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Lofexidine
Lofexidine
Lofexidine
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Lofexidine
Clinical data
Trade namesBritlofex, Lucemyra, others
AHFS/Drugs.comMonograph
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability>90%
Protein binding80–90%
MetabolismLiver (glucuronidation)
Elimination half-life11 hours
ExcretionKidney
Identifiers
  • (RS)-2-[1-(2,6-dichlorophenoxy)ethyl]-4,5-dihydro-1H-imidazole
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC11H12Cl2N2O
Molar mass259.13 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
  • Clc2c(OC(C/1=N/CCN\1)C)c(Cl)ccc2
  • InChI=1S/C11H12Cl2N2O/c1-7(11-14-5-6-15-11)16-10-8(12)3-2-4-9(10)13/h2-4,7H,5-6H2,1H3,(H,14,15) checkY
  • Key:KSMAGQUYOIHWFS-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Lofexidine, sold under the brand name Lucemyra among others,[1] is a medication historically used to treat high blood pressure; today, it is more commonly used to help with the physical symptoms of opioid withdrawal.[2] It is taken by mouth.[3] It is an α2A-adrenergic receptor agonist.[3] It was approved for use by the Food and Drug Administration in the United States in 2018,[3] considering it to be a first-in-class medication.[4]

Medical uses

[edit]

In the United States, lofexidine is approved for the "mitigation of withdrawal symptoms to facilitate abrupt discontinuation of opioids in adults," for a treatment duration of 14 days.[1] In the United Kingdom, lofexidine is commonly used in conjunction with the opioid receptor antagonist naltrexone in rapid detoxification cases. When these two drugs are paired, naltrexone is administered to induce an opioid receptor blockade, sending the subject into immediate withdrawal and accelerating the detoxification process, while lofexidine is given to relieve the symptoms associated with the withdrawal including chills, sweating, stomach cramps, muscle pain, and runny nose.[citation needed]

Opioid withdrawal

[edit]

The United Kingdom's National Institute for Health and Care Excellence (NICE) guidelines recommend the use of methadone or buprenorphine as first-line agents in the management of opioid use disorder. However, lofexidine is considered an acceptable alternative for people with mild or uncertain opioid dependence in need of short-term detoxification.[5]

Lofexidine is not an opioid.[3] It does not eliminate the symptoms of opioid withdrawal but reduces them.[3] Indeed, one suggested use for lofexidine is to ease withdrawal symptoms of methadone dependence. Its use is approved in the United States for up to 14 days.[3]

Other clinical uses

[edit]

The possibility of using lofexidine to treat alcohol withdrawal symptoms has been investigated, and has not yet been shown to be an effective treatment.[6] It is also used in treatment of cases with postmenopausal hot flashes.

Special populations

[edit]

Lofexidine's safety in pregnancy or in the setting of breastfeeding are unknown.[7] Caution is warranted if chronic kidney impairment is present.[7]

Adverse effects

[edit]

Adverse effects that have occurred after taking lofexidine include the following:[7]

In addition, people may experience a sudden jump in blood pressure after stopping lofexidine.[1]

Overdose

[edit]

The LD50 of lofexidine is above 77 mg/kg in animals. Studies of high-dose, single administrations of lofexidine proved tolerable for animals, but repeat administration induced symptoms consistent with toxicity. In studies on mice, rats, and dogs, these included ataxia, somnolence, and tremors. It is expected that an overdose of lofexidine would result in symptoms akin to its pharmacological side effects in humans, such as bradycardia and hypotension.[8]

Interactions

[edit]

Many drug-drug interactions with lofexidine are possible.[9]

QT prolongation

[edit]

Lofexidine prolongs the QT interval, which can result in a severe interaction (torsade de pointes) when combined with other drugs that also prolong the QT interval. Patient-specific characteristics that increase the risk for a clinically significant drug-drug interaction include:[9]

As a result, there are many QT-prolonging drugs that may interact with lofexidine. These include medications such as methadone, amiodarone, citalopram, and fluconazole. Other medications may increase the risk for a low level of potassium in the blood, thereby indirectly increasing the risk for QT prolongation. For example, dexamethasone, hydrochlorothiazide, and theophylline can lower the level of potassium in the blood.[9]

CNS depression

[edit]

Lofexidine can depress the central nervous system (CNS), which, in combination with other CNS depressants, may reduce a person's ability to perform tasks that require skills and attention. For example, clobazam, gabapentin, and levetiracetam all can depress the CNS.[9]

Hypotension

[edit]

The risk of hypotension (low blood pressure) is increased when lofexidine is combined with other drugs that lower blood pressure. These may include losartan, metoprolol, and pramipexole.[9]

Pharmacology

[edit]

Lofexidine is an agonist at the alpha-2A, 2B, and 2C adrenergic receptor subtypes, with the highest activity at the α2A-adrengergic receptor.[10]

Ki for lofexidine[10]
Adrenergic receptor Ki (nM)
α2A 4
α2B 67
α2C 69

Ki represents the dissociation constant[11] for lofexidine's binding to a specific subtype of α2 receptor. The smaller the Ki value, the stronger the drug binds to the receptor to exert its activity.

Lofexidine inhibits the release of norepinephrine in the central and peripheral nervous system, thereby reducing some of the symptoms of opioid withdrawal, but it has no documented effect on drug craving and endogenous opioid levels.[2]

Pharmacokinetics

[edit]

Lofexidine's oral bioavailability is about 90%, with extensive oral absorption. Peak plasma concentrations occur at 3 hours after a single administration, with a half-life of 11 hours. Lofexidine is extensively metabolized by the liver, and primarily cleared by the kidney. It is 80–90% plasma protein bound.[8]

Chemistry

[edit]

Lofexidine exists as a solid at room temperature, with a melting point of 127 degrees C.[8] The pair of ortho chlorine (Cl−) atoms on the phenyl ring are necessary for lofexidine's agonism at the α2A adrenergic receptor subtype; removal of either chlorine atom results in antagonism at the receptor.[10]

Comparison to clonidine

[edit]
Structure of clonidine and lofexidine

Lofexidine is structurally analogous to clonidine, another α2 adrenergic receptor agonist used for treatment of opioid withdrawal symptoms. A comparison of the two structures is shown at right. Both contain an imidazoline ring and a 2,6-dichlorinated phenyl ring. The differences in structure are shown in red, while the similarities are in black. In addition to the structural differences, administration of lofexidine to people who abuse opioids has been shown to be more effective for a longer duration, with fewer withdrawal symptoms than clonidine even after one day.[12] However, clonidine is often preferred as it is substantially cheaper than lofexidine when purchased with a private (non-NHS) prescription. This factor is exacerbated by the considerable number of and quantities of medications prescribed to alleviate the constellation of withdrawal signs and symptoms. Additionally, clonidine has been shown to significantly lower blood pressure. Therefore, although similar to lofexidine, clonidine is most frequently prescribed to treat high blood pressure.[citation needed]

Society and culture

[edit]

Britannia Pharmaceuticals has licensed lofexidine to be sold by US WorldMeds for sale in North America.[13] In the United Kingdom, the hydrochloride form, lofexidine HCl, has been licensed and sold since 1992 for opioid withdrawal relief in tablet form as BritLofex by Britannia Pharmaceuticals.[2] BritLofex is only available by prescription. Lofexidine was first approved by the US FDA on May 16, 2018, under the brand name Lucemyra, produced by US WorldMeds.[14] It was noted as the first non-opioid drug approved in the US for the treatment of opioid withdrawal.[1]

See also

[edit]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Lofexidine

View on Grokipedia
from Grokipedia
Lofexidine is a centrally selective α2- agonist indicated for the mitigation of symptoms in adults to facilitate abrupt discontinuation of . Approved by the U.S. (FDA) on May 16, 2018, it represents the first non- medication specifically authorized for this purpose , marketed under the brand name Lucemyra. Unlike opioid agonists, lofexidine does not activate mu-opioid receptors and thus avoids producing , tolerance, or dependence. The drug's mechanism of action involves binding to presynaptic α2-adrenergic receptors in the , which inhibits the release of norepinephrine and reduces sympathetic outflow, thereby alleviating noradrenergic symptoms of such as anxiety, restlessness, muscle aches, and autonomic hyperactivity. Pharmacologically, lofexidine is well-absorbed after , with peak plasma concentrations reached in 3-5 hours and an elimination of 11-22 hours; it is primarily metabolized in the liver and excreted renally, with about 15-20% eliminated unchanged. It is structurally similar to but exhibits a more favorable profile, with a lower risk of severe . Originally synthesized in the 1980s and initially studied for the treatment of , lofexidine was repurposed for following preclinical research demonstrating its ability to suppress withdrawal-induced sympathetic activation in animal models. It received approval for management in the and several European countries during the , and its U.S. development was supported through a collaboration between the (NIDA) and US WorldMeds. Generic versions were approved by the FDA in 2024, and in March 2025, the brand Lucemyra was acquired by BioCorRx Pharmaceuticals. Clinical trials, including two pivotal phase 3 studies, confirmed its efficacy in reducing withdrawal symptom severity compared to placebo, with common adverse effects including , , , , and dry mouth. Lofexidine is typically dosed at 0.54 mg (three 0.18 mg tablets) four times daily for up to 14 days, followed by a 2- to 4-day taper to minimize rebound symptoms.

Medical uses

Opioid withdrawal management

syndrome refers to the physiological and psychological symptoms that occur upon abrupt cessation or significant reduction of opioid use after prolonged exposure, characterized by key manifestations such as anxiety, muscle aches, , , and sweating. Lofexidine targets these symptoms by acting as an that reduces noradrenergic hyperactivity in the . The standard dosing regimen for lofexidine in management involves an initial dose of 2.16 mg per day administered as 0.54 mg (three 0.18 mg tablets) four times daily, with gradual titration up to a maximum of 2.88 mg per day divided into four doses of 0.72 mg each, administered every 5 to 6 hours as needed based on symptom severity. Treatment duration is typically up to 14 days, followed by a tapering schedule over 2 to 4 days—such as reducing the dose by 0.4 mg per dose every 1 to 2 days—to minimize withdrawal symptoms. Clinical efficacy has been demonstrated in pivotal phase 3, randomized, double-blind, -controlled trials involving adults undergoing abrupt discontinuation. In one multicenter trial with 603 participants, lofexidine at doses of 2.16 mg/day and 2.88 mg/day significantly reduced mean Short Opiate Withdrawal Scale-Gossop (SOWS-Gossop) scores over days 1 through 7 compared to (differences of -0.21 and -0.26, respectively; P<0.05), with notable improvements in peak withdrawal symptoms on days 2 and 3 as measured by both SOWS-Gossop and Clinical Opiate Withdrawal Scale (COWS) assessments. These trials also showed higher treatment completion rates with lofexidine (39.6% to 49% versus 27.8% to 33% for ), indicating superior mitigation of symptoms like anxiety, muscle tension, and gastrointestinal distress. Lofexidine serves a supportive role in short-term detoxification protocols for opioid use disorder, helping to alleviate acute withdrawal to enable transition to longer-term treatments such as opioid agonist therapy with or , but it is not intended as a standalone cure for the underlying disorder. Head-to-head studies comparing lofexidine to , another alpha-2 agonist, have shown similar efficacy in reducing opioid withdrawal symptom severity, with no significant differences in detoxification completion rates across four of five reviewed trials. However, lofexidine demonstrates potentially better tolerability, with fewer instances of hypotension and associated adverse effects like feeling unwell compared to in multiple studies.

Other indications

Lofexidine was initially investigated in the late 1970s and 1980s as an antihypertensive agent due to its alpha-2 adrenergic agonist properties, which reduce sympathetic outflow and lower blood pressure. However, clinical development for this indication was discontinued because it demonstrated limited efficacy compared to clonidine, another alpha-2 agonist. Preliminary research has explored lofexidine's potential in managing , leveraging its ability to attenuate noradrenergic hyperactivity associated with withdrawal symptoms. A randomized controlled trial involving 63 patients found that lofexidine reduced some autonomic symptoms over 48 hours compared to placebo, though overall symptom relief was modest. Subsequent small studies, including one assessing its adjunctive use with , indicated limited additional benefit in alleviating anxiety or physiological symptoms, highlighting inconsistent efficacy in this context. Evidence for its role in other remains sparse, primarily from mechanistic studies on alpha-2 agonism rather than large-scale trials. Emerging investigations have examined lofexidine for neonatal opioid withdrawal syndrome (NOWS) in infants exposed to opioids in utero. A Phase 1 trial launched in 2024 by Marshall University is evaluating the safety, pharmacokinetics, and preliminary efficacy of oral lofexidine in newborns with NOWS, using the Modified Finnegan Neonatal Scoring System to assess symptom reduction. This study, supported by an NIH grant, aims to provide a non-opioid alternative to traditional treatments like morphine, addressing the need for shorter hospital stays and reduced medication exposure in neonates. Off-label use of lofexidine has been considered for conditions involving hyperadrenergic states, such as certain anxiety disorders, based on its noradrenergic modulation similar to clonidine. However, this application lacks robust clinical trial support, with evidence limited to case reports and extrapolations from its mechanism rather than controlled studies. None of these indications are FDA-approved, and the available evidence is preliminary, consisting mainly of small-scale studies, Phase 1/2 trials, or historical data without recent validation.

Use in special populations

Lofexidine is not recommended for use in pediatric patients under 18 years of age due to limited safety and efficacy data, as its approval by the FDA in 2018 was specifically for adults experiencing opioid withdrawal symptoms. A phase 1 trial (NCT06711640) funded by the (NIDA) to evaluate its pharmacokinetics, safety, and tolerability in adolescents aged 12 to 17 years abruptly discontinuing opioids was planned but withdrawn as of 2025. Ongoing studies, including those in neonates with opioid withdrawal syndrome, aim to support potential future approval in younger populations, but current guidelines advise against its use in children and adolescents pending further evidence. In elderly patients, lofexidine requires cautious use and potential dose reductions, as age-related declines in renal function increase the risk of adverse effects such as hypotension and bradycardia. Dosing should not exceed recommendations for moderate renal impairment (e.g., starting at approximately 1.44 mg/day, or 0.36 mg four times daily), with close monitoring of vital signs to mitigate cardiovascular risks. For pregnant individuals, lofexidine lacks established safety data in humans, though animal reproduction studies have demonstrated adverse fetal effects, including reduced body weights and increased resorptions, at exposures lower than those expected in humans; potential risks also include maternal hypotension affecting fetal perfusion. It is not assigned a formal FDA pregnancy category but is generally considered higher risk, with alternatives preferred during pregnancy unless benefits clearly outweigh potential harms. In lactation, no data exist on lofexidine's presence in human milk or its effects on breastfed infants, though it may pass into breast milk; use with caution and consider an alternate drug if breastfeeding is continued. Patients with renal or hepatic impairment require dose adjustments to avoid accumulation and heightened toxicity. No modification is needed for mild renal impairment (eGFR ≥90 mL/min/1.73 m²) or mild hepatic impairment (Child-Pugh class A), but reductions are advised for moderate to severe cases: for renal impairment, 1.44 mg/day in moderate (eGFR 30-89.9 mL/min/1.73 m²) and 0.72 mg/day in severe (eGFR <30 mL/min/1.73 m² or on dialysis); for hepatic impairment, 1.44 mg/day in moderate (Child-Pugh B) and 0.72 mg/day in severe (Child-Pugh C). Clinical trials of lofexidine have shown variable completion rates across subgroups, with overall rates of 37-41% in active treatment arms compared to 27% with placebo, but lower retention in certain at-risk groups (e.g., females experiencing more cardiovascular events) underscores the need for enhanced monitoring in special populations to improve outcomes.

Contraindications and precautions

Absolute contraindications

The U.S. (FDA) prescribing information lists no absolute contraindications for lofexidine. Lofexidine should be avoided in patients with known hypersensitivity to lofexidine or any of its excipients, as this may lead to severe allergic reactions such as . Lofexidine should be avoided in individuals with congenital or a history of , due to the drug's potential to prolong the QT interval and increase the risk of life-threatening arrhythmias. Use lofexidine with caution in patients with severe bradycardia or second- and third-degree atrioventricular heart block without an implanted pacemaker, as the drug can further decrease heart rate and impair cardiac conduction through its central alpha-2 adrenergic agonism, potentially leading to hemodynamic instability. Avoid lofexidine in patients with recent myocardial infarction or severe coronary insufficiency, such as unstable angina, given the heightened risk of exacerbating cardiac ischemia from drug-induced hypotension and bradycardia. Concurrent administration with certain QT interval-prolonging drugs should be used with caution and ECG monitoring if it cannot be avoided, as this combination may substantially elevate the risk of QT prolongation and ventricular arrhythmias; detailed interactions are discussed in the drug interactions section. These warnings and precautions stem from lofexidine's pharmacological profile as a selective alpha-2 adrenergic agonist, which suppresses sympathetic nervous system activity, resulting in reduced blood pressure, heart rate, and potential cardiac conduction abnormalities, alongside its independent QT-prolonging effects.

Precautions in specific conditions

Patients with a history of syncope or orthostatic hypotension should be initiated on a low dose of lofexidine, with slow titration to minimize the risk of exacerbation, and vital signs monitored closely before each dose. In such cases, patients are advised to self-monitor for symptoms of hypotension, orthostasis, or bradycardia, and to reduce, delay, or skip doses if symptomatic; maintaining hydration and rising slowly from sitting or lying positions is recommended. For individuals with concurrent cardiovascular disease, such as controlled hypertension or congestive heart failure, frequent blood pressure and heart rate monitoring is essential due to the potential for bradycardia and hypotension. Electrocardiogram (ECG) monitoring is advised in patients with bradyarrhythmias or those at risk for QT interval prolongation, particularly if co-administered with QT-prolonging agents like methadone. In patients with mild to moderate liver or kidney disease, dose adjustments are recommended to prevent accumulation and enhanced effects: for mild hepatic impairment (Child-Pugh class A), the maximum daily dose is 2.16 mg; for moderate (Child-Pugh class B), 1.44 mg; and for mild to moderate renal impairment (eGFR 30-89 mL/min/1.73 m²), 1.44 mg daily, with ongoing surveillance of vital signs and ECG if QT risks are present. Severe impairment requires further reduction to 0.72 mg daily. Elderly or debilitated patients face heightened risks of falls due to sedation, dizziness, and hypotension induced by lofexidine, necessitating cautious use with consideration of potential renal impairment and close monitoring. Patients should be warned against driving or operating machinery, especially during initial dosing and titration, owing to central nervous system effects like dizziness that may impair alertness. Clinical guidelines from the FDA labeling emphasize routine orthostatic blood pressure checks and ECG evaluation in the presence of QT prolongation risk factors to guide safe administration.

Adverse effects

Common side effects

In clinical trials of for opioid withdrawal management, the most common adverse reactions (occurring at an incidence of ≥10% and notably higher than placebo) were cardiovascular and central nervous system effects, including orthostatic hypotension, bradycardia, hypotension, dizziness, somnolence, sedation, and dry mouth. Pooled data from three randomized, double-blind, placebo-controlled studies (N=935 adults) showed orthostatic hypotension in 29% of patients on 2.16 mg/day and 42% on 2.88 mg/day (vs. 5% placebo), bradycardia in 24% and 32% (vs. 5%), hypotension in 30% for both doses (vs. 1%), dizziness in 19% and 23% (vs. 3%), somnolence in 11% and 13% (vs. 5%), sedation in 13% and 12% (vs. 5%), and dry mouth in 10% and 11% (vs. 0%). These effects reflect lofexidine's alpha-2 adrenergic agonist mechanism and were generally mild to moderate, with cardiovascular events like bradycardia and orthostatic hypotension showing dose dependence. Gastrointestinal effects primarily involved dry mouth, while nausea and constipation occurred less frequently and were not notably elevated over placebo rates in pivotal trials. Neurological effects encompassed sedation, somnolence, dizziness, headache, and fatigue, with headache and fatigue reported at lower incidences (<10%) in supporting studies. To manage these effects, patients should maintain adequate hydration to relieve dry mouth and rise slowly from sitting or lying positions to prevent dizziness and orthostatic hypotension; vital signs monitoring is recommended during initiation and dose adjustments. Post-marketing surveillance has revealed a profile consistent with clinical trial findings, dominated by hypotension, bradycardia, dizziness, and syncope, though voluntary reporting may capture events in diverse real-world settings.

Serious adverse effects

Lofexidine, acting as an alpha-2 adrenergic agonist, is associated with serious cardiovascular adverse effects that can require immediate medical intervention. These effects stem from its sympatholytic properties, which can lead to significant hemodynamic changes. Patients should be monitored closely, particularly those with preexisting cardiovascular conditions. Hypotension and syncope represent leading serious risks, potentially causing falls, injury, or hospitalization. In pivotal clinical trials, syncope occurred in 0.9% of patients on 2.16 mg/day and 1.4% on 2.88 mg/day, compared to none on placebo. Discontinuations and dose-holds due to bradycardia and orthostatic hypotension occurred in 13-31% of patients, with higher rates in females at the 2.88 mg/day dose. Bradycardia, another critical concern, affected 24% and 32% of patients at these doses versus 5% on placebo; symptomatic bradycardia may necessitate dose reduction or cessation. QT interval prolongation is a notable risk, with a maximum mean increase of 9.3 msec observed at 2.88 mg/day in trials; this can predispose at-risk patients to , particularly when combined with QT-prolonging agents or electrolyte imbalances. ECG monitoring is recommended for patients with heart failure, bradyarrhythmias, or relevant risk factors. Postmarketing surveillance since 2018 has identified rare cases of , including one associated with bradycardia and cardiac arrest, and three with concomitant use. Abrupt discontinuation of lofexidine can trigger rebound hypertension, with marked elevations in blood pressure reported; a gradual taper over 2 to 4 days is advised to mitigate this risk. The FDA label includes prominent warnings for these blood pressure-related effects, emphasizing avoidance in patients with severe coronary insufficiency, recent , or other contraindications. Allergic reactions, though rare, may manifest as rash or angioedema, warranting immediate discontinuation if suspected.

Overdose

Symptoms and management

Lofexidine overdose primarily presents with exaggerated alpha-2 adrenergic agonist effects, including profound hypotension, bradycardia, and sedation, which can progress to syncope or coma in severe cases. These symptoms reflect the drug's central and peripheral actions, with cardiovascular collapse posing the greatest risk due to marked reductions in blood pressure and heart rate. There is no specific antidote for lofexidine overdose, making supportive care the cornerstone of management. Initial management focuses on stabilizing vital signs and preventing further absorption. For recent ingestion, gastric lavage or administration of activated charcoal may be considered if the patient presents within a few hours. Hypotension and bradycardia should be managed with symptomatic and supportive therapy, including intravenous fluids. Patients should undergo continuous electrocardiographic monitoring for prolongation, particularly if electrolyte imbalances or concurrent QT-prolonging drugs like are present. Hemodialysis is ineffective for removal due to moderate protein binding (approximately 55%) and the drug's pharmacokinetics. Case reports of lofexidine overdose are limited, with postmarketing experience documenting rare severe events such as QT prolongation leading to torsades de pointes and cardiac arrest in one instance, where the patient recovered following resuscitation. Outcomes are generally favorable with prompt intervention, as seen in clinical settings where higher-than-recommended doses (up to 3.2 mg/day) resulted in manageable hypotension and bradycardia without long-term sequelae. The duration of toxicity is influenced by lofexidine's elimination half-life of 11 to 22 hours. No new overdose case reports have been identified in recent pharmacovigilance data as of November 2025.

Toxicity profile

Lofexidine exhibits a favorable acute toxicity profile in preclinical models, indicating a relatively high threshold for lethality compared to therapeutic doses. In humans, the overall therapeutic index is wide, supporting safe use at recommended doses of up to 2.88 mg per day for short-term opioid withdrawal management; however, the margin is narrower for cardiovascular effects, where bradycardia and hypotension can occur even within the therapeutic range, necessitating careful monitoring. Chronic toxicity studies in rats and dogs, conducted over periods up to 12 months, revealed no significant adverse effects at doses up to 1 mg/kg/day, with target organs including the gastrointestinal tract, liver, and kidneys at higher exposures. Carcinogenicity assessments in 2-year rat models and 18-month mouse models showed no evidence of treatment-related neoplasms, though study designs were noted as inadequate for definitive conclusions due to non-GLP compliance and dosing limitations; no further studies were required given the drug's intended short-term use. Reproductive toxicity was observed in animal models at high doses, including reduced fetal weights and increased pup mortality in rats (at ≥1.0 mg/kg/day) and increased post-implantation loss in rabbits (at ≥5.0 mg/kg/day), with safety margins less than 1-fold clinical exposure based on AUC, raising caution for use in pregnancy. Lofexidine demonstrates low dependence potential, with no binding to receptors associated with abuse and no evidence of reinforcing effects in preclinical assessments, leading to its classification outside the DEA controlled substances schedules in the US. Discontinuation after therapeutic use results in mild withdrawal symptoms, such as insomnia and hypertension, which are substantially less severe than those associated with opioids. Data on environmental toxicology for lofexidine remain minimal, with no specific ecotoxicity studies identified; however, as a centrally acting alpha-2 adrenergic agonist with low environmental persistence predicted from its physicochemical properties, it poses low risk to aquatic ecosystems at expected exposure levels. Postmarketing experience, as reported in the product labeling (revised August 2023), has identified no new major safety signals beyond those outlined, such as cardiovascular risks; available data as of November 2025 confirm no additional signals in FDA Adverse Event Reporting System monitoring. Compared briefly to clonidine, lofexidine offers a higher therapeutic index, particularly for central effects with reduced sedation.

Drug interactions

Cardiovascular effects

Lofexidine, an alpha-2 adrenergic agonist, can produce additive hypotensive effects when coadministered with antihypertensive agents such as beta-blockers (e.g., atenolol) or diuretics, increasing the risk of excessive blood pressure reduction and orthostatic hypotension. Close monitoring of blood pressure is recommended, and coadministration should be avoided if possible to mitigate these risks. Concomitant use with drugs that prolong the QT interval, such as certain antipsychotics (e.g., haloperidol) or antiarrhythmics, may potentiate lofexidine's own QT-prolonging effects, heightening the risk of torsades de pointes and other arrhythmias. Such combinations should be avoided when feasible, particularly in patients with risk factors like electrolyte imbalances or pre-existing cardiac conditions. Lofexidine may also enhance bradycardia when combined with agents like calcium channel blockers (e.g., diltiazem), necessitating dose adjustments or careful vital sign monitoring to prevent symptomatic heart rate decreases. In clinical trials evaluating lofexidine for opioid withdrawal, patients with baseline symptomatic bradycardia (pulse <50 bpm) or a history of clinically significant hypotension were excluded to ensure safety, reflecting concerns over amplified cardiovascular risks in vulnerable populations. Post-marketing reports have included cases of syncope associated with these interactions, underscoring the need for vigilance. Guidelines recommend obtaining a baseline ECG prior to initiating lofexidine in patients on potential interactors and conducting follow-up monitoring, along with spacing doses from interacting medications to minimize cumulative effects on heart rate and blood pressure.

Central nervous system effects

Lofexidine, an alpha-2 adrenergic agonist, potentiates the central nervous system (CNS) depressant effects of benzodiazepines, increasing the risk of excessive sedation and respiratory depression when co-administered. This pharmacodynamic synergy extends to other CNS depressants, including opioids, alcohol, and barbiturates, where additive effects heighten drowsiness and impair cognitive function, particularly during early opioid withdrawal when residual opioids may still be present. Clinicians are advised to avoid or closely monitor such combinations, as they can exacerbate withdrawal management challenges through enhanced CNS inhibition. Tricyclic antidepressants (TCAs), such as desipramine, interact with lofexidine by potentially reducing its efficacy, resulting in breakthrough opioid withdrawal symptoms that manifest as intensified CNS disturbances like anxiety and restlessness. These interactions arise from pharmacodynamic antagonism at alpha-2 receptors, compounded by additive sedative effects that further compromise cognition and alertness. To mitigate these risks, healthcare providers should taper interacting CNS depressants gradually and monitor patients for signs of excessive drowsiness or cognitive impairment. Lofexidine exhibits no significant cytochrome P450 (CYP) interactions, emphasizing that observed effects stem predominantly from additive pharmacodynamic mechanisms rather than metabolic alterations. Sedation, a common adverse effect of lofexidine itself, may be amplified in these scenarios, necessitating precautions against activities requiring mental acuity.

Pharmacology

Mechanism of action

Lofexidine is a selective alpha-2A adrenergic receptor agonist that primarily exerts its effects by binding to presynaptic alpha-2 receptors on adrenergic neurons in the central nervous system, particularly in the locus coeruleus, thereby inhibiting the release of norepinephrine. This reduction in norepinephrine turnover suppresses the hyperadrenergic state associated with opioid withdrawal, decreasing sympathetic outflow and alleviating symptoms such as tachycardia, hypertension, anxiety, and gastrointestinal distress. Unlike opioids, lofexidine has no activity at opioid receptors and is not antagonized by naloxone, making it non-addictive and suitable for facilitating abrupt opioid discontinuation without reinforcing dependence. Its selectivity for the alpha-2A subtype, with higher affinity compared to clonidine and lower activity at alpha-2B and alpha-2C receptors, contributes to reduced sedation and hypotension relative to less selective alpha-2 agonists like clonidine. Preclinical studies in animal models, including rodents and nonhuman primates, demonstrate that lofexidine produces a dose-dependent reduction in brain noradrenaline levels, correlating with attenuation of opioid withdrawal-like behaviors and stress-induced reinstatement of drug seeking.

Pharmacokinetics

Lofexidine is well absorbed after oral administration, exhibiting an absolute bioavailability of 72% due to approximately 30% first-pass metabolism. Peak plasma concentrations are typically reached 3 to 5 hours following a dose, with pharmacokinetics that are linear and dose-proportional across the recommended daily range of 0.72 to 2.88 mg. Administration with a high-fat meal delays the time to peak concentration to about 6 hours but does not alter the overall extent of absorption or maximum plasma levels. Steady-state concentrations are attained within 2 to 3 days of multiple dosing, consistent with its elimination half-life. The drug undergoes extensive distribution in the body, with an apparent volume of distribution of 480 L after oral dosing, reflecting broad tissue penetration. Lofexidine is moderately bound to plasma proteins, approximately 55%, and it readily crosses the blood-brain barrier to exert its central nervous system effects. Metabolism occurs predominantly in the liver through cytochrome P450 enzymes, primarily and to a lesser extent and , yielding only inactive metabolites with no active species formed. Elimination of lofexidine is mainly via the renal route, with 93.5% of the administered dose recovered in urine (15 to 20% as unchanged parent drug) and less than 1% in feces. The terminal elimination half-life averages 11 to 13 hours after a single dose and extends to 17 to 22 hours at steady state, while apparent oral clearance is approximately 20 L/h.

Chemistry

Chemical structure and properties

Lofexidine, chemically designated as 2-[1-(2,6-dichlorophenoxy)ethyl]-4,5-dihydro-1H-imidazole, is an imidazoline derivative featuring a 4,5-dihydro-1H-imidazole ring attached to a 2,6-dichlorophenoxyethyl moiety. The hydrochloride salt form, employed in medicinal applications, has the molecular formula C11H12Cl2N2O · HCl and a molecular weight of 295.6 g/mol. Lofexidine hydrochloride manifests as a white to off-white crystalline solid, with a melting point ranging from 236°C to 238°C. It exhibits good aqueous solubility, dissolving at concentrations exceeding 20 mg/mL in water to form a clear solution, and is classified as freely soluble across a broad pH range according to USP standards. The compound possesses a basic pKa of approximately 9.3, reflecting the protonation behavior of the imidazoline nitrogen. The synthesis of lofexidine proceeds through a multi-step sequence beginning with the of 2,6-dichlorophenol using ethyl 2-chloropropionate in the presence of a base such as , yielding ethyl 2-(2,6-dichlorophenoxy)propanoate as a key intermediate. This ester is then reacted with under conditions involving titanium catalysts like in , facilitating amidation and subsequent cyclization to form the ring, followed by acidification to obtain the salt with yields exceeding 90%. Lofexidine demonstrates stability under standard pharmaceutical storage conditions, maintaining integrity for a retest period of 24 months at 25°C and 60% relative humidity, and supporting an expiry of 36 months when packaged in bottles with . The molecule contains a chiral center at the alpha-carbon of the ethyl linker, resulting in a in commercial preparations, with no resolution into stereoisomers for therapeutic use. Lofexidine and are both centrally acting alpha-2 adrenergic agonists that mitigate symptoms by reducing noradrenergic hyperactivity in the . Unlike , which has comparable affinity for alpha-2A, alpha-2B, and alpha-2C subtypes, lofexidine demonstrates higher selectivity and affinity for the alpha-2A subtype, contributing to its reduced impact on peripheral alpha-2 receptors. This selectivity results in fewer hypotensive and effects compared to , making lofexidine better tolerated in clinical settings. Additionally, lofexidine has a shorter elimination of approximately 11 hours, versus 12 to 16 hours for , allowing for more predictable dosing in short-term withdrawal management. In head-to-head clinical trials from the and , lofexidine showed similar efficacy to in alleviating symptoms, such as anxiety, muscle aches, and autonomic instability, but with lower patient dropout rates due to improved tolerability. A 1998 randomized double-blind study in outpatient addicts found no significant differences in withdrawal symptom control between the two drugs, though caused more pronounced requiring additional medical oversight. Meta-analyses, including a 2016 Cochrane review of multiple trials, confirmed lofexidine's non-inferiority to in and withdrawal, with equivalent completion rates but reduced severity of side effects like dry mouth and drowsiness. Lofexidine's primary advantages over include minimized peripheral effects, such as less lowering, which reduces the risk of and supports its use in non-hospitalized patients. However, lofexidine has limited data supporting its efficacy for management; early 1980s studies indicated it requires higher doses than clonidine to achieve comparable control, and it is not approved for this indication. Compared to , an intravenous alpha-2 agonist used primarily as a in intensive care and procedural , lofexidine is administered orally and exhibits lower potency at alpha-2A receptors. Dexmedetomidine's higher affinity enables more profound central and analgesia, but its parenteral route limits outpatient use, whereas lofexidine's profile suits treatment without the need for monitoring in a clinical setting.

History

Development and research

Lofexidine was initially developed in the by Pharmaceuticals as a selective for the treatment of . Early clinical studies, including Phase 2 and 3 trials conducted in the and , demonstrated modest antihypertensive effects, such as reductions in and urinary noradrenaline excretion by approximately 28%, though these were accompanied by side effects like sodium and water retention. Despite these findings, the compound did not gain widespread adoption for blood pressure management due to limited efficacy compared to other agents. In the , preclinical research shifted focus toward lofexidine's potential in managing dependence, leveraging its ability to suppress noradrenergic hyperactivity associated with symptoms. This repurposing was informed by observations of its central alpha-2 agonism reducing sympathetic outflow without the sedative potency of . UK-based trials in the , including randomized controlled studies, confirmed its efficacy in alleviating withdrawal symptoms, leading to marketing authorization by Pharmaceuticals in under the brand BritLofex. These early European investigations established lofexidine as a non-opioid alternative for short-term , with completion rates in withdrawal protocols comparable to or better than . In the , an (IND) application was filed in the early 2000s by collaborators including WorldMeds, initiating a series of clinical trials amid growing recognition of the . Phase 3 studies spanned from approximately 2005 to 2015, with a key multicenter, double-blind, -controlled trial in 2007 evaluating lofexidine's safety and efficacy in inpatient ; it showed significant reductions in withdrawal symptoms (measured by the Clinical Opiate Withdrawal Scale) and higher treatment retention rates compared to . Development faced delays due to shifting priorities in addiction research funding and the need for additional data on non- therapies during the escalating . Post-approval research has continued to explore expanded applications, including a 2024 Phase 2 trial assessing lofexidine's , safety, and preliminary efficacy in neonates with syndrome (NOWS), aiming to provide a non-opioid option that avoids respiratory depression risks associated with traditional treatments. The overall development timeline for lofexidine spanned over 40 years, influenced by intermittent funding challenges for addiction pharmacotherapies, such as a $15 million grant awarded in 2013 to support final Phase 3 efforts.

Regulatory approvals and availability

Lofexidine was first approved in the in 1992 under the brand name BritLofex for the symptomatic relief of in patients undergoing . It received national approvals across much of during the 1990s for similar indications and is now available generically in several European countries. In the United States, the (FDA) granted approval to lofexidine hydrochloride on May 16, 2018, under the brand name Lucemyra and marketed by US WorldMeds LLC, designating it as the first non-opioid medication specifically indicated for mitigating symptoms in adults to facilitate abrupt discontinuation of opioids. The drug has since been acquired by BioCorRx Pharmaceuticals Inc. in 2025. Approvals in other regions remain limited; lofexidine lacks formal approval in and has restricted availability in , where alternative treatments like are more commonly used for . The FDA prescribing information was updated in 2024 to highlight risks associated with hypotension, including , particularly when transitioning from to upright positions, with recommendations for blood pressure monitoring. No Risk Evaluation and Mitigation Strategy (REMS) program is required for lofexidine. As of 2025, ongoing pediatric investigations include Phase 1 pharmacokinetic and safety studies in adolescents aged 12 to under 18 years and neonates with syndrome, potentially supporting future label expansions. Lofexidine is formulated as 0.18 mg oral tablets and is indicated for short-term use only, with a maximum recommended duration of 14 consecutive days to manage acute withdrawal symptoms.

Society and culture

Brand names and formulations

Lofexidine is commercially available under the brand name Lucemyra , formulated as 0.18 mg film-coated tablets for oral use. This immediate-release is the only approved presentation, with no extended-release or injectable formulations available. In the , lofexidine is marketed as BritLofex by Pharmaceuticals. Generic lofexidine is available in other international markets, often in similar oral tablet forms. Prior to 2025, Lucemyra was manufactured and distributed by US WorldMeds. In March 2025, BioCorRx Pharmaceuticals acquired the rights to Lucemyra from US WorldMeds, LLC. Lucemyra tablets are packaged in bottles containing 36 or 96 tablets, each including a packet to protect against moisture. The standard treatment course supports up to 14 days of use, typically requiring multiple bottles based on the dosing regimen of up to 2.88 mg daily. Lofexidine is not classified as a controlled substance under the U.S. (DEA) schedules, reflecting its low potential for abuse compared to opioids. It is available only by prescription in the United States, requiring oversight by a healthcare provider for safe use in managing symptoms. The U.S. () has determined that a Risk Evaluation and Mitigation Strategy (REMS) is not necessary for lofexidine, though clinical guidelines recommend monitoring due to potential . At its U.S. launch in 2018 under the brand name Lucemyra, a 14-day course of lofexidine cost approximately $3,000, significantly higher than generic alternatives like . This pricing positioned it as a premium option for short-term withdrawal management, with the high cost driven by its status as the first FDA-approved non-opioid treatment for this indication. Generic versions of lofexidine received FDA approval in August 2024, with market availability starting in late 2024. As of November 2025, generic prices have decreased significantly, with a 14-day course available for around $430 through discount programs. Access to lofexidine is supported by coverage under some private insurance plans for (OUD) treatment, often requiring to confirm medical necessity. However, plans generally do not cover it, limiting affordability for older adults or those on federal programs. In underserved communities, barriers include the drug's out-of-pocket costs (reduced post-generics), scarcity of prescribing providers trained in OUD management, and broader systemic issues like transportation and stigma, exacerbating disparities in rural and low-income areas. In March 2025, BioCorRx Pharmaceuticals acquired Lucemyra from US WorldMeds, LLC, with plans to leverage its behavioral health network to expand distribution and improve access to treatment. This acquisition aligns with ongoing , including a Phase 1 study for potential label expansion to adolescents aged 12-17, though no such approval has been granted as of November 2025. Lofexidine plays a targeted role in the public health response to the opioid crisis by providing a non-addictive option for mitigating acute withdrawal, facilitating transitions to long-term OUD therapies like . Its cost-effectiveness relative to remains debated, as lofexidine offers similar efficacy with fewer hypotensive side effects but at a historically higher price; with generics, adoption may increase in resource-constrained settings.

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