Lofexidine
Lofexidine
Generic Name
Lofexidine
Mechanism
- Selective α₂‑adrenergic receptor agonist that activates pre‑synaptic inhibitory autoreceptors in the locus coeruleus.
- ↓ Sympathetic outflow → ↓ norepinephrine release.
- Inhibits “central noradrenergic hyperactivity” that drives withdrawal signs (rigidity, diaphoresis, lacrimation, tachycardia).
- Provides symptomatic control (e.g., tremor, sweating) without the pronounced hypotension of non‑selective α‑agonists.
Pharmacokinetics
| Parameter | Typical Value |
| Absorption | Oral bioavailability ≈ 15% (first‑pass) |
| Cₘₐₓ | 1–1.5 h post‑dose (rapid onset) |
| Half‑life (t½) | 3–4 h (short, supports BID dosing) |
| Metabolism | Primarily CYP2D6 → active metabolites; 15%‑20% unchanged |
| Elimination | Urine: ~80 % unchanged; kidney & biliary routes |
| Protein binding | 45 % |
| Drug interactions | ↑↑CYP2D6 inhibitors (e.g., fluoxetine) ↑ plasma levels; caution with other α‑agonists or β‑blockers |
> Key point: Lofexidine is safe in mild‑to‑moderate hepatic or renal impairment; dose adjustment required only in severe renal/ hepatic disease.
Indications
- Approved: *Short‑term (≤ 72 h) management of opioid withdrawal* in adults.
- Off‑label (studied): Adjunct analgesia for neuropathic pain; not a first‑line analgesic.
Contraindications
| Contraindication / Warning | Rationale |
| Hypersensitivity to lofexidine, other α₂‑agonists, or excipients | Allergic reactions |
| Severe cardiovascular disease (eg. advanced heart block, uncontrolled hypotension) | Risk of exacerbated bradycardia/Hypotension |
| Severe hepatic impairment | ↓ metabolism → ↑ exposure |
| Concurrent use of strong CYP2D6 inhibitors | ↑ systemic exposure → increased adverse events |
| Co‑administration with other CNS depressants (benzodiazepines, opioids) | Additive hypotension/bradycardia |
| Pregnancy Category C – Use only if benefits outweigh risks | Fetal safety data limited |
| Pediatric (< 12 yr) – Not indicated | Safety profile not established |
Dosing
| Situation | Dose | Titration | Administration |
| Initial | 0.1 mg PO BID (≥ 4 h apart) | Increase by 0.1 mg every 8 h up to max 0.6 mg/day if needed | Oral (tablet) |
| Max | 0.3 mg PO Q4H (not > 0.6 mg/day) | Stop if BP < 90 mmHg or HR < 45 bpm | Oral |
| Renal impairment (CrCl 15‑30 mL/min) | 0.05 mg BID | Titrate more slowly | Oral |
| Severe hepatic impairment | Hold or use with extreme caution | • | • |
• Initiate 1 h after opioid cessation or when withdrawal signs appear.
• Typically discontinued after 48–72 h once withdrawal is controlled.
Adverse Effects
- Hypotension, dizziness, light‑headedness
- Bradycardia
- Fatigue, somnolence
- Dry mouth, constipation
- Nausea, flushing
- Headache
Monitoring
- Vital signs (BP, HR) q2–4 h during initiation/ titration.
- COWS (Clinical Opioid Withdrawal Scale) or equivalent to gauge symptom relief.
- Liver function if pre‑existing hepatic disease; re‑check after 1–2 weeks of therapy.
- Renal function if dose adjustments required.
- Signs of allergic reaction: rash, swelling, wheezing.
Clinical Pearls
- Titration is key: A 0.1 mg increment every 8 h keeps bradycardia risk low while quickly alleviating withdrawal.
- Lofexidine vs. clonidine: Lofexidine has less CNS sedation, lower risk of nausea & constipation, and a shorter half‑life—ideal for abrupt withdrawal protocols.
- CYP2D6 polymorphisms affect clearance; poor metabolizers may show exaggerated hypotension—monitor more closely.
- Concurrent benzodiazepines are often used for anxiety; avoid overlapping α‑agonists (e.g., clonidine) to reduce additive CV depressant effects.
- Withdrawal assessment: Even mild hypotension can precipitate fainting in patients who have been withdrawing (dehydrated). Encourage adequate hydration.
- Adjunct analgesia: While not labeled for pain, low‑dose lofexidine (≤ 0.1 mg BID) has shown limited benefit for neuropathic pain—use cautiously and monitor tolerability.
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• *References: FDA label (2023), Goodman & Gilman’s Pharmacological Basis of Therapy (13th ed.), Clinical Pharmacokinetics of Lofexidine 2023.*