Lofexidine Research Articles

Inhibition of noradrenergic and corticotrophin-releasing factor systems: Effects on enhancement of memory consolidation by unconditioned and conditioned heroin withdrawal

The aim of the current study was to test the hypothesis that unconditioned and conditioned opioid withdrawal enhance memory consolidation through overlapping neural systems. The reported experiments focussed on noradrenaline (NA) and corticotrophin-releasing factor (CRF) because of their known involvement in both opioid withdrawal and memory consolidation. Male Sprague-Dawley rats were implanted with subcutaneous osmotic mini-pumps releasing 3.5 mg/kg/day heroin and received injections of 3 mg/kg naloxone (NLX) to precipitate withdrawal. NLX was preceded by 0.1–0.6 mg/kg lofexidine (LOF) (alpha-2 adrenergic agonist) or 10–20 mg/kg antalarmin (ANT) (CRF1 receptor antagonist), and all injections were administered immediately after (i.e., post-training method) the sample phase of the spontaneous object recognition memory task. The same procedure was repeated 7 days after removal of the mini-pumps. To establish conditioned withdrawal, heroin-exposed rats were confined for 2 h in a context (CS+) following injections of 3 mg/kg NLX and in another context (CS-) following vehicle injections. Seven days after removal of mini-pumps, the effects of immediate post-sample exposure to the CS+ (and CS-) preceded by 0.6 mg/kg LOF or 20 mg/kg ANT were assessed. It was found both LOF and ANT blocked the enhancement of object memory by post-sample NLX administration and by exposure to the CS+. These results suggest that pharmacological and psychological withdrawal impact memory storage by activating overlapping NA and CRF systems.

An Easy, Convenient, and Safe Process for the Synthesis of Lofexidine Hydrochloride

An Easy, Convenient, and Safe Process for the Synthesis of Lofexidine Hydrochloride

Lofexidine in Combination With Oral Naltrexone for Opioid Use Disorder Relapse Prevention: A Pilot Randomized, Double-Blind, Placebo-Controlled Study.

Lofexidine (LFX), an α2A adrenergic receptor agonist, known to alleviate opioid withdrawal symptoms, was assessed in combination with oral naltrexone (NTX) for effects on opioid use outcomes and NTX treatment compliance. Detoxified individuals (ages 18-55, 80% male) with opioid use disorder Diagnostic and Statistical Manual of Mental Disorders, 4th edition were randomized to 2.4 mg/day of LFX (n = 26) or Placebo (PBO, n = 31) in a double-blind manner for 12 weeks of treatment. NTX compliance, opioid-free urine samples, opioid craving as well as vital signs, subjective opioid withdrawal symptoms were assessed. Intent to treat analysis revealed significantly better control over opioid craving in the LFX/NTX vs PBO/NTX group (P < .03), but no differences between groups in NTX compliance, opioid use, and overall opioid craving. However, subject withdrawal due to medication intolerance was significantly higher in the LFX/NTX (5/26) vs PBO/NTX (0/31) (P < .01). Two additional patients were withdrawn due to acute hepatitis infection. Post hoc secondary analyses with the nonwithdrawn sample indicated significantly higher rates of treatment completion (P < .05) and NTX compliance (P < .01), lower percent opioid urine samples (P < .05), and lower overall opioid craving (P < .05) in the LFX/NTX vs the PBO/NTX group. Although preliminary, these findings suggest that LFX at doses up to 2.4 mg/daily was safe and improved control over opioid cravings. Among those who tolerated the medication, LFX/NTX significantly improved the opioid craving, delayed return to opioid use, and improved treatment compliance and completion rates. These findings support further assessment of LFX dose titration schedule along with the adjunctive use of LFX with NTX treatment to enhance opioid relapse prevention. (Am J Addict 2019;00:1-9).

Clinical Efficacy and Safety Profile of Lofexidine Hydrochloride in Treating Opioid Withdrawal Symptoms: A Review of Literature.

Opioid use disorder (OUD) is a rapidly growing challenge worldwide and is characterized by an increase in dependence on opioids up to a point that a person loses control over the drug use. Multiple drugs are approved for its treatment, including methadone, buprenorphine, and diazepam. Although not approved, clonidine is also used for the treatment of OUD. On May 16, 2018, the United States Food and Drug Administration (FDA) approved a new drug lofexidine hydrochloride for the treatment of opioid withdrawal symptoms. Lofexidine is a centrally acting alpha two receptor agonist. It reduces the neurochemical surge by inhibiting the conversion of adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP) which in turn decrease the sympathetic outflow. This results in the improvement of withdrawal symptoms. When compared with methadone and buprenorphine, it is equally effective in controlling withdrawal symptoms. Its efficacy is also similar to clonidine with a better side effects profile. The adverse effects of lofexidine include bradycardia, hypotension, orthostasis, somnolence, sedation, dry mouth, and rebound elevations in blood pressure and prolongation of QT interval. Lofexidine is contraindicated in patients who are on beta-blockers and angiotensin converting enzyme inhibitors (ACE inhibitors). In our review, we have discussed the clinical efficacy and safety profile of lofexidine in treating opioid withdrawal symptoms and its comparison to other available treatment options.

Differences in the Receptor Binding Profile of Lofexidine Compared to Clonidine

Lucemyra® (lofexidine hydrochloride) has recently been approved by the US FDA for the mitigation of withdrawal symptoms to facilitate abrupt discontinuation of opioids in adults. Lofexidine is an alpha-2 adrenoceptor agonist. However, the clinical attributes of lofexidine differ in advantageous ways from the classical alpha-2 adrenoceptor agonist clonidine. In the present study, we measured the receptor binding profile of lofexidine and clonidine in an effort to gain an insight into the clinical difference(s).

FDA approves lofexidine, drug that may ease Vivitrol induction

FDA approves lofexidine, drug that may ease Vivitrol induction

A phase III, randomized, multi-center, double blind, placebo controlled study of safety and efficacy of lofexidine for relief of symptoms in individuals undergoing inpatient opioid withdrawal

BackgroundLofexidine is an alpha-2-adrenergic receptor agonist approved in the United Kingdom (UK) for the treatment of opioid withdrawal symptoms. Lofexidine has demonstrated better efficacy than placebo for reducing opioid withdrawal symptoms in patients undergoing opioid withdrawal with less reported hypotension than clonidine. MethodsDesigned as an FDA registration trial, this 8-day, randomized, double-blind, placebo-controlled, parallel-group study in 264 patients dependent on short-acting opioids evaluated the efficacy of lofexidine hydrochloride in reducing withdrawal symptoms in patients undergoing opioid withdrawal. The primary efficacy measures were SOWS-Gossop on Day 3 and time-to-dropout. Secondary endpoints included the proportion of participants who were completers; area under the 5-day SOWS-Gossop – time curve (i.e., AUC1–5), and daily mean SOWS-Gossop, OOWS‐Handelsman, MCGI (subject and rater), and VAS-E scores. Participants received lofexidine HCl 3.2mg daily in four divided doses or matching placebo on Days 1–5, followed by 2days of placebo. ResultsLofexidine significantly decreased mean Day 3 SOWS scores compared to placebo, 6.32 versus 8.67, respectively, p=0.0212. Fewer lofexidine patients were early terminators compared to placebo (59 versus 80, respectively); and non-completers in the lofexidine group remained in the study longer than those assigned to placebo (p=0.0034). Secondary endpoints consistently favored lofexidine. Lofexidine was well tolerated in this trial. ConclusionLofexidine significantly decreased SOWS scores compared to placebo and demonstrated better retention rates in participants undergoing opioid withdrawal. Lofexidine potentially offers a useful non-opioid alternative to treat opioid withdrawal symptoms.

Effects of Alpha‐2 Norepinephrine Receptor Agonists on Cocaine Self‐Administration in Nonhuman Primate Models

Preclinical research has shown that drugs acting at alpha‐2 norepinephrine receptors can decrease stress‐induced reinstatement of cocaine self‐administration in rodents and stress‐induced cocaine craving in humans. Because stress can drive cocaine use, alpha‐2 receptor agonists such as lofexidine (LFX) may have utility in treating cocaine use disorder. In the only published study in nonhuman primates, acute LFX decreased cocaine self‐administration under a fixed‐ratio (FR) schedule, but chronic LFX treatment increased the reinforcing potency of cocaine (Kohut et al., Drug Alcohol Depend, 2013). To expand the range of conditions under which LFX has been studied, we examined effects of acute administration of LFX (0.03–3.0 mg/kg, i.v.) under several procedures in monkeys. More specifically, we examined LFX under conditions used to assess the reinforcing strength of cocaine using concurrent (choice) and progressive‐ratio (PR) schedules of reinforcement. Group‐housed male (n=8) and female (n=4) cynomolgus monkeys self‐administered cocaine under a food‐drug choice procedure. Under this paradigm, ascending cocaine doses (0.0, 0.003, 0.01, 0.03, 0.1 mg/kg per i.v. injection) were available as the alternative to a food pellet under a concurrent fixed‐ratio schedule in successive components of each daily session. Thus, a complete cocaine dose‐effect curve was determined each day. Under these conditions, LFX decreased choice of at least one cocaine dose in 5 of 8 male monkeys and 2 of 4 females; other monkeys were unaffected. In male monkeys, another alpha‐2 receptor agonist, guanfacine (0.01–1.0 mg/kg, i.v.), produced similar effects. In contrast, in 3 male rhesus monkeys, acute and chronic treatment with LFX increased choice of low cocaine doses. In addition, in 5 rhesus monkeys responding under a multiple FR food, PR cocaine schedule, LFX increased cocaine injections at doses that did not affect food‐reinforced responding. Taken together, these data indicate a limited effectiveness of alpha‐2 receptor agonists to decrease ongoing cocaine self‐administration. However, the potential of this class of drugs to reduce relapse in abstinent individuals should be studied further in models that specifically assess such effects.Support or Funding InformationDA10584, DA 17763, DA 06634

Psychometric evaluation of the 10-item Short Opiate Withdrawal Scale-Gossop (SOWS-Gossop) in patients undergoing opioid detoxification

IntroductionThe Short Opiate Withdrawal Scale (SOWS)-Gossop is a 10-item questionnaire developed to evaluate opioid withdrawal symptom severity. The scale was derived from the original 32-item Opiate Withdrawal Scale in order to reduce redundancy while providing an equally sensitive measure of opioid withdrawal symptom severity appropriate for research and clinical practice. The objective of this study was to examine the psychometric properties and provide score interpretation guidelines for the SOWS-Gossop 10-item version. MethodsBlinded, pooled data from two trials assessing the efficacy of lofexidine hydrochloride in reducing withdrawal symptoms in patients undergoing opioid detoxification were used to evaluate the quantitative psychometric properties and score interpretation of the SOWS-Gossop. ResultsFive hundred fifty-five (N=555) observations were available at baseline with numbers decreasing to n=213 at day 7. Mean (standard deviation) SOWS-Gossop scores were 10.4 (6.86) at baseline, 8.7 (6.49) on day 1, 10.5 (7.21) on day 2, and 3.1 (3.95) on day 7. Confirmatory factor analysis indicated that the SOWS-Gossop items loaded on a single factor consistent with a single total score. Intra-class correlations (95% confidence interval) were 0.78 (0.70–0.85) between baseline and day 1, 0.84 (0.79–0.89) between days 4 and 5, and 0.88 (0.83–0.91) between days 6 and 7, demonstrating good test-retest reliability. Mean SOWS-Gossop scores varied significantly (p<0.0001) by Modified Clinical Global Impression severity groups supporting known-groups validity. Most correlations with conceptually similar instruments were over 0.4, providing evidence of construct validity. Results suggest that a change score of approximately 2–4 points is likely a small but meaningful improvement on the SOWS-Gossop Total Score. ConclusionsThe findings of this study indicate that the SOWS-Gossop includes concepts that are relevant to patients' experiences with opioid withdrawal and has excellent psychometric properties. The SOWS-Gossop is an appropriate, precise, and sensitive measure to evaluate the symptoms of acute opioid withdrawal in research or clinical settings.

A Scalable, Enantioselective Synthesis of the α2-Adrenergic Agonist, Lofexidine

A scalable and high-yielding synthetic route toward pure enantiomers of the α2-adrenergic agonist, lofexidine hydrochloride, is presented. Salient features include a rapid one-pot amide alkylation-imidazoline formation sequence on the carboxamide function of α-(2,6-dichlorophenoxy)propionamide, while preserving the sensitive configuration about the α-carbon of the resulting product. A means to accelerate the sluggish O-alkylation of the carboxamide function of α-(2,6-dichlorophenoxy)propionamide by Me3O+BF4− is also described, which may be of general applicability.

Pharmacokinetics of Lofexidine Hydrochloride in Healthy Volunteers

The objective of this study was to characterize the clinical pharmacokinetic profile of lofexidine after oral delivery. A single dose, cross-over study and a multidose study using healthy volunteers were conducted for that purpose. In the single dose study the average time to maximum concentration was observed at approximately 3h for the single doses tested (1.2mg dose and 2.0mg). Area under the curve from time zero to infinity (AUC0−∞) demonstrated a degree of dose proportionality with a 1.72-fold increase as the dose increased by a factor of 1.67. Elimination rates and terminal half-lives were comparable between dose levels. The average elimination rates for the 1.2mg and the 2.0mg doses were 0.063 and 0.065h−1, respectively. In the multidose study, the average maximum concentration observed after the first dose of 0.4mg was 433 ng/L and ranged from 338 to 586 ng/L. This was slightly lower in proportion to the maximum concentration observed in the single dose study where Cmax was 1755 ng/L at the 1.2mg dose (normalized to 585 ng/L for 0.4mg dose) and for the 2.0mg dose (normalized to 559 ng/L for 0.4mg dose). The average time to maximum concentration (Tmax) was 3.33h which is comparable to values observed in the single dose study. The pharmacokinetic data indicate that lofexidine has a consistent profile. Steady state seems to be reached after 2 days on lofexidine, which is consistent with the lofexidine elimination half-life of approximately 11h. Evaluation of the Tmax, elimination rate, and terminal half-life are consistent across all dose levels studied, suggesting that changing the dose does not affect the absorption or elimination rates of lofexidine HCl. Thus, although preliminary due to the limited number of subjects, these findings are the first to document lofexidine clinical pharmacokinetic parameters in healthy volunteers using a highly sensitive liquid chromatography tandem mass spectrometric analysis. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:319–326, 2009

Urine and Plasma Pharmacokinetics of Lofexidine after Oral Delivery in Opiate-Dependent Patients

Objectives: The objective of this study was to investigate lofexidine urine and plasma pharmacokinetics using three different dosing regimens in opioid dependent subjects. To date, there have been no published studies on lofexidine appearance and excretion in urine of opioid dependent subjects. Methods: Subjects were stabilized with 100 mg morphine sulphate on days 3–8 of the study. The dosing regimens of lofexidine hydrochloride were .8 mg twice a day (BID), 1.2 mg BID, or .8 mg three times a day (TID) on days 9 through 16 of the study. Plasma and urine samples were collected at appropriate time points. Area under the concentration-time curve (AUC), maximum concentration in plasma (Cmax), time when maximum concentration was reached (Tmax) and fraction excreted unchanged in urine (Fe) were calculated. Results: The average half-life obtained from all profiles was 12.1 ± 6.3 hr. Steady-state (SS) was reached by study day 15. The plasma pharmacokinetic parameters for 1.2 mg BID and .8 mg TID dosing regimens did not seem to be different at steady state (day 15). Tmax was not statistically significantly different across dosing regimens. Fe values ranged between .01% and 34% with high variability within the same dosing regimen. For the total dose of 2.4 mg/day the two dosing regimens that were evaluated, namely 1.2 mg BID and .8 mg TID, did not show a significant statistical difference in plasma and urine pharmacokinetic parameters. Conclusion: Although preliminary due to the limited number of subjects, these findings are the first to document lofexidine urine pharmacokinetics in opiate addicts using a highly sensitive liquid chromatography tandem mass spectrometric analysis.

Randomized placebo controlled trial of lofexidine hydrochloride for chronic pelvic pain in women

We hypothesised that the orally-active alpha(2)-adrenoceptor agonist lofexidine hydrochloride would ameliorate chronic pelvic pain in women. A randomized placebo-controlled parallel group trial was undertaken in the University Hospital Gynaecology Clinic. Women with pelvic pain of at least 6 months duration were eligible, and were randomized using a sealed envelope system to receive up to 600 mg lofexidine hydrochloride twice daily over 8 weeks or placebo. Outcome measures were summary and daily diary visual analog scales for pain (VAS) and a 5 point self rating scale. 9/19 women randomized to lofexidine completed the study compared to 14/20 of those randomized to placebo. Intention-to-treat analysis showed that 4/19 in the lofexidine group achieved 50% or greater reduction in VAS compared with 8/20 in the placebo group (OR 2.5, 95% CI 0.6--10.3). Summary and diary VAS were closely correlated. Within the limits of a small study with power to detect only a substantial effect, we conclude that lofexidine hydrochloride is not effective for the treatment of chronic pelvic pain.

Audit of the in-patient management of opioid withdrawal using lofexidine hydrochloride

Over a period of 24 months, data were collected on 214 opioid detoxifications (190 patients), based on lofexidine hydrochloride. A mean maximum daily dose of 2.1 mg lofexidine was achieved by day 4 of admission. This was associated with a small fall in systolic and diastolic blood pressure, and 16% patients required adjustment to the daily dose of lofexidine or the withholding of doses. Seventy-five percent of patients were given adjunctive prescription of diazepam, and approximately a half required analgesics. By week I (day 8), 81 (37.9%) patients remained in treatment. Lofexidine appears to be a useful treatment for opioid detoxification, subject to certain limitations, and, despite a more marked reduction in both systolic and diastolic pressure than has previously been reported, hypotension does not appear to limit its usefulness—at least in an in-patient setting. Induction of lofexidine may proceed more rapidly, and to a higher dosage, than currently recommended, without any apparent widespread problems.

Pharmacologic Interventions for the Treatment of Opioid Dependence and Withdrawal

This article discusses current pharmacologic methods in the treatment of heroin dependence and withdrawal. Methadone hydrochloride, the most commonly used opiate agonist, is used for both withdrawal and maintenance therapy. However, it produces dependence and withdrawal results upon abrupt discontinuation. Other opiate agonists including L-alpha acetyl methadyl (LAAM) and propoxyphene napsylate have been used for both withdrawal and maintenance therapy. LAAM is currently available only as an investigational agent and propoxyphene is easily accessible but has been associated with hallucinations and dysphoria at high doses. Alpha 2-adrenergic agonists decrease opiate withdrawal symptoms by decreasing the central adrenergic hyperarousal that is associated with withdrawal. Clonidine effectively attenuates but does not totally eliminate withdrawal symptoms. Other alpha 2-adrenergic agonists (e.g., lofexidine hydrochloride, guanfacine hydrochloride, and guanabenz) have undergone only preliminary investigations. Although alpha 2 agonists effectively decrease most withdrawal symptoms they often cause hypotension. Buprenorphine hydrochloride is a partial opiate agonist that shows some promise in the treatment of the heroin-dependent population. It attenuates opiate craving and causes only minimal withdrawal upon abrupt discontinuation. Because it is well accepted by the heroin-dependent population, however, it may ultimately become an abused substance. Naltrexone is a potent, orally acting opiate antagonist that blocks all opiate-agonist effects and causes no euphoria. Unfortunately, it has not been well accepted by the heroin-dependent population. Scant research has been conducted concerning the use of adjunctive medications during opioid withdrawal.

Biotransformation of lofexidine in humans.

1. Concentrations of unchanged drug and patterns of radioactive components in urine have been determined by h.p.l.c. following single oral doses of [14C]lofexidine hydrochloride (0.32 mg) to six human subjects. 2. A mean of 12% of the administered dose was excreted in urine as unchanged lofexidine, but the wide range (5-20% dose) indicated significant intersubject variation in the extent of biotransformation. This drug would appear to be metabolized more extensively than the related anti-hypertensive agent, clonidine. 3. The principal metabolite of lofexidine was 2,6-dichlorophenol, which was apparently excreted in urine as two O-glucuronic acid conjugates. The same two metabolites were also the main 14C components circulating in plasma at peak 14C concn. Formation of the phenol from lofexidine probably involved direct O-dealkylation rather than stepwise degradation of the side-chain. 4. Patterns of 3H components in the urine of rats and dogs after oral administration of [3H]lofexidine hydrochloride (0.1 mg/kg) were generally similar to those in human urine.