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Medications used for palliative sedation in patients with refractory symptoms at end of life*

Medications used for palliative sedation in patients with refractory symptoms at end of life*
Agent Pharmacology Dosing (adult) Role in palliative sedation
Benzodiazepines
Midazolam

Short-acting GABAA agonist

Rapidly penetrates CNS

Brief duration of action

Continuous infusion is generally required to maintain effect

Acute: 1 to 5 mg IV every 5 to 15 minutes as needed until calm.

Continuous infusion: Initially 1 mg/hour IV or SQ then 0.5 to 5 mg per hour titrated to calm. Doses of up to 20 mg/hour have been used.

A ceiling effect can occur.

Role: First-line choice. Often given in combination with an antipsychotic to relieve accompanying symptoms of agitated delirium.

Advantages: Rapid onset. Water soluble and compatible with most drugs given by CSQI. Potent sedative and anxiolytic also useful for control of seizures, muscle spasms, nausea, vomiting, and intractable central pruritus. Reversal agent available (flumazenil).

Disadvantages: Risk of paradoxical agitation and delirium. Risk of apnea with large individual doses in combination with opioid or if low cardiac output. Accumulation, prolonged sedation, and tolerance can occur after several days of continuous use.
Lorazepam

Intermediate-acting GABAA agonist

Relatively slow onset

Longer duration of effect compared with midazolam

Intermittent: 1 to 4 mg IV every 2 to 6 hours or 1 to 2 mg SQ every 6 to 8 hours.

Continuous infusion: 0.01 to 0.1 mg/kg/hour IV or SQ. Doses of up to 10 mg/hour have been used.

A ceiling effect can occur.

Role: An alternative to midazolam for patients likely to require a longer period of sedation or receiving care where midazolam continuous infusion is unavailable. Often given in combination with an antipsychotic.

Advantages: Potent sedative and anxiolytic also useful for control of seizures (IV/SQ but not orally), muscle spasms, nausea, and vomiting. Prolonged onset and duration of effect may permit management with intermittent IV or SQ injections in some patients. Reversal agent available (flumazenil).

Disadvantages: Relatively slow onset. Risk of oversedation when titrating due to delayed response. Risk of paradoxical agitation and delirium. IV and CSQI line incompatibilities, risk of line precipitate, tissue injury, and phlebitis. Accumulation of toxic propylene glycol solvent. Drug accumulation, prolonged sedation, and tolerance can occur after several days of continuous use.
First-generation antipsychotics
Levomepromazine (methotrimeprazine) Sedating dopamine D2, 5HT2A, H1, alpha1, alpha2, and muscarinic antagonist with analgesic and amnestic effects. Usual onset within 20 to 40 minutes.

Initial loading dose: 12.5 to 25 mg SQ, IM or IV.

Continuous infusion: 2 to 3 mg/hour SQ; usual effective dose 50 to 300 mg daily.

Intermittent: 6.25 mg SQ every hour as needed with background dose of 12.5 to 25 mg daily in 1 or 2 divided doses (titrate based on as-needed dose requirements).

Role: Sedating antipsychotic for control of delirium and/or agitation in imminently dying patient. Often given when large doses of benzodiazepine (eg, midazolam 30 mg daily) do not provide sufficient anxiolysis or calm. NOTE: Not available in the United States.

Advantages: Effective sedative, analgesic, and anxiolytic with rapid onset and useful for control of nausea, vomiting, delirium, and agitation. Flexible delivery options include CSQI that is compatible for delivery with analgesics and anticholinergics often used in palliative care.

Disadvantages: Anticholinergic effects, orthostatic hypotension with rapid IV administration, akathisia, acute dystonic reactions, seizures, and cardiotoxicity associated with QT prolongation.
Chlorpromazine See levomepromazine

Intermittent: 12.5 to 25 mg IV or IM every 4 to 12 hours.

Continuous infusion: 3 to 5 mg/hour IV. Usual effective dose 37.5 to 150 mg daily (parenteral).

Rectal: 100 mg every 6 to 12 hours.

Role: A sedating antipsychotic alternative in settings where levomepromazine is not available.

Advantages: Effective sedative and anxiolytic with rapid onset; also useful for control of delirium, agitation, nausea, vomiting, and intractable hiccups. Wide availability.

Disadvantages: SQ administration is not an option due to tissue damage and pain. Anticholinergic effects, orthostatic hypotension (which can be severe) with rapid IV administration, akathisia, acute dystonic reactions, seizures, and cardiotoxicity associated with QT prolongation.
Barbiturate
Phenobarbital Enhances GABA and inhibits glutamate, providing long-acting sedative, hypnotic, and anticonvulsant actions (higher doses)

Initial loading dose: 1 to 3 mg/kg IV or IM (100 to 200 mg); repeat after 30 minutes if needed.

Continuous infusion: 0.5 mg/kg/hour IV or SQ (800 mg daily); may increase if needed up to 2400 mg daily.

Role: A second-line option for refractory agitation in imminently dying patients who have not adequately responded to full doses of midazolam with either levomepromazine or chlorpromazine.

Advantages: Provides effective sedation to patients who have developed extreme tolerance to benzodiazepines and antipsychotics; controls refractory seizures. Maintenance dose may be administered by CSQI.

Disadvantages: Paradoxical excitement, especially among older adults. Other adverse effects include hypotension, bradycardia, nausea, vomiting, and serious cutaneous allergic reactions. Phenobarbital increases drug metabolism and can decrease serum concentrations of other drugs. It should not be abruptly discontinued due to occurrence of rebound seizures.
Short-acting anesthetic
Propofol Ultra rapid-acting general anesthetic providing global CNS depression by GABAA potentiation and possibly inhibition of glutamate Initiate as continuous infusion at 5 micrograms/kg/minute IV and titrate every 5 to 10 minutes in increments of 5 to 10 micrograms/kg/minute. Effective dose range: 5 to 50 micrograms/kg/minute.

Role: A second-line option for refractory intolerable agitation and delirium in imminently dying patient who has not adequately responded to full doses of benzodiazepines and antipsychotics receiving care in a specialty setting (ie, critical care unit) with access to necessary expertise and equipment.

Advantages: Produces reliable and rapid unconsciousness. Useful in patients who have developed extreme tolerance to benzodiazepines and antipsychotics; controls refractory nausea, vomiting, and seizures.

Disadvantages: Infusion site pain and phlebitis if given via peripheral vein. Delivered in an oil-in-water emulsion that can support bacterial growth, requiring strict adherence to aseptic technique and frequent bottle and tubing changes. Requires computer-controlled infusion pump. Other adverse effects: apnea with bolus injection, hypotension, allergic reactions, and bradycardia.
GABA: gamma-aminobutyric acid; CNS: central nervous system; IV: intravenous; SQ: subcutaneous; CIVI: continuous intravenous infusion; CSQI: continuous subcutaneous infusion; 5HT: serotonin; IM: intramuscular.
* The medications listed in this table for palliative sedation in general do NOT provide analgesia. Analgesia must be provided prior to and during use of palliative sedation with appropriate opioid and non-opioid options. For additional information, refer to UpToDate topic reviews of pain assessment and management at end of life.
¶ Immediate deep sedation is rarely needed, ie, for sudden massive hemorrhage.
Courtesy of author with additional data from:
  1. De Graeff A, Dean M. Palliative sedation therapy in the last weeks of life: A literature review and recommendations for standards. J Pall Med 2007; 10:67.
  2. Twycross R, Wilcock A (Eds). Palliative care formulary, 4th ed, Palliativedrugs.com Ltd, Nottingham, UK, 2012.
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