Lofexidine

Mechanism of action

◎Alpha-2A adrenergic receptorLofexidine

ⓘ The figure shows dexmedetomidine bound to the human alpha-2A receptor; lofexidine, another imidazoline alpha-2 agonist, acts at the same orthosteric site.

During opioid withdrawal, noradrenergic neurons (especially in the locus coeruleus) fire excessively, causing many withdrawal symptoms. Lofexidine stimulates presynaptic alpha-2 adrenergic receptors, which reduces noradrenaline release and sympathetic outflow. It eases autonomic symptoms such as sweating, chills, cramps, aches and runny eyes, but does not treat opioid craving or replace opioid agonist therapy.

1. Opioid withdrawal causes a noradrenergic surge
2. Lofexidine stimulates presynaptic alpha-2 receptors
3. Noradrenaline release and sympathetic outflow fall
4. Autonomic withdrawal symptoms ease

Indications

• Relief of opioid withdrawal symptoms to help abrupt opioid discontinuation in adults Opioid use disorder, overdose and withdrawal →

Adverse effects

Common

• Low blood pressure and orthostatic dizziness
• Slow heart rate
• Insomnia
• Dry mouth
• Drowsiness
• Ringing in the ears

Contraindications

• No absolute contraindications in the label; avoided in severe coronary insufficiency, recent myocardial infarction, cerebrovascular disease, chronic kidney failure, marked bradycardia and congenital long QT syndrome

Key interactions

Methadone and other QT-prolonging drugs

Additive QT prolongation; ECG monitoring is recommended.

CYP2D6 inhibitors (e.g. paroxetine)

Raise lofexidine levels; watch for hypotension and bradycardia.

Benzodiazepines, alcohol, barbiturates and other sedatives

Increased CNS depression.

Oral naltrexone

Its efficacy may be reduced if taken within about two hours of lofexidine.

Other drugs that slow the heart or lower blood pressure

Excessive bradycardia and hypotension.

What is monitored

• Blood pressure and pulse before each dose, including standing
• ECG in patients with QT risk or on methadone
• Electrolytes (potassium, magnesium) in those at QT risk
• Withdrawal symptoms and sedation

Administration and safety

• Oral tablets, usually four times a day at regular intervals during the withdrawal period.
• Stopped gradually over a few days to avoid a rebound rise in blood pressure.
• Doses are held or reduced if hypotension or bradycardia appear.
• Do not confuse with clonidine or other alpha-2 agonists on order sets.

Pregnancy and breastfeeding

Safety in pregnancy has not been established; animal studies showed harm to the fetus at exposures below human levels.

Nursing care

• Before each dose: blood pressure (lying and standing) and pulse.
• Teach to rise slowly, stay hydrated and avoid overheating.
• Teach that after detoxification opioid tolerance is lost and a previous dose can be fatal.
• Watch sedation, especially with benzodiazepines or alcohol.

Pharmacokinetics

Absorption

Oral, with or without food.

Metabolism

Liver, mainly CYP2D6; poor metabolizers and CYP2D6 inhibitors raise exposure.

Elimination

Slower in liver and kidney impairment, where the dose is adjusted.

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Connections

← Back to the class: Centrally acting antihypertensives

Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.

Sources: Lofexidine: MedlinePlus Drug Information (MedlinePlus (U.S. National Library of Medicine), 2018); DailyMed - LOFEXIDINE HYDROCHLORIDE tablet, film coated (DailyMed (U.S. National Library of Medicine), 2026); Structure of the alpha2A-adrenergic receptor GoA signaling complex bound to dexmedetomidine (RCSB Protein Data Bank, 2022); ATCDDD - ATC/DDD Index (WHO Collaborating Centre for Drug Statistics Methodology, 2026).

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Representative model, for educational purposes only.