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

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- 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 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].

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- 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]

- 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: Lofexide is rapidly absorbed after oral administration to 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: Lofexide 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]

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Absorption, Distribution and Excretion Lofexide has good oral bioavailability, reaching peak plasma concentration 2-5 hours after oral administration. Its bioavailability is even higher than 72%. Approximately 30% of the administered dose of lofexide is lost during first-pass metabolism. After absorption, the drug circulates rapidly in the intestine. Following oral administration of 0.8 mg lofexidine, the peak plasma concentration of 1.26 ng/ml was reached after 3 hours. Lofexidine is primarily excreted via the kidneys (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%. Lofexidine has a volume of distribution of 300 liters, indicating its easy distribution into tissues. The total clearance after intravenous administration is 17.6 liters/hour. Metabolites/Metabolites: The metabolic rate of lofexidine varies considerably among individuals. It is primarily metabolized via CYP2D6, with smaller amounts metabolized via CYP1A2 and CYP2C19. These enzymes catalyze the hydroxylation of lofexidine and the ring-opening of the imidazoline ring to generate 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.

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

Acute toxicity: The oral LD50 in rats is >2000 mg/kg, indicating low acute toxicity [1]
- Cardiovascular effects: Bradycardia and hypotension occurred in dogs after administration of high doses of lofexidine, which were reversible upon discontinuation of the drug [2]
- QT interval prolongation: In vitro electrophysiological studies have shown that lofexidine has minimal effect on potassium current at therapeutic concentrations [1]

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Use during pregnancy and lactation
◉ Overview of use during lactation
There is currently no information on the use of lofexidine during lactation. Lofexidine is chemically and pharmacologically related to clonidine, which is present in higher concentrations in breast milk and breastfed infants. Although lofexidine is not contraindicated during lactation, it should be used with caution by lactating women, especially when nursing newborns or premature infants. Lactating women, especially when nursing newborns or premature infants, should prioritize other medications.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Protein binding
Lofexidin has moderate protein binding, approximately 55% of the administered dose.

[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.

Mechanism of action: Lofexide reduces sympathetic nerve output by activating presynaptic α2-adrenergic receptors in the locus coeruleus, thereby inhibiting norepinephrine release and relieving opioid withdrawal symptoms [1] - Clinical application: Lofexide has been approved in the UK and EU for the treatment of opioid withdrawal. It is 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] - Lofexide belongs to the imidazole, dichlorobenzene, aromatic ether and carboxymidine classes. It is both an α-adrenergic agonist and an antihypertensive drug. - Lofexide is a non-opioid central α2-adrenergic receptor agonist and was first approved in the UK in 1992 for the treatment of opioid withdrawal symptoms. It was initially investigated in 1980 for its antihypertensive effects, but research was discontinued due to its lower efficacy compared to clonidine. Lofexidine was subsequently reintroduced for treating opioid withdrawal symptoms because it is more economical and has fewer side effects than clonidine. Lofexidine was developed by Woldmeds LLC in the United States and was approved by the U.S. Food and Drug Administration (FDA) on May 16, 2018.
See also: Lofexidine hydrochloride (salt form).

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Drug Indications
Lofexidine is indicated for the relief of acute opioid withdrawal symptoms and helps in the completion of opioid withdrawal therapy. It is the first non-opioid drug used for the management of opioid withdrawal symptoms. Opioid withdrawal syndrome is a severe manifestation of opioid dependence. This condition is extremely uncomfortable and can last for several days. Key symptoms include abdominal pain, nausea, diarrhea, dilated pupils, tearing, and piloerection. These symptoms usually appear after a sudden reduction in the opioid dose and are relieved upon reintroduction of the opioid.
FDA Label

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Mechanism of Action
Lofexidin is a potent α2-adrenergic receptor agonist with agonistic affinity for α1A-adrenergic receptors as well as 5-HT1a, 5-HT7, 5-HT2c, and 5-HT1d receptors. α2-adrenergic receptors are commonly targeted by norepinephrine; activation of these receptors inhibits cAMP synthesis, leading to potassium efflux, inhibition of neuronal firing, and suppression of norepinephrine release. All these effects reduce heart rate and blood pressure and weaken the sympathetic stress response. Opioids inhibit cAMP in norepinephrine neurons, and discontinuation of opioids leads to elevated cAMP levels. This, in turn, results in elevated norepinephrine levels, triggering withdrawal symptoms. Long-term opioid use exacerbates this effect due to a compensatory mechanism of persistent negative feedback. Therefore, long-term opioid use leads to increased cAMP production and norepinephrine release. Lofexide alleviates opioid withdrawal symptoms by activating α2-adrenergic receptors, thus replacing the inhibitory effect of opioids on cAMP production. This effect is achieved without involving opioid receptors that mediate other activities related to opioid dependence or addiction.
Pharmacodynamics
In clinical trials, lofexide-induced opioid withdrawal symptoms were more severe than methadone. On the other hand, in clinical trials of methadone withdrawal, lofexide effectively reduced withdrawal symptoms, especially hypotension. Clinical reports also indicate that short-term use of lofexide is more effective. In phase 3 clinical trials, lofexide showed a significantly higher opioid discontinuation completion rate. Several pharmacological studies have also been completed, but no off-target effects have been reported.

C11H12CL2N2O

259.13

258.032

C, 50.99; H, 4.67; Cl, 27.36; N, 10.81; O, 6.17

31036-80-3

Lofexidine hydrochloride; 21498-08-8

30668

White to off-white solid powder

1.4±0.1 g/cm3

421.5±35.0 °C at 760 mmHg

215-225 °C

208.7±25.9 °C

0.0±1.0 mmHg at 25°C

1.611

3.59

1

2

3

16

263

0

CC(C1=NCCN1)OC2=C(Cl)C=CC=C2Cl

KSMAGQUYOIHWFS-UHFFFAOYSA-N

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)

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

RMI-14042A; MDL-14,042; MDL 14,042; 31036-80-3; Lofexidina; Lofexidinum; 2-[1-(2,6-dichlorophenoxy)ethyl]-4,5-dihydro-1H-imidazole; Lofexidinum [INN-Latin]; Lofexidina [INN-Spanish]; 2-(1-(2,6-Dichlorophenoxy)ethyl)-4,5-dihydro-1H-imidazole; MDL14,042; Lofexidine; Loxacor; RMI14042A; RMI 14042A; BA 168; Lofetensin; Lucemyra

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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 (8.03 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 (8.03 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 (8.03 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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 (Please use freshly prepared in vivo formulations for optimal results.)