Dezocine

Dezocine, sold under the brand name Dalgan, is an atypical opioid analgesic which is used in the treatment of pain.^[1][2] It is used by intravenous infusion and intramuscular injection.^[1][2]

Dezocine

Clinical data
Trade names	Dalgan
Other names	WY-16225
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Routes of administration	Intravenous infusion, intramuscular injection^[1]
ATC code	N02AX03 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Pharmacokinetic data
Metabolism	Hepatic
Elimination half-life	2.2 hours
Identifiers
IUPAC name (5R,11S,13R)-13-Amino-5-methyl-5,6,7,8,9,10,11,12-octahydro-5,11-methanobenzo[10]annulen-3-ol
CAS Number	53648-55-8^Y
PubChem CID	3033053
DrugBank	DB01209^N
ChemSpider	2297867^Y
UNII	VHX8K5SV4X
KEGG	D00838^Y
ChEBI	CHEBI:4474^Y
ChEMBL	ChEMBL1685^Y
CompTox Dashboard (EPA)	DTXSID2022911
Chemical and physical data
Formula	C16H23NO
Molar mass	245.366 g·mol^−1
3D model (JSmol)	Interactive image
SMILES Oc1ccc2c(c1)[C@@]3(C)CCCCC[C@@H](C2)[C@H]3N
InChI InChI=1S/C16H23NO/c1-16-8-4-2-3-5-12(15(16)17)9-11-6-7-13(18)10-14(11)16/h6-7,10,12,15,18H,2-5,8-9,17H2,1H3/t12-,15-,16+/m0/s1^Y Key:VTMVHDZWSFQSQP-VBNZEHGJSA-N^Y
^NY (what is this?)  (verify)

Dezocine is an opioid receptor modulator, acting as a partial agonist of the μ- and κ-opioid receptors.^[2] It has a similar profile of effects to related opioids acting at the μ-opioid receptor, including analgesia and euphoria.^[2][3] Unlike other opioids acting at the κ-opioid receptor however, dezocine does not produce side effects such as dysphoria or hallucinations at any therapeutically used dose.^[4]

Dezocine was first synthesized in 1970.^[5] It was introduced for medical use in the United States in 1986 but was not marketed in other countries.^[2][6] Dezocine was discontinued in the United States in 2011 with no official reason given.^[2] However, it has become one of the most widely used analgesics in China.^[2] In light of the opioid epidemic, dezocine has seen a resurgence in use and interest.^[2]

Medical uses

Dezocine is generally administered intravenously (as Dalgan) to relieve post-operative pain in patients.^[1] 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).^[7][8] It is a more effective analgesic than pentazocine, but causes relatively more respiratory depression than pentazocine.^[9] Dezocine is a useful drug for the treatment of pain,^[1] but side effects such as dizziness limit its clinical application,^[10] and it can produce opioid withdrawal syndrome in patients already dependent on other opioids.^[11] 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

Opioid activity of dezocine and morphine^[2][12]

Opioid	Opioid receptor affinity (Ki, nM)
	MORTooltip μ-Opioid receptor	KORTooltip κ-Opioid receptor	DORTooltip δ-Opioid receptor
Dezocine	3.67 ± 0.7	31.9 ± 1.9	527 ± 70
Morphine	2.8 ± 0.2	55.96 ± 6.99	648.8 ± 59.7

Dezocine acts as an opioid receptor receptor modulator.^[2] It is specifically a mixed agonist–antagonist or partial agonist of the μ- and κ-opioid receptors.^{[2][13][14][15]} Dezocine could also act as a biased agonist of the μ-opioid receptor, although more research is needed to confirm this.^[2] The binding affinity of dezocine varies depending on the opioid receptor, with it 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.^[2] 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).^[12][16] These actions theoretically might contribute to its analgesic efficacy.^[2]

Dezocine is five times as potent as pethidine and one-fifth as potent as butorphanol as an analgesic.^[1] 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.^[12] 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.^[12] 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.^[17]

Pharmacokinetics

Dezocine has an bioavailability by intramuscular injection of 97%.^[18] It has a mean t_1/2α of fewer than two minutes, and its biological half-life is 2.2 hours.^{[citation needed]}

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).^{[2][additional citation(s) needed]}

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.^[19]

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.^[20] 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,^[21] dezocine's usage is discontinued in the United States, but it is still widely used in some other countries such as China.^[2][22]

Society and culture

Generic names

Dezocine is the generic name of the drug and its INNTooltip International Nonproprietary Name and USANTooltip United States Adopted Name.^{[23][24][25][6]}

Brand names

The major brand name of dezocine is Dalgan.^[6]

Availability

In 2000, dezocine was listed as being marketed only in the United States.^[6] It has since been marketed in China.^[2] Dezocine was discontinued in the United States in 2011.^[2]

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,^[21] nor is it offered as a prescribed analgesic for postoperative care. In China however, it is commonly used after surgery.^[7]

References

1. O'Brien JJ, Benfield P (August 1989). "Dezocine. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy". Drugs. 38 (2): 226–48. doi:10.2165/00003495-198938020-00005. PMID 2670517. S2CID 195697572.
2. Childers WE, Abou-Gharbia MA (June 2021). ""I'll Be Back": The Resurrection of Dezocine". ACS Med Chem Lett. 12 (6): 961–968. doi:10.1021/acsmedchemlett.1c00233. PMC 8201756. PMID 34141081.
3. Zacny JP, Lichtor JL, de Wit H (April 1992). "Subjective, behavioral, and physiologic responses to intravenous dezocine in healthy volunteers". Anesthesia and Analgesia. 74 (4): 523–30. doi:10.1213/00000539-199204000-00010. PMID 1348168. S2CID 34394471.
4. Westmoreland C (August 1991). "Opioid agonist-antagonists". Current Opinion in Anesthesiology. 4 (4): 556–562. doi:10.1097/00001503-199108000-00017.
5. "Espacenet". Espacenet Patent Search.
6. Swiss Pharmaceutical Society (2000). Swiss Pharmaceutical Society (ed.). Index Nominum 2000: International Drug Directory. Taylor & Francis. p. 320. ISBN 9783887630751.
7. Gharagozlou P, Demirci H, David Clark J, Lameh J (January 2003). "Activity of opioid ligands in cells expressing cloned mu opioid receptors". BMC Pharmacology. 3: 1. doi:10.1186/1471-2210-3-1. PMC 140036. PMID 12513698.
8. Camu F, Gepts E (1979). "Analgesic properties of dezocine for relief of postoperative pain". Acta Anaesthesiologica Belgica. 30 (Suppl): 183–91. PMID 398127.
9. Wuest HP, Bellville JW (April 1979). "The respiratory effects of dezocine and pentazocine in man". Journal of Clinical Pharmacology. 19 (4): 205–10. doi:10.1002/j.1552-4604.1979.tb01653.x. PMID 438355. S2CID 45928473.
10. Oosterlinck W, Verbaeys A (1980). "Preliminary clinical experience with dezocine, a new potent analgesic". Current Medical Research and Opinion. 6 (7): 472–4. doi:10.1185/03007998009109470. PMID 7363647.
11. Strain EC, Preston KL, Liebson IA, Bigelow GE (August 1996). "Opioid antagonist effects of dezocine in opioid-dependent humans". Clinical Pharmacology and Therapeutics. 60 (2): 206–17. doi:10.1016/S0009-9236(96)90137-X. PMID 8823239. S2CID 10183991.
12. Liu R, Huang XP, Yeliseev A, Xi J, Roth BL (March 2014). "Novel molecular targets of dezocine and their clinical implications". Anesthesiology. 120 (3): 714–23. doi:10.1097/ALN.0000000000000076. PMC 3944410. PMID 24263237.
13. Wang YH, Chai JR, Xu XJ, Ye RF, Zan GY, Liu GY, Long JD, Ma Y, Huang X, Xiao ZC, Dong H, Wang YJ (September 2018). "Pharmacological Characterization of Dezocine, a Potent Analgesic Acting as a κ Partial Agonist and μ Partial Agonist". Sci Rep. 8 (1): 14087. Bibcode:2018NatSR...814087W. doi:10.1038/s41598-018-32568-y. PMC 6148296. PMID 30237513.
14. Gharagozlou P, Hashemi E, DeLorey TM, Clark JD, Lameh J (January 2006). "Pharmacological profiles of opioid ligands at kappa opioid receptors". BMC Pharmacology. 6: 3. doi:10.1186/1471-2210-6-3. PMC 1403760. PMID 16433932.
15. Young AM, Stephens KR, Hein DW, Woods JH (April 1984). "Reinforcing and discriminative stimulus properties of mixed agonist-antagonist opioids". The Journal of Pharmacology and Experimental Therapeutics. 229 (1): 118–26. PMID 6142942.
16. Wang YX, Mao XF, Li TF, Gong N, Zhang MZ (February 2017). "Dezocine exhibits antihypersensitivity activities in neuropathy through spinal μ-opioid receptor activation and norepinephrine reuptake inhibition". Scientific Reports. 7: 43137. Bibcode:2017NatSR...743137W. doi:10.1038/srep43137. PMC 5322378. PMID 28230181.
17. Romagnoli A, Keats AS (March 1984). "Ceiling respiratory depression by dezocine". Clinical Pharmacology and Therapeutics. 35 (3): 367–73. doi:10.1038/clpt.1984.45. PMID 6421529. S2CID 19569628.
18. Locniskar A, Greenblatt DJ, Zinny MA (1986). "Pharmacokinetics of dezocine, a new analgesic: effect of dose and route of administration". European Journal of Clinical Pharmacology. 30 (1): 121–3. doi:10.1007/bf00614208. PMID 3709625. S2CID 20426334.
19. Malis JL, Rosenthale ME, Gluckman MI (September 1975). "Animal pharmacology of Wy-16,225, a new analgesic agent". The Journal of Pharmacology and Experimental Therapeutics. 194 (3): 488–98. PMID 808600.
20. Freed ME, Potoski JR, Freed EH, Conklin GL, Malis JL (June 1973). "Bridged aminotetralins as novel potent analgesic sunstances". Journal of Medicinal Chemistry. 16 (6): 595–9. doi:10.1021/jm00264a003. PMID 4714986.
21. "FDA Drugs". Archived from the original on 2013-01-27. Retrieved 2012-11-01.
22. Wang L, Liu X, Wang J, Sun Y, Zhang G, Liang L (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. 37 (3). doi:10.1042/BSR20170243. PMC 5463259. PMID 28533424.
23. Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 368–. ISBN 978-1-4757-2085-3.
24. Morton IK, Hall JM (2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. p. 96. ISBN 9789401144391.
25. Kar A (2005). Medicinal Chemistry. New Age International. p. 268. ISBN 9788122415650.