, though this requires specialized monitoring 6

Safety Profile in Depression Treatment

• Overall attrition rate is only 3.1%, with <2% of infusions discontinued due to adverse events 4
• No cases of persistent psychotomimetic effects, adverse medical outcomes, or increased substance use have been documented in long-term follow-up 4
• Common transient side effects include drowsiness, dizziness, poor coordination, blurred vision, and dissociative symptoms, all resolving within 4 hours 4
• Ketamine demonstrates superior cognitive safety compared to ECT, with ECT causing significant memory impairment (T-score decrease of -9.7±1.2) while ketamine shows minimal cognitive effects (-0.9±1.1) 1

Contraindications for Depression Treatment

• Avoid in patients with uncontrolled cardiovascular disease, as ketamine causes dose-dependent increases in heart rate, blood pressure, and cardiac output 7, 8
• Contraindicated in ischemic heart disease, cerebrovascular disease, uncontrolled hypertension, active psychosis, severe hepatic dysfunction, elevated intracranial pressure, and pregnancy 2, 8

Pain Management Protocol

Acute Pain Dosing

• Initiate with 0.5 mg/kg IV bolus followed by continuous infusion at 1-2 μg/kg/min 2, 3
• This low-dose regimen reduces opioid requirements by approximately 22 mg morphine equivalents without increasing side effects 3
• For ICU patients, use continuous infusion of 0.5-2 mg/kg/hr (maximum 100 mg/hour) at the lowest effective dose 3

Route-Specific Efficacy for Pain

• Local infiltration provides superior analgesia compared to IV administration and effectively reduces pain and analgesic requirements in surgical patients 3
• Subcutaneous administration provides similar analgesia to IV route 3
• Intramuscular route lacks analgesic efficacy and should be avoided for pain management 3
• Oral administration is less effective than infiltration 3

Special Population: Shock Patients

• Ketamine is the preferred analgesic in shock states due to maintained cardiovascular stability through central NMDA blockade and preserved adrenal function 3, 9
• Start at lower dosing range (0.5 mg/kg IV bolus) with careful titration in hemodynamically compromised patients 9
• Superior to propofol or dexmedetomidine, which may worsen hemodynamic compromise 3
• Monitor for myocardial suppression in patients with depleted catecholamine reserves 9

Advantages Over Opioids

• Ketamine at ≤0.5 mg/kg represents a superior alternative to opioids for patients with substance abuse history or addiction risk 3
• Provides comparable analgesic efficacy without respiratory depression or life-threatening cardiovascular events 3
• In geriatric ED patients, subdissociative ketamine (0.3 mg/kg IV over 15 minutes) provides analgesia comparable to morphine for short-term treatment 3

Critical Safety Considerations

Mandatory Monitoring Requirements

• Emergency airway equipment must be immediately available 8
• Continuous monitoring of oxygen saturation, heart rate, blood pressure, and capnography throughout administration 2, 3
• Vital signs documented at least every 5 minutes during deep sedation 2
• Regular assessment of sedation level, respiratory status, and hemodynamics 3

Preparation and Administration

• Never administer 100 mg/mL concentration IV without proper dilution 8
• Dilute with equal volume of Sterile Water, Normal Saline, or 5% Dextrose 8
• Use immediately after dilution 8
• Administer slowly over 60 seconds to prevent respiratory depression and enhanced vasopressor response 8

Managing Emergence Reactions

• Co-administer benzodiazepines (midazolam 0.05-0.1 mg/kg) to minimize psychotomimetic effects including dysphoria, nightmares, and hallucinations 7, 3, 8
• Emergence reactions occur in 10-30% of adults but are significantly reduced with benzodiazepine co-administration 7
• In patients over 10 years old, adding midazolam reduces recovery agitation from 35.7% to 5.7% 2

Hepatobiliary Monitoring

• Obtain baseline liver function tests (including alkaline phosphatase and gamma glutamyl transferase) before initiating recurrent ketamine dosing 8
• Monitor LFTs at periodic intervals during treatment with recurrent dosing 8
• Ketamine is associated with hepatobiliary dysfunction (cholestatic pattern) and biliary duct dilatation with recurrent use 8

Genitourinary Considerations

• Monitor for genitourinary symptoms including dysuria, increased urinary frequency, urgency, and hematuria, particularly with chronic use 8
• Consider cessation if genitourinary pain continues alongside other urinary symptoms 8

Common Pitfalls to Avoid

• Do not use ketamine in patients who have not followed nil per os guidelines due to aspiration risk despite preserved airway reflexes 8
• Administer antisialagogue prior to induction to manage increased salivation 8
• Avoid rapid IV administration, which causes respiratory depression and enhanced vasopressor response 8
• Do not confuse purposeless tonic-clonic movements during ketamine anesthesia with inadequate sedation—these do not indicate need for additional doses 8
• Avoid theophylline or aminophylline co-administration, which lowers seizure threshold 8
• Exercise caution with sympathomimetics and vasopressin, which enhance ketamine's sympathomimetic effects 8