I went to the Abstract where this compound is described:
-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel mu-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties.
Tzschentke TM, Christoph T, Kögel B, Schiene K, Hennies HH, Englberger W, Haurand M, Jahnel U, Cremers TI, Friderichs E, De Vry J.
ABSTRACT
()-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol
hydrochloride (tapentadol HCl) is a novel -opioid receptor
(MOR) agonist (Ki 0.1 M; relative efficacy compared with
morphine 88% in a [35S]guanosine 5-3-O-(thio)triphosphate
binding assay) and NE reuptake inhibitor (Ki 0.5 M for
synaptosomal reuptake inhibition). In vivo intracerebral microdialysis
showed that tapentadol, in contrast to morphine, produces
large increases in extracellular levels of NE (450% at
10 mg/kg i.p.). Tapentadol exhibited analgesic effects in a wide
range of animal models of acute and chronic pain [hot plate,
tail-flick, writhing, Randall-Selitto, mustard oil colitis, chronic
constriction injury (CCI), and spinal nerve ligation (SNL)], with
ED50 values ranging from 8.2 to 13 mg/kg after i.p. administration
in rats. Despite a 50-fold lower binding affinity to MOR, the
analgesic potency of tapentadol was only two to three times
lower than that of morphine, suggesting that the dual mode of
action of tapentadol may result in an opiate-sparing effect. A
role of NE in the analgesic efficacy of tapentadol was directly
demonstrated in the SNL model, where the analgesic effect of
tapentadol was strongly reduced by the 2-adrenoceptor antagonist
yohimbine but only moderately attenuated by the MOR
antagonist naloxone, whereas the opposite was seen for morphine.
Tolerance development to the analgesic effect of tapentadol
in the CCI model was twice as slow as that of morphine.
It is suggested that the broad analgesic profile of tapentadol
and its relative resistance to tolerance development may be
due to a dual mode of action consisting of both MOR activation
and NE reuptake inhibition.
This abstract suggests that the risk of RD is attenuated because much of the analgesic effect is mediated by NE receptor activation, which is corroborated by the slower rate of tolerance development.
My hope is that this compound will at best claim the chronic pain management market, without affecting cor's prospects in post-operative RD. Still for me it is a real wake-up call, in that I hadn't considered the possibility that cor might get scooped. Certainly, if this drug is approved for chronic use, the manufacturer shouldn't have too hard a time expanding its use to the post-operative arena.
AI
