Mechanism of action<unk>  induces analgesic effects through a variety of different targets on the noradrenergic system, serotoninergic system and opioid receptors system.<unk>  exists as a racemic mixture, the positive enantiomer inhibits serotonin reuptake while the negative enantiomer inhibits noradrenaline re-uptake, by binding to and blocking the transporters.<unk>  has also been shown to act as a serotonin releasing agent. Both enantiomers of<unk>  are agonists of the μ-opioid receptor and its M1 metabolite, O-desmetramadol, is also a μ-opioid receptor agonist but is 6 times more potent than<unk>  itself. All these effects work synergistically to induce analgesia. +<unk>  (and metabolite) Site<unk>  Species Ref 1,600–12,4862,120–8,300≥1,000 (EC50) 5.4–18.617 ()≥240 (EC50) HumanRatHuman >10,00057,600–100,000 ≥2,900690 ) HumanRat >10,00042,700–81,000 ≥4501,800 ) HumanRat ~900 (IC50)992–1,190 >20,000 (IC50)2,980 () (IC50) HumanRat 14,600785 1,080 (IC50) >860 (IC50) HumanRat >100,000 >20,000 Rat 5-HT1A >20,000 >20,000 Rat 5-HT2A >20,000 >20,000 Rat 5-HT2C 1,000 (IC50) 1,300 (IC50) Rat 5-HT3 >20,000 >20,000 Rat NK1 ? Rat M1 >20,0003,400 (IC50) >20,0002,000 (IC50) RatMultiple M2 M3 1,000 (IC50) Human M4 M5 α7 7,400 Chicken σ1 >10,000 Rat σ2 >10,000 Rat 16,400 (IC50) 16,500 (IC50) Human (MK-801) >20,000 >20,000 Rat >100,000 (IC50) >100,000 (IC50) Human >100,000 (IC50) >100,000 (IC50) Human 100–10,000 () 1,000–10,000 () Human >10,000 (IC50) >10,000 (IC50) Human Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site. +<unk>  and mono-amine reuptake/release Action Value reuptake 1,820 release >10,000 reuptake 2,770 release >10,000 reuptake >10,000 release >10,000 Values for reuptake inhibition are Ki (nM) and for release induction are EC50 (nM).<unk>  has been found to possess these actions: * Agonist of the μ-opioid receptor (MOR) and to a far lesser extent of the δ-opioid receptor (DOR) and κ-opioid receptor (KOR) * Serotonin reuptake inhibitor (SRI) and norepinephrine reuptake inhibitor; hence, an SNRI * Serotonin 5-HT2C receptor antagonist * M1 and M3 muscarinic acetylcholine receptor antagonist * α7 nicotinic acetylcholine receptor antagonist * NMDA receptor antagonist (very weak) * TRPA1 inhibitor<unk>  acts on the opioid receptors through its major active metabolite desmetramadol, which has as much as 700-fold higher affinity for the MOR relative to<unk> . Moreover,<unk>  itself has been found to possess no efficacy in activating the MOR in functional activity assays, whereas desmetramadol activates the receptor with high intrinsic activity (Emax equal to that of morphine). As such, desmetramadol is exclusively responsible for the opioid effects of<unk> . Both<unk>  and desmetramadol have pronounced selectivity for the MOR over the DOR and KOR in terms of binding affinity.<unk>  is well-established as an SRI. In addition, a few studies have found that it also acts as a serotonin releasing agent (1–10 μM), similar in effect to fenfluramine. The serotonin releasing effects of<unk>  could be blocked by sufficiently high concentrations of the serotonin reuptake inhibitor 6-nitroquipazine, which is in accordance with other serotonin releasing agents such as fenfluramine and MDMA. However, two more recent studies failed to find a releasing effect of<unk>  at respective concentrations up to 10 and 30 μM. In addition to serotonergic activity,<unk>  is also a norepinephrine reuptake inhibitor. It is not a norepinephrine releasing agent.<unk>  does not inhibit the reuptake or induce the release of dopamine. A positron emission tomography imaging study found that single oral 50-mg and 100-mg doses of<unk>  to human volunteers resulted in 34.7% and 50.2% respective mean occupation of the serotonin transporter (SERT) in the thalamus. The estimated median effective dose (ED50) for SERT occupancy hence was 98.1 mg, which was associated with a plasma<unk>  level of about 330 ng/ml (1,300 nM). The estimated maximum daily dosage of<unk>  of 400 mg (100 mg ) would result in as much as 78.7% occupancy of the SERT (in association with a plasma concentration of 1,220 ng/ml or 4,632 nM). This is close to that of SSRIs, which occupy the SERT by 80% or more. Peak plasma concentrations during treatment with clinical dosages of<unk>  have generally been found to be in the range of 70 to 592 ng/ml (266–2,250 nM) for<unk>  and 55 to 143 ng/ml (221–573 nM) for desmetramadol. The highest levels of<unk>  were observed with the maximum oral daily dosage of 400 mg per day divided into one 100-mg dose every 6 hours (i.e., four 100-mg doses evenly spaced out per day). Some accumulation of<unk>  occurs with chronic administration; peak plasma levels with the maximum oral daily dosage (100 mg ) are about 16% higher and the area-under-the-curve levels 36% higher than following a single oral 100-mg dose. Positron emission tomography imaging studies have reportedly found that<unk>  levels are at least four-fold higher in the brain than in plasma. Conversely, brain levels of desmetramadol "only slowly approach those in plasma". The plasma protein binding of<unk>  is only 4 to 20%; hence, almost all<unk>  in circulation is free, thus bioactive. Correspondence to effects Co-administration of quinidine, a potent CYP2D6 enzyme inhibitor, with<unk> , a combination which results in markedly reduced levels of desmetramadol, was found not to significantly affect the analgesic effects of<unk>  in human volunteers. However, other studies have found that the analgesic effects of<unk>  are significantly decreased or even absent in CYP2D6 poor metabolizers. The analgesic effects of<unk>  are only partially reversed by naloxone in human volunteers, hence indicating that its opioid action is unlikely the sole factor;<unk> 's analgesic effects are also partially reversed by α2-adrenergic receptor antagonists such as yohimbine, the 5-HT3 receptor antagonist ondansetron, and the 5-HT7 receptor antagonists SB-269970 and SB-258719. Pharmacologically,<unk>  is similar to tapentadol and methadone in that it not only binds to the MOR, but also inhibits the reuptake of serotonin and norepinephrine due to its action on the noradrenergic and serotonergic systems, such as its "atypical" opioid activity.<unk>  has inhibitory actions on the 5-HT2C receptor. Antagonism of 5-HT2C could be partially responsible for<unk> 's reducing effect on depressive and obsessive–compulsive symptoms in patients with pain and co-morbid neurological illnesses. 5-HT2C blockade may also account for its lowering of the seizure threshold, as 5-HT2C knockout mice display significantly increased vulnerability to epileptic seizures, sometimes resulting in spontaneous death. However, the reduction of seizure threshold could be attributed to<unk> 's putative inhibition of GABAA receptors at high doses (significant inhibition at 100 μM). In addition, desmetramadol is a high-affinity ligand of the DOR, and activation of this receptor could be involved in<unk> 's ability to provoke seizures in some individuals, as DOR agonists are well known for inducing seizures. Nausea and vomiting caused by<unk>  are thought to be due to activation of the 5-HT3 receptor via increased serotonin levels. In accordance, the 5-HT3 receptor antagonist ondansetron can be used to treat<unk> -associated nausea and vomiting.<unk>  and desmetramadol themselves do not bind to the 5-HT3 receptor. Pharmacokinetics Desmetramadol.<unk>  undergoes hepatic metabolism via the cytochrome P450 isozyme CYP2B6, CYP2D6, and CYP3A4, being O- and N-demethylated to five different metabolites. Of these, desmetramadol (O-desmethyltramadol) is the most significant, since it has 200 times the μ-affinity of (+)-tramadol, and furthermore has an elimination half-life of 9 hours, compared with 6 hours for<unk>  itself. As with codeine, in the 6% of the population who have reduced CYP2D6 activity (hence reducing metabolism), a reduced analgesic effect is seen. Those with decreased CYP2D6 activity require a dose increase of 30% to achieve the same degree of pain relief as those with a normal level of CYP2D6 activity. Phase II hepatic metabolism renders the metabolites water-soluble, which are excreted by the kidneys. Thus, reduced doses may be used in renal and hepatic impairment. Its volume of distribution is around 306 l after oral administration and 203 l after parenteral administration.
Tramadol
Tapentadol
Desmetramadol
Hydrocodone
Etodolac
Ketorolac
Oxycodone
Acetylmethadol