Pharmacodynamics Opioid receptor blockade +<unk>  at human opioid receptors Affinities () Ratios Refs MOR:KOR:DOR 1.0 nM 3.9 nM 149 nM 1:4:149 0.0825 nM 0.509 nM 8.02 nM 1:6:97 0.2 nM 0.4 nM 10.8 nM 1:2:54 0.23 nM 0.25 nM 38 nM 1:1.1:165 0.62 nM 1.88 nM 12.3 nM 1:3:20 0.11 nM 0.19 nM 60 nM 1:1.7:545<unk>  and its active metabolite 6β-naltrexol are competitive antagonists of the opioid receptors.<unk>  is specifically an antagonist preferentially of the μ-opioid receptor (MOR), to a lesser extent of the κ-opioid receptor (KOR), and to a much lesser extent of the δ-opioid receptor (DOR). However,<unk>  is not actually a silent antagonist of these receptors but instead acts as a weak partial agonist, with Emax values of 14 to 29% at the MOR, 16 to 39% at the KOR, and 14 to 25% at the DOR in different studies. In accordance with its partial agonism, although<unk>  is described as a pure opioid receptor antagonist, it has shown some evidence of weak opioid effects in clinical and preclinical studies. By itself,<unk>  acts as an antagonist or weak partial agonist of the opioid receptors. In combination with agonists of the MOR such as morphine however,<unk>  appears to become an inverse agonist of the MOR. Conversely,<unk>  remains a neutral antagonist (or weak partial agonist) of the KOR and DOR. In contrast to<unk> , 6β-naltrexol is purely a neutral antagonist of the opioid receptors. The MOR inverse agonism of<unk>  when it is co-present with MOR agonists may in part underlie its ability to precipitate withdrawal in opioid-dependent individuals. This may be due to suppression of basal MOR signaling via inverse agonism. Occupancy of the opioid receptors in the brain by<unk>  has been studied using positron emission tomography (PET).<unk>  at a dose of 50 mg/day has been found to occupy approximately 90 to 95% of brain MORs and 20 to 35% of brain DORs.<unk>  at a dose of 100 mg/day has been found to achieve 87% and 92% brain occupancy of the KOR in different studies. Per simulation, a lower dose of<unk>  of 25 mg/day might be expected to achieve around 60% brain occupancy of the KOR but still close to 90% occupancy of the MOR. In a study of the duration of MOR blockade with<unk> , the drug with a single 50 mg dose showed 91%11Ccarfentanil (a selective MOR ligand) binding at 48 hours (2 days), 80% blockade at 72 hours (3 days), 46% blockade at 120 hours (5 days), and 30% blockade at 168 hours (7 days). The half-time of brain MOR blockade by<unk>  in this study was 72 to 108 hours (3.0 to 4.5 days). Based on these findings, doses of<unk>  of even less than 50 mg/day would be expected to achieve virtually complete brain MOR occupancy. Blockade of brain MORs with<unk>  is much longer-lasting than with other opioid antagonists like<unk> oxone (half-time of ~1.7 hours intranasally) or<unk> mefene (half-time of ~29 hours). The half-life of occupancy of the brain MOR and duration of clinical effect of<unk>  are much longer than suggested by its plasma elimination half-life. A single 50 mg oral dose of<unk>  has been found to block brain MORs and opioid effects for at least 48 to 72 hours. The half-time of brain MOR blockade by<unk>  (72–108 hours) is much longer than the fast plasma clearance component of<unk>  and 6β-naltrexol (~4–12 hours) but was reported to correspond well to the longer terminal phase of plasma<unk>  clearance (96 hours). As an alternative possibility, the prolonged brain MOR occupancy by opioid antagonists like<unk>  and<unk> mefene may be due to slow dissociation from MORs consequent to their very high MOR affinity (<1.0 nM).<unk>  blocks the effects of MOR agonists like morphine, heroin, and hydromorphone in humans via its MOR antagonism. Following a single 100 mg dose of<unk> , the subjective and objective effects of heroin were blocked by 90% at 24 hours, with blockade then decreasing up to 72 hours. Similarly, 20 to 200 mg<unk>  dose-dependently antagonized the effects of heroin for up to 72 hours.<unk>  also blocks the effects of KOR agonists like salvinorin A, pentazocine, and butorphanol in humans via its KOR antagonism. In addition to opioids,<unk>  has been found to block or reduce the rewarding and other effects of other euphoriant drugs including alcohol, nicotine, and amphetamines. The opioid receptors are involved in neuroendocrine regulation. MOR agonists produce increases in levels of prolactin and decreases in levels of luteinizing hormone (LH) and testosterone. Doses of<unk>  of 25 to 150 mg/day have been found to produce significant increases in levels of β-endorphin, cortisol, and LH, equivocal changes in levels of prolactin and testosterone, and no significant changes in levels of adrenocorticotrophic hormone (ACTH) or follicle-stimulating hormone (FSH).<unk>  influences the hypothalamic–pituitary–adrenal axis (HPA axis) probably through interference with opioid receptor signaling by endorphins. Blockade of MORs is thought to be the mechanism of action of<unk>  in the management of opioid dependence—it reversibly blocks or attenuates the effects of opioids. It is also thought to be involved in the effectiveness of<unk>  in alcohol dependence by reducing the euphoric effects of alcohol. The role of KOR modulation by<unk>  in its effectiveness for alcohol dependence is unclear but this action may also be involved based on theory and animal studies. Other activities In addition to the opioid receptors,<unk>  binds to and acts as an antagonist of the opioid growth factor receptor (OGFR) and toll-like receptor 4 (TLR4) and interacts with high- and low-affinity binding sites in filamin-A (FLNA). It is said that very low doses of<unk>  (<0.001–1 mg/day) interact with FLNA, low doses (1 to 5 mg/day) produce TLR4 antagonism, and standard clinical doses (50 to 100 mg/day) exert opioid receptor and OGFR antagonism. The interactions of<unk>  with FLNA and TLR4 are claimed to be involved in the therapeutic effects of low-dose<unk> . Pharmacokinetics steady state during treatment with 50 mg/day<unk> .<unk>  levels following a 380 mg dose of<unk>  in microspheres (Vivitrol) by intramuscular injection at steady state during monthly treatment with 380 mg<unk>  in microspheres. The absorption of<unk>  with oral administration is rapid and nearly complete (96%). The bioavailability of<unk>  with oral administration is 5 to 60% due to extensive first-pass metabolism. Peak concentrations of<unk>  are 19 to 44 μg/L after a single 100 mg oral dose and time to peak concentrations of<unk>  and 6β-naltrexol (metabolite) is within 1 hour. Linear increases in circulating<unk>  and 6β-naltrexol concentrations over an oral dose range of 50 to 200 mg.<unk>  does not appear to be accumulated with repeated once-daily oral administration and there is no change in time to peak concentrations with repeated administration. The plasma protein binding of<unk>  is about 20% over a<unk>  concentration range of 0.1 to 500 μg/L. Its apparent volume of distribution at 100 mg orally is 16.1 L/kg after a single dose and 14.2 L/kg with repeated doses.<unk>  is metabolized in the liver mainly by dihydrodiol dehydrogenases into 6β-naltrexol (6β-hydroxynaltrexone). Levels of 6β-naltrexol are 10- to 30-fold higher than those of<unk>  with oral administration due to extensive first-pass metabolism. Conversely, 6β-naltrexol exposure is only about 2-fold higher than that of<unk>  with intramuscular injection of<unk>  in microspheres (brand name Vivitrol). 6β-Naltrexol is an opioid receptor antagonist similarly to<unk>  and shows a comparable binding profile to the opioid receptors. However, 6β-naltrexol is peripherally selective and crosses into the brain much less readily than does<unk> . In any case, 6β-naltrexol does still show some central activity and may contribute significantly to the central actions of oral<unk> . Other metabolites of<unk>  include 2-hydroxy-3-methoxy-6β-naltrexol and 2-hydroxy-3-methoxynaltrexone. Following their formation, the metabolites of<unk>  are further metabolized by conjugation with glucuronic acid to form glucuronides.<unk>  is not metabolized by the cytochrome P450 system and has low potential for drug interactions. The elimination of<unk>  is biexponential and rapid over the first 24 hours followed by a third extremely slow decline after 24 hours. The fast elimination half-lives of<unk>  and its metabolite 6β-naltrexol are about 4 hours and 13 hours, respectively. In Contrave oral tablets, which also contain bupropion and are described as extended-release, the half-life of<unk>  is 5 hours. The slow terminal-phase elimination half-life of<unk>  is approximately 96 hours. As microspheres of<unk>  by intramuscular injection (Vivitrol), the elimination half-lives of<unk>  and 6β-naltrexol are both 5 to 10 days. Whereas oral<unk>  is administered daily,<unk>  in microspheres by intramuscular injection is suitable for administration once every 4 weeks or once per month.<unk>  and its metabolites are excreted in urine. Pharmacogenetics Tentative evidence suggests that family history and presence of the Asn40Asp polymorphism predicts<unk>  being effective.
Naltrexone
Normethadone
Isomethadone
Methadone
Buprenorphine
Guanfacine
Nabilone
Atomoxetine