Lofexidine

Lofexidine, sold under the brand name Lucemyra, is an α2-adrenergic receptor agonist designed to help manage symptoms of opioid withdrawal.

It is approved by the FDA for the mitigation of withdrawal symptoms to facilitate abrupt opioid discontinuation in adults. Common withdrawal symptoms include sweating, tachycardia, anxiety, and nausea.

Mechanistically, lofexidine binds to central α2 receptors, reducing the release of norepinephrine and dampening the hyperactive sympathetic response associated with opioid withdrawal.

The primary gene associated with lofexidine pharmacokinetics is CYP2D6, a cytochrome P450 enzyme responsible for phase I oxidative metabolism of many medications. CYP2D6 converts lofexidine into inactive metabolites that can be eliminated by the kidneys.

CYP2D6 genetic variants give rise to metabolic phenotypes—poor, intermediate, normal (extensive), rapid, and ultrarapid metabolizers—depending on the combination of functional, reduced-function, or nonfunctional alleles. These differences affect how quickly lofexidine is cleared and can influence both efficacy and side-effect risk.

CYP2D6 metabolizer status influences lofexidine clearance and systemic exposure: ultrarapid and rapid metabolizers process the drug quickly, potentially reducing efficacy, while poor metabolizers clear it slowly, leading to higher blood levels and increased risk of adverse reactions such as hypotension and bradycardia.

Ultrarapid Metabolizer

• Effect on drug levels: Faster clearance leading to potentially lower drug concentrations
• Clinical consequence: May experience reduced efficacy of lofexidine
• Side effects: Similar risk to normal metabolizers; no increase in severity or frequency

Normal Metabolizer

• Effect on drug levels: Expected standard clearance and drug concentrations
• Clinical consequence: Typical therapeutic response as described in the label
• Side effects: Typical side-effect profile (e.g., dry mouth, dizziness) with expected frequency

Intermediate Metabolizer

• Effect on drug levels: Moderately reduced clearance, slightly higher drug concentrations
• Clinical consequence: Possible mild increase in side effects without requiring dose change
• Side effects: Slightly higher likelihood of hypotension or sedation; generally mild

Poor Metabolizer

• Effect on drug levels: Significantly reduced clearance leading to higher systemic concentrations
• Clinical consequence: Increased risk of orthostatic hypotension and bradycardia
• Side effects: Moderate to severe hypotension and bradycardia; monitor frequency and severity carefully

Indeterminate/Not Available

• Effect on drug levels: Unknown
• Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring
• Side effects: Unknown

CYP2D6 Dosing Guideline

The FDA guidance does not list any genotype-specific alternative drugs or dosing strategies for lofexidine. Clinicians may consider adjunctive nonpharmacologic approaches (e.g., behavioral therapy) or other medications such as clonidine to manage opioid withdrawal symptoms. These are examples only and not medical advice.

• FDA – Table of Pharmacogenetic Associations