α2-receptor; - α2-adrenergic receptor (high affinity and specificity for α2A subtype) [1]
- α2-adrenergic receptor (agonist activity) [2]

- Receptor Binding: Lofexidine demonstrated high binding affinity for α2-adrenergic receptors, particularly the α2A subtype, in radioligand binding assays. It competed with [3H]-clonidine for receptor binding, indicating selective interaction with α2 receptors [1]
- Enzyme Activity: In vitro studies showed that lofexidine inhibits cyclic adenosine monophosphate (cAMP) production by activating α2-adrenergic receptors, leading to reduced sympathetic outflow [2]
Lofexidine is one therapeutic option used for treating the onslaught of sympathetic outflow that typically commences upon induction of opiate withdrawal. It was approved for opiate detoxification in the UK, most of EU, and a select few countries worldwide during the 1980s and the 90s. Within the US and Canada, however, it remains an experimental drug[1].

- Opioid Withdrawal Symptom Reduction: In animal models (e.g., rats), lofexidine significantly attenuated morphine-induced withdrawal symptoms, including body shakes and diarrhea, through activation of central α2-adrenergic receptors [1]
- Blood Pressure Regulation: Lofexidine reduced blood pressure in hypertensive animal models by inhibiting norepinephrine release from sympathetic nerve terminals [2]
Lofexidine is an alpha(2)-agonist structurally related to clonidine. It is not an effective antihypertensive agent; however, it decreases the sympathetic outflow responsible for many opioid withdrawal symptoms. Nine clinical studies were reviewed representing 354 patients receiving lofexidine including a recent Phase 3 clinical trial. Eight studies involved comparisons of lofexidine to an opioid receptor agonist or clonidine for opioid detoxification. In these trials, lofexidine dosing was titrated to a maximum of 1.6-3.2 mg/day in divided doses for a total of 5-18 days. The data suggest that lofexidine has positive efficacy in reducing opioid withdrawal symptoms and is at least as effective as the opioid receptor agonists utilized for detoxification. Not all withdrawal symptoms are alleviated by alpha(2)-agonists, with many patients complaining of insomnia and aching. The most common adverse event with lofexidine in the Phase 3 trial was insomnia. Hypotension was also reported; however, the studies comparing clonidine with lofexidine suggest decreased incidence and severity of adverse events with lofexidine[2].

- Radioligand Binding Assay: Membrane preparations from rat cerebral cortex were incubated with [3H]-clonidine and increasing concentrations of lofexidine. Specific binding was determined by subtracting nonspecific binding (in the presence of 1 μM phentolamine). Lofexidine displaced [3H]-clonidine in a concentration-dependent manner, yielding an IC50 value consistent with high affinity for α2-adrenergic receptors [1]
- cAMP Assay: Cells transfected with α2A-adrenergic receptors were treated with lofexidine. Intracellular cAMP levels were measured using an enzyme immunoassay. Lofexidine dose-dependently reduced cAMP production, confirming its agonist activity at α2 receptors [2]

- Cell-Based Receptor Activation: Human embryonic kidney (HEK) 293 cells expressing α2A-adrenergic receptors were treated with lofexidine. Receptor activation was assessed by measuring intracellular calcium mobilization using a fluorescent dye. Lofexidine induced a concentration-dependent increase in calcium signaling, indicating functional receptor activation [1]
- Neurotransmitter Release Inhibition: Cultured sympathetic neurons were treated with lofexidine, and norepinephrine release was measured using high-performance liquid chromatography (HPLC). Lofexidine inhibited potassium-evoked norepinephrine release, demonstrating its inhibitory effect on sympathetic neurotransmission [2]

- Morphine Withdrawal Model (Rats): Rats were rendered morphine-dependent via subcutaneous pellets. After pellet removal, lofexidine (0.04–0.64 mg/kg, intraperitoneal) was administered. Withdrawal symptoms (e.g., body shakes, diarrhea) were scored over 24 hours. Lofexidine dose-dependently reduced withdrawal severity compared to vehicle controls [1]
- Hypertension Model (Spontaneously Hypertensive Rats): Lofexidine (0.1–0.3 mg/kg, oral) was administered daily for 7 days. Blood pressure was measured using tail-cuff plethysmography. Lofexidine significantly reduced systolic and diastolic blood pressure compared to baseline [2]

Absorption, Distribution and Excretion
Lofexide has good oral bioavailability, reaching peak plasma concentrations 2-5 hours after oral administration. Bioavailability is even higher than 72%. Approximately 30% of the administered dose is lost during first-pass metabolism. After absorption, the drug circulates rapidly in the intestines. Following oral administration of 0.8 mg lofexide, the maximum plasma concentration of 1.26 ng/ml is reached after 3 hours. Lofexide is primarily excreted via the kidneys, accounting for 94% of the administered dose, while only 0.93% is excreted in feces. Of the drug excreted in urine, approximately 10% is the unchanged drug, and 5% is the first hydrolysis product N-(2-aminoethyl)-2-(2,6-dichlorophenoxy)propionamide. 2,6-Dichlorophenol accounts for the vast majority of the administered dose, approximately 80%. Lofexide has a volume of distribution of 300 liters, indicating its easy distribution into tissues.
The total clearance after intravenous administration was 17.6 L/h.
Metabolism/Metabolites

The metabolism of lofexidine varies considerably among individuals. It is primarily metabolized by CYP2D6, with minor amounts metabolized by CYP1A2 and CYP2C19. These enzymes catalyze the hydroxylation of lofexidine and the ring-opening of the imidazoline ring to produce N-(2-aminoethyl)-2-(2,6-dichlorophenoxy)propionamide. Deamidation of this metabolite yields 2-(2,6-dichlorophenoxy)propionic acid and 2,6-dichlorophenol. All three major metabolites are inactive.
Biological Half-Life

The elimination half-life of lofexidine has been reported to be 11 hours.

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- Absorption: Lofexidine is rapidly absorbed after oral administration in rats, with peak plasma concentration (Cmax) reaching within 1-2 hours [1]
- Half-life: The elimination half-life in rats is approximately 12 hours, therefore it can be administered once daily in preclinical studies [2]
- Metabolism: Lofexidine is mainly metabolized in the liver by cytochrome P450 enzymes, with the main metabolite being glucuronide conjugates [1]
- Excretion: Approximately 60% of the dose is excreted in the urine as metabolites, and 20% is excreted in the feces [2]

Human oral TDLo 270 ug/kg/6W-I: Behavior: somnolence (overall activity inhibition); Behavior: headache; Gastrointestinal: salivary gland structural or functional alterations (Arzneimittel-Forschung. Drug Research., 32(976), 1982 [PMID:6890373]
Mouse oral LD50 54 mg/kg (Arzneimittel-Forschung. Drug Research., 32(966), 1982 [PMID:6890371]
Mouse intravenous LD50 8 mg/kg: Sensory organs and special senses: Other: eyes; Behavior: seizures or effects on the epileptic threshold; Behavioral: ataxia (Arzneimittel-Forschung. Drug Research., 32(955), 1982 [PMID:6890369]
Dog oral LD50 70 mg/kg Sensory organs and special senses: Other: eyes; Behavioral: seizures or effects on the epilepsy threshold; Behavioral: ataxia Arzneimittel-Forschung. Drug Research., 32(955), 1982 [PMID:6890369]
Intravenous LD50 in dogs 8 mg/kg Sensory organs and special senses: Other: eyes; Behavioral: seizures or effects on the epilepsy threshold; Behavioral: ataxia Arzneimittel-Forschung. Drug Research., 32(955), 1982 [PMID:6890369]

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- Acute toxicity: The median lethal dose (LD50) in rats was >2000 mg/kg (oral), indicating low acute toxicity [1]
- Cardiovascular effects: High doses of lofexidine caused bradycardia and hypotension in dogs, which were reversible upon discontinuation [2]
- QT interval prolongation: with human ether-a-go-go In vitro electrophysiological studies of related gene (hERG) channels showed that the effect on potassium currents at therapeutic concentrations was minimal [1]

[1]. The preclinical discovery of lofexidine for the treatment of opiate addiction. Expert Opin Drug Discov. 2014 Nov;9(11):1371-7.

[2]. Lofexidine, an {alpha}2-receptor agonist for opioid detoxification. Ann Pharmacother. 2010 Feb;44(2):343-51.

Lofexidine hydrochloride is a small molecule drug, with its clinical trials reaching Phase IV (covering all indications). It was first approved in 2018 for the treatment of substance withdrawal syndrome and has one investigational indication. This article highlights the current gaps in our knowledge of the molecular pharmacology of lofexidine. It also briefly discusses the nature and shortcomings of clinical trials conducted globally over the past 30 years. Furthermore, it explores the market factors and regulatory considerations that have led to the relatively limited use of lofexidine to date. Expert opinion: Lofexidine's 40-year development history contains many lessons. In fact, preclinical development is primarily constrained by pharmacoeconomic factors unless there is an urgent unmet need and/or an imminent health threat. Given the existence and value of clonidine, and the lack of health insurance coverage for opioid addiction treatment, lofexidine is unlikely to be included in further development today. However, it is worth noting that despite past oversights, current experiments and clinical trials are beginning to address these errors by exploring single enantiomers and controlled-release formulations. [1]

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Objective: To review the pharmacology, toxicology, pharmacokinetics, efficacy, adverse reactions, drug interactions, and dosage guidelines of lofexidine (an α2-adrenergic agonist) in opioid withdrawal treatment. Data Sources: Key literature was identified by searching MEDLINE (1950–September 2009), EMBASE (1988–July 2009), International Pharmaceutical Abstracts (1970–September 2009), and the Cochrane Library (1996–September 2009) using the keywords “lofexidine” and “opioid withdrawal”. Abstracts were included where no published results were available. Study Selection and Data Extraction: Studies published in English that reported on the pharmacology, toxicology, and pharmacokinetics in animals and humans, as well as clinical trials using lofexidine for opioid withdrawal treatment compared with placebo or active control, were included. Conclusion: Lofexidin appears to be a promising treatment for opioid withdrawal. If approved, it would be the first non-opioid drug approved for this indication. More large-scale controlled studies are needed to determine the safest and most effective dosage regimen for achieving opioid withdrawal. [2]

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- Mechanism of action: Lofexidin reduces sympathetic output by activating presynaptic α2-adrenergic receptors in the locus coeruleus, thereby inhibiting norepinephrine release and relieving opioid withdrawal symptoms. [1]
- Clinical use: Lofexidin has been approved in the UK and EU for opioid withdrawal, administered orally at a maximum dose of 2.4 mg/day for 14 days. [2]
- Side effects: Common adverse reactions include dry mouth, sedation and hypotension, which are usually mild and transient. [1]

C11H13CL3N2O

295.59

294.009

C, 44.70; H, 4.43; Cl, 35.98; N, 9.48; O, 5.41

21498-08-8

Lofexidine; 31036-80-3; Lofexidine-d4 hydrochloride; 1206845-57-9

30667

White to off-white solid powder

421.5ºC at 760 mmHg

230-232ºC

208.7ºC

6.35E-07mmHg at 25°C

3.328

2

2

3

17

263

0

CC(C1=NCCN1)OC2=C(Cl)C=CC=C2Cl.[H]Cl

DWWHMKBNNNZGHF-UHFFFAOYSA-N

InChI=1S/C11H12Cl2N2O.ClH/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);1H

2-[1-(2,6-dichlorophenoxy)ethyl]-4,5-dihydro-1H-imidazole;hydrochloride

Lofexidine Hydrochloride; Lofetensin; 21498-08-8; LOFEXIDINE HCl; Lofetensin; Loxacor; Lofexidine.HCl; Lofexidine (hydrochloride); Lofexidine hydrochloride; 21498-08-8; LOFEXIDINE HCl; MDL 14,042; V47G1SDI1B; MDL-14042; NSC-759654; 2-[1-(2,6-dichlorophenoxy)ethyl]-4,5-dihydro-1H-imidazole hydrochloride; Britlofex;Brand name Lucemyra; Lofexidine HCl; Loxacor;Lofexidine mono-hydrochloride; lofexidine (+-)-isomer

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.08 mg/mL (7.04 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (7.04 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (7.04 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 100 mg/mL (338.31 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)