A Phase 3 placebo-controlled, double-blind, multi-site trial of the alpha-2-adrenergic agonist, lofexidine, for opioid withdrawal☆

Yu, Elmer; Miotto, Karen; Akerele, Evaristo; Montgomery, Ann Elizabeth; Elkashef, Ahmed; Walsh, Robert J.; Montoya, Iván D.; Fischman, Marian W.; Collins, J. G.; McSherry, Frances

doi:10.1016/j.drugalcdep.2008.04.002

Cited by 59 publications

(44 citation statements)

References 39 publications

(47 reference statements)

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“…For instance, the clinical utility of the ␣ 2 AR agonist clonidine in opioid withdrawal has been known for some time (Gold et al, 1978), and ␣ 2 AR agonists are often used "off label" to treat or prevent opioid withdrawal. Furthermore, the ␣ 2 AR agonist lofexidine could become the first nonopiate U.S. Food and Drug Administration-approved treatment of opioid withdrawal (Yu et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

G_i/o-Coupled Receptors Compete for Signaling to Adenylyl Cyclase in SH-SY5Y Cells and Reduce Opioid-Mediated cAMP Overshoot

2010

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Organization of G protein-coupled receptors and cognate signaling partners at the plasma membrane has been proposed to occur via multiple mechanisms, including membrane microdomains, receptor oligomerization, and protein scaffolding. Here, we investigate the organization of six types of G i/o -coupled receptors endogenously expressed in SH-SY5Y cells. The most abundant receptor in these cells was the -opioid receptor (MOR), the activation of which occluded acute inhibition of adenylyl cyclase (AC) by agonists to ␦-opioid (DOR), nociceptin/orphanin FQ peptide (NOPr), ol]-enkephalin (DAMGO) also occluded the ability of DOR agonist to stimulate G proteins. However, at lower agonist concentrations and at shorter incubation times when G proteins were not limiting, the relationship between MOR and DOR agonists was additive. The additive relationship was confirmed by isobolographic analysis. Long-term coadministration of MOR and DOR agonists caused cAMP overshoot that was not additive, suggesting that sensitization of AC mediated by these two receptors occurs by a common pathway. Furthermore, heterologous inhibition of AC by agonists to DOR, NOPr, and ␣ 2 AR reduced the expression of cAMP overshoot in DAMGO-dependent cells. However, this cross-talk did not lead to heterologous tolerance. These results indicate that multiple receptors could be tethered into complexes with cognate signaling proteins and that access to shared AC by multiple receptor types may provide a means to prevent opioid withdrawal.

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Section: Discussionmentioning

confidence: 99%

G_i/o-Coupled Receptors Compete for Signaling to Adenylyl Cyclase in SH-SY5Y Cells and Reduce Opioid-Mediated cAMP Overshoot

2010

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“…Lofexidine is structurally related to clonidine but may have a greater selectivity for the subtype of α -2 receptors. Specifically, while lofexidine retains potent noradrenergic antagonist activity, which is useful in the alleviation of withdrawal, it has limited effect on the blood pressure (1,2,40,41). However, lofexidine can adversely affect cardiac conduction, particularly when given in combination with methadone; therefore close ECG monitoring is warranted.…”

Section: Regimens For Detoxification and Naltrexone Inductionmentioning

confidence: 99%

Opioid Detoxification and Naltrexone Induction Strategies: Recommendations for Clinical Practice

Sigmon

Bisaga

Nunes

et al. 2012

The American Journal of Drug and Alcohol Abuse

106

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Background Opioid dependence is a significant public health problem associated with high risk for relapse if treatment is not ongoing. While maintenance on opioid agonists (i.e., methadone, buprenorphine) often produces favorable outcomes, detoxification followed by treatment with the μ-opioid receptor antagonist naltrexone may offer a potentially useful alternative to agonist maintenance for some patients. Method Treatment approaches for making this transition are described here based on a literature review and solicitation of opinions from several expert clinicians and scientists regarding patient selection, level of care, and detoxification strategies. Conclusion Among the current detoxification regimens, the available clinical and scientific data suggest that the best approach may be using an initial 2–4 mg dose of buprenorphine combined with clonidine, other ancillary medications, and progressively increasing doses of oral naltrexone over 3–5 days up to the target dose of naltrexone. However, more research is needed to empirically validate the best approach for making this transition.

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“…The prototypical α-2R agonist clonidine blocks cocaine-induced activation, reinstatement of cocaine-seeking and stress-induced increases in craving measures in dependent individuals (Carey et al 2008; Jobes et al 2011). A newer α-2R agonist, lofexidine, also attenuates stress-induced reinstatement of cocaine-seeking in rats (Erb et al 2000; Highfield et al 2001) and decreases drug withdrawal and stress-induced craving in humans (Sinha et al 2007; Yu et al 2008). Recently, acute treatment with lofexidine was shown to significantly reduced cocaine self-administration in rhesus monkeys, however, chronic treatment produced a leftward shift in the cocaine self-administration dose-effect curve (Kohut et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Assessment of safety, cardiovascular and subjective effects after intravenous cocaine and lofexidine

Garza

Newton

Mendelson

et al. 2014

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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The primary objective of this study was to determine the safety of lofexidine, an α2 receptor agonist, alone and concurrent with cocaine in non-treatment seeking cocaine-dependent or cocaine-abusing participants. After screening, eligible participants received double-blind, randomized infusions of saline and 20 mg of cocaine on Day 1, and saline and 40 mg of cocaine on Day 2. Subjects were randomized and started receiving daily administration of placebo (N=4) or lofexidine on Day 3 and continued on this schedule until Day 7. Two dosing regimens for lofexedine were investigated: 0.8 QID (N=3) and 0.2 mg QID (N=11). On Days 6 and 7, subjects received double-blind infusions of saline and 20 mg of cocaine on Day 6, and saline and 40 mg of cocaine on Day 7. The data reveal a notable incidence of hemodynamic-related AEs over the course of the study. Two of the three participants at the 0.8 mg dose level discontinued, and five of 11 participants at the 0.2 mg dose level were withdrawn (or voluntarily discontinued) after hemodynamic AEs. Subjective effects and cardiovascular data were derived from all participants who were eligible to receive infusions (i.e., did not meet stopping criteria) on Days 6 and 7 (6 received lofexidine 0.2 mg, QID and 4 received placebo, QID). As expected, cocaine significantly increased heart rate and blood pressure, as well as several positive subjective effects. There was a trend for lofexidine to decrease cocaine-induced cardiovascular changes and cocaine-induced ratings for "Any Drug Effect", "Good Effects", and “Desire Cocaine”, but sample size issues limit the conclusions that can be drawn. Despite the trends to reduce cocaine-induced subjective effects, cardiovascular AEs may limit future utility of lofexidine as a treatment for this population.

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A Phase 3 placebo-controlled, double-blind, multi-site trial of the alpha-2-adrenergic agonist, lofexidine, for opioid withdrawal☆

Abstract: Lofexidine is well tolerated and more efficacious than placebo for reducing opioid withdrawal symptoms in inpatients undergoing medically supervised opioid detoxification.

Cited by 59 publications

References 39 publications

G_i/o-Coupled Receptors Compete for Signaling to Adenylyl Cyclase in SH-SY5Y Cells and Reduce Opioid-Mediated cAMP Overshoot

G_i/o-Coupled Receptors Compete for Signaling to Adenylyl Cyclase in SH-SY5Y Cells and Reduce Opioid-Mediated cAMP Overshoot

Opioid Detoxification and Naltrexone Induction Strategies: Recommendations for Clinical Practice

Assessment of safety, cardiovascular and subjective effects after intravenous cocaine and lofexidine

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A Phase 3 placebo-controlled, double-blind, multi-site trial of the alpha-2-adrenergic agonist, lofexidine, for opioid withdrawal☆

Abstract: Lofexidine is well tolerated and more efficacious than placebo for reducing opioid withdrawal symptoms in inpatients undergoing medically supervised opioid detoxification.

Cited by 59 publications

References 39 publications

Gi/o-Coupled Receptors Compete for Signaling to Adenylyl Cyclase in SH-SY5Y Cells and Reduce Opioid-Mediated cAMP Overshoot

Gi/o-Coupled Receptors Compete for Signaling to Adenylyl Cyclase in SH-SY5Y Cells and Reduce Opioid-Mediated cAMP Overshoot

Opioid Detoxification and Naltrexone Induction Strategies: Recommendations for Clinical Practice

Assessment of safety, cardiovascular and subjective effects after intravenous cocaine and lofexidine

Contact Info

Product

Resources

About

G_i/o-Coupled Receptors Compete for Signaling to Adenylyl Cyclase in SH-SY5Y Cells and Reduce Opioid-Mediated cAMP Overshoot

G_i/o-Coupled Receptors Compete for Signaling to Adenylyl Cyclase in SH-SY5Y Cells and Reduce Opioid-Mediated cAMP Overshoot