Dezocine

Medical uses

Dezocine is generally administered intravenously (as Dalgan) to relieve post-operative pain in patients. It can also be administered in intramuscular doses, and is given once rather than continuously. It is often administered in post-operative laparoscopy patients as an alternative to fentanyl. Dezocine has potent analgesic effects, and comparable or greater pain-relieving ability than morphine, codeine, and pethidine (meperidine). It is a more effective analgesic than pentazocine, but causes relatively more respiratory depression. Dezocine 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. Because of its high efficacy, dezocine 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 to 0.4 mg/kg.

Side effects

Side effects at lower doses include mild gastrointestinal discomfort and dizziness. Because decozine has mixed agonist/antagonist effects at the opioid receptors, it has a lowered dependence potential than purely agonistic opioids. 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 to 0.4 mg/kg.

Pharmacology

Pharmacodynamics

Dezocine acts as an opioid receptor receptor modulator. It is specifically a mixed agonist–antagonist or partial agonist of the μ- and κ-opioid receptors. It is a biased agonist of the μ-opioid receptor and activates G protein signaling but not the β-arrestin pathway. This may account for some of dezocine's unique and atypical pharmacological properties. The binding affinity of dezocine varies depending on the opioid receptor, with the drug having the highest affinity for the μ-opioid receptor, intermediate affinity for the κ-opioid receptor, and the lowest affinity for the δ-opioid receptor. In addition to its opioid activity, 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). These actions theoretically might contribute to its analgesic efficacy.

Dezocine is five times as potent as pethidine and one-fifth as potent as butorphanol as an analgesic. Due to its partial agonist nature at the μ-opioid receptor, dezocine has significantly reduced side effects relative to opioid analgesics acting as full agonists of the receptor 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 μ-opioid receptor agonists (including weak partial agonists like buprenorphine), and for reasons that are not fully clear, it is apparently non-addictive. This unique benefit makes long-term low-dose treatment of chronic pain and/or opioid dependence with dezocine more feasible than with most other opioids. 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.

Pharmacokinetics

Dezocine has a bioavailability by intramuscular injection of 97%. It has a mean t1/2α of fewer than two minutes, and its biological half-life is 2.2 hours.

Chemistry

Dezocine has a structure similar to the benzomorphan group of opioids. Dezocine is unusual among opioids as it is one of the only primary amines known to be active as an opioid (along with bisnortilidine, an active metabolite of tilidine).

Synthesis

Dezocine [(−)-13β-amino-5,6,7,8,9,10,11,12-octahydro-5α-methyl-5,11-methanobenzocyclodecen-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 tert-butoxide. 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.

History

Dezocine was patented by American Home Products Corp. in 1978. Clinical trials ran from 1979 to 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, but it is still widely used in some other countries such as China.

Society and culture

Generic names

Dezocine is the generic name of the drug and its and .

Brand names

The major brand name of dezocine is Dalgan.

Availability

In 2000, dezocine was listed as being marketed only in the United States. It has since been marketed in China. Dezocine was discontinued in the United States in 2011.

Legal status

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.

Research

Depression

Dezocine shows antidepressant-like effects in animals. Its antidepressant-like effects in animals appear to be dependent on activation of serotonin 5-HT1A receptors and inhibition of κ-opioid receptors (KORs) but not on activation of the μ-opioid receptor. A clinical trial found that dezocine added to sufentanil for postoperative analgesia significantly reduced depressive symptoms in people undergoing colorectal cancer surgery relative to sufentanil alone. There is a case report of a single incidental dose of dezocine resulting in rapid and sustained improvement in depression, anhedonia, and motivational deficits in a woman with treatment-resistant depression. On the basis of the preceding findings, there is interest in dezocine as a potential antidepressant in the treatment of depression, for instance in people with opioid use disorder.

References

References

1. (August 1989). "Dezocine. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy". Drugs.
2. (June 2021). ""I'll Be Back": The Resurrection of Dezocine". ACS Med Chem Lett.
3. (April 1992). "Subjective, behavioral, and physiologic responses to intravenous dezocine in healthy volunteers". Anesthesia and Analgesia.
4. (August 1991). "Opioid agonist-antagonists". Current Opinion in Anesthesiology.
5. "Espacenet".
6. (1979). "Analgesic properties of dezocine for relief of postoperative pain". Acta Anaesthesiologica Belgica.
7. (April 1979). "The respiratory effects of dezocine and pentazocine in man". Journal of Clinical Pharmacology.
8. (1980). "Preliminary clinical experience with dezocine, a new potent analgesic". Current Medical Research and Opinion.
9. (August 1996). "Opioid antagonist effects of dezocine in opioid-dependent humans". Clinical Pharmacology and Therapeutics.
10. (March 2014). "Novel molecular targets of dezocine and their clinical implications". Anesthesiology.
11. (September 2018). "Pharmacological Characterization of Dezocine, a Potent Analgesic Acting as a κ Partial Agonist and μ Partial Agonist". Sci Rep.
12. (January 2006). "Pharmacological profiles of opioid ligands at kappa opioid receptors". BMC Pharmacology.
13. (April 1984). "Reinforcing and discriminative stimulus properties of mixed agonist-antagonist opioids". The Journal of Pharmacology and Experimental Therapeutics.
14. (February 2017). "Dezocine exhibits antihypersensitivity activities in neuropathy through spinal μ-opioid receptor activation and norepinephrine reuptake inhibition". Scientific Reports.
15. (March 1984). "Ceiling respiratory depression by dezocine". Clinical Pharmacology and Therapeutics.
16. (1986). "Pharmacokinetics of dezocine, a new analgesic: effect of dose and route of administration". European Journal of Clinical Pharmacology.
17. (September 1975). "Animal pharmacology of Wy-16,225, a new analgesic agent". The Journal of Pharmacology and Experimental Therapeutics.
18. (June 1973). "Bridged aminotetralins as novel potent analgesic sunstances". Journal of Medicinal Chemistry.
19. "FDA Drugs".
20. (June 2017). "Comparison of the efficacy and safety between dezocine injection and morphine injection for persistence of pain in Chinese cancer patients: a meta-analysis". Bioscience Reports.
21. (14 November 2014). "The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies". Springer.
22. (2012). "Concise Dictionary of Pharmacological Agents: Properties and Synonyms". Springer Science & Business Media.
23. (2005). "Medicinal Chemistry". New Age International.
24. Swiss Pharmaceutical Society. (2000). "Index Nominum 2000: International Drug Directory". Taylor & Francis.
25. (January 2003). "Activity of opioid ligands in cells expressing cloned mu opioid receptors". BMC Pharmacology.
26. (September 2024). "Revisiting dezocine for opioid use disorder: A narrative review of its potential abuse liability". CNS Neurosci Ther.
27. (May 2023). "Defensive and Emotional Behavior Modulation by Serotonin in the Periaqueductal Gray". Cell Mol Neurobiol.
28. (September 2021). "Antidepressant-like effects of dezocine in mice: involvement of 5-HT1A and κ opioid receptors". Behav Pharmacol.
29. (2020). "Postoperative analgesia using dezocine alleviates depressive symptoms after colorectal cancer surgery: A randomized, controlled, double-blind trial". PLOS ONE.
30. (2024). "Case report: Dezocine's rapid and sustained antidepressant effects". Front Pharmacol.
31. (2022). "Dezocine is a Biased Ligand without Significant Beta-Arrestin Activation of the mu Opioid Receptor". Transl Perioper Pain Med.