Introduction
Lofexidine is a centrally acting alpha-2 adrenergic agonist approved by the FDA in 2018 for the mitigation of opioid withdrawal symptoms. Originally developed in the 1980s, it represents a non-opioid medication option for managing the physical symptoms of opioid discontinuation. Unlike clonidine, which has been used off-label for this purpose, lofexidine is specifically indicated and studied for opioid withdrawal management.
Mechanism of Action
Lofexidine selectively agonizes alpha-2 adrenergic receptors in the central nervous system, primarily in the locus coeruleus. This action inhibits the release of norepinephrine, which is typically elevated during opioid withdrawal. By reducing noradrenergic hyperactivity, lofexidine alleviates characteristic withdrawal symptoms including anxiety, agitation, muscle aches, sweating, and tachycardia without possessing any opioid agonist activity or abuse potential.
Indications
- FDA-approved for the mitigation of opioid withdrawal symptoms to facilitate abrupt opioid discontinuation in adults
- Used as part of a comprehensive treatment program that may include counseling and psychosocial support
Dosage and Administration
Initial dosing: 0.54 mg orally three times daily (every 5-6 hours); may be adjusted based on symptoms and tolerability Dose titration: May increase by 0.18 mg per dose to a maximum of 2.88 mg daily (0.72 mg four times daily) Treatment duration: Typically 5-7 days, with a maximum recommended duration of 14 days Discontinuation: Taper gradually over 2-4 days to avoid rebound hypertension Renal impairment: Use with caution in moderate to severe impairment (CrCl <30 mL/min) Hepatic impairment: No specific dosage adjustment recommended, but use with cautionPharmacokinetics
Absorption: Well absorbed orally with peak plasma concentrations reached within 3-5 hours Distribution: Volume of distribution approximately 480 L; protein binding ~55% Metabolism: Primarily metabolized via CYP2D6 with minor contributions from CYP1A2 and CYP2C19 Elimination: Half-life approximately 11-13 hours; excreted primarily in urine (55%) and feces (20%) Special populations: CYP2D6 poor metabolizers may have increased exposure; no significant differences based on age, gender, or raceContraindications
- Known hypersensitivity to lofexidine or any component of the formulation
- Concomitant use with medications that prolong QT interval
- Patients with severe cardiac conduction disorders or arrhythmias
Warnings and Precautions
QT prolongation: May dose-dependently prolong QT interval. Avoid use in patients with congenital long QT syndrome, history of torsades de pointes, or with other QT-prolonging drugs Hypotension and bradycardia: Monitor vital signs regularly, especially in patients with cardiovascular disease Sedation: May cause drowsiness; advise patients against operating machinery or driving Renal impairment: Use with caution in patients with moderate to severe renal impairment Abrupt discontinuation: May cause rebound hypertension and tachycardia; taper gradually Suicidal ideation: Monitor patients with history of depression or suicidal thoughtsDrug Interactions
QT-prolonging agents: Contraindicated with drugs known to prolong QT interval (antiarrhythmics, antipsychotics, antibiotics) CNS depressants: Additive sedation with alcohol, benzodiazepines, barbiturates, and other sedating medications CYP2D6 inhibitors: Paroxetine, fluoxetine, bupropion may increase lofexidine concentrations Antihypertensives: Additive hypotensive effects with other blood pressure medications Opioids: May reduce opioid withdrawal symptoms without reversing opioid effectsAdverse Effects
Common (≥10%): Orthostatic hypotension (28%), bradycardia (15%), sedation/somnolence (15%), dry mouth (13%), dizziness (11%) Less common (1-10%): Insomnia, fatigue, hypotension, tinnitus, QT prolongation Serious: Syncope, severe bradycardia, torsades de pointes (rare) Postmarketing reports: Suicidal ideation, hallucinations, withdrawal symptoms upon discontinuationMonitoring Parameters
- Blood pressure and heart rate (standing and supine) before initiation and regularly during treatment
- ECG monitoring at baseline and during treatment, especially with dose increases
- Renal function assessment before initiation
- Mental status and mood assessment
- Signs and symptoms of opioid withdrawal using validated scales (COWS, SOWS)
- Adherence to gradual taper schedule upon discontinuation
Patient Education
- Take exactly as prescribed; do not stop abruptly due to risk of rebound hypertension
- Rise slowly from sitting or lying position to prevent dizziness
- Avoid alcohol and other sedating substances during treatment
- Report any fainting, dizziness, or unusual heart rhythms immediately
- Do not operate heavy machinery or drive until effects are known
- Continue with recommended counseling and support services
- Keep all follow-up appointments for monitoring
- Store at room temperature away from moisture
References
1. FDA prescribing information: LUCEMYRA® (lofexidine) tablets 2. Gish EC, Miller JL, Honey BL, et al. Lofexidine, an α2-receptor agonist for opioid detoxification. Ann Pharmacother. 2010;44(2):343-351. 3. Yu E, Miotto K, Akerele E, et al. A phase 3, randomized, double-blind, placebo-controlled study of lofexidine for opioid withdrawal. JAMA Psychiatry. 2018;75(5):455-463. 4. Gorodetzky CW, Walsh SL, Martin PR, et al. A phase III, randomized, multi-center, double-blind, placebo-controlled study of safety and efficacy of lofexidine for relief of symptoms in individuals undergoing inpatient opioid withdrawal. Drug Alcohol Depend. 2017;176:79-88. 5. Khemiri A, Kharitonova E, Zah V, et al. Analysis of opioid withdrawal symptoms and safety of lofexidine hydrochloride in opioid-dependent individuals. Clin Drug Investig. 2017;37(6):559-568.