Dezocine

History

Dezocine was patented by American Home Products Corp. in 1978. Clinical trials ran from 1979-1985, before its approval by the U.S. Food and Drug Administration (FDA) in 1986. As of 2011, dezocine's usage is discontinued in the United States.

Synthesis

Dezocine [(−)-13β-amino-5,6,7,8,9,10,11,12-octahydro-5α-methyl-5,11-methanobenxocyclodecen-31-ol, hydrobromide] is a pale white crystal powder. It has no apparent odor. The salt is soluble at 20 mg/ml, and a 2% solution has a pH of 4.6.

The synthesis of dezocine begins with the condensation of 1-methyl-7-methoxy-2-tetralone with 1,5-dibromopentane through use of NaH or potassium tertbutylate. This yields 1-(5-bromopentyl)-1-methyl-7-methoxy-2-tetralone, which is then cyclized with NaH to produce 5-methyl-3-methoxy-5,6,7,8,9,10,11,12-octahydro-5,11-methanobenzocyclodecen-13-one. The product is then treated with hydroxylamine hydrochloride, to yield an oxime. A reduction reaction in hydrogen gas produces an isomeric mixture, from which the final product is crystallized and cleaved with HBr.

Legal status in United States

As of 2011, dezocine is not used in the United States or Canada. It is not commercially available in either of these countries, nor is it offered as a prescribed analgesic for postoperative care. In China however, it is commonly used after surgery.

Target action

Dezocine has an intramuscular bioavailability of 97%. It has a mean t_1/2 α of fewer than two minutes, and its half-life is 2.2 hours. Its binding affinity varies with regards to the receptor type, as it acts as a partial agonist primarily on mu-opioid receptors. At kappa-opioid receptors, it acts as an antagonist. Overall, it has a high efficacy as an analgesic.

With regards to its potency, it has a Bmax of 3326 fmol/mg of protein in HEK cells. Dezocine is five times as potent as pethidine and one-fifth as potent as butorphanol.

Dezocine is unusual among opiates as it is one of the only primary amines known to be an active opioid (along with bisnortilidine, an active metabolite of tilidine). It is a mixed agonist–antagonist as with other drugs in this class, and despite having a stronger respiratory depressant effect than morphine, dezocine shows a ceiling effect on its respiratory depressive action so above a certain dose this effect does not get any more severe.

Dezocine possesses affinities (K_i) of 3.7 nM, 31.9 nM, and 527 nM for the μ-, κ-, and δ-opioid receptors (MOR, KOR, and DOR), respectively. It is a partial agonist of the MOR and a silent antagonist of the KOR. In addition to its opioid actions, dezocine has been found to act as a serotonin-norepinephrine reuptake inhibitor (SNRI), with pIC₅₀ values of 5.86 for the serotonin transporter (SERT) and 5.68 for the norepinephrine transporter (NET).

Due to its partial agonist nature at the MOR, dezocine has significantly reduced side effects relative to opioid analgesics acting as full agonists of the MOR such as morphine. Moreover, dezocine is not a controlled substance and there are no reports of addiction related to its use, indicating that, unlike virtually all other clinically-employed MOR agonists (including weak partial agonists like buprenorphine) and for reasons that are not fully clear, it is apparently non-addictive.

Administration

Dezocine is generally administered intravenously. It can also be administered in intramuscular doses, and is given singularly rather than continuously. Dezocine has been found to be an effective painkiller comparable to meperidine (pethidine), and so is a more effective analgesic than pentazocine, but causes relatively more respiratory depression than pentazocine. It is a useful drug for the treatment of pain, but side effects such as dizziness limit its clinical application, and it can produce opioid withdrawal syndrome in patients already dependent on other opioids.

Prescription

Dezocine is generally administered intravenously (as Dalgan) to relieve post-operative pain in patients. Because of its high efficacy, it is often administered at a base dose of 0.1 mg/kg. Respiratory depression, a side-effect of dezocine, reaches a ceiling at 0.3-0.4 mg/kg. It has potent analgesic results, and greater pain-relieving ability than morphine, codeine, and pethidine.

Side effects

Because decozine has mixed agonist/antagonist effects on mu-, delta-, and kappa-opioid receptors, it has a lowered dependence potential than purely agonistic opiates. It can be prescribed, therefore, in small doses over an extended period of time without causing patients to develop and sustain an addiction. Its efficacy as an analgesic is dose-dependent; however, it displays a ceiling effect in induced respiratory depression at 0.3-0.4 mg/kg.

Side effects at lower doses include mild gastrointestinal discomfort and dizziness. It is often administered in post-operative laproscopy patients as an alternative to fentanyl.