Dezocine

Dezocine
Clinical data
Trade namesDalgan
Other namesWY-16,225; WY-16225
AHFS/Drugs.comMicromedex Detailed Consumer Information
Routes of
administration		Intravenous infusion, intramuscular injection[1]
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
MetabolismHepatic
Elimination half-life2.2 hours
Identifiers
  • (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
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC16H23NO
Molar mass245.366 g·mol−1
3D model (JSmol)
  • Oc1ccc2c(c1)[C@@]3(C)CCCCC[C@@H](C2)[C@H]3N
  • 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 checkY
  • Key:VTMVHDZWSFQSQP-VBNZEHGJSA-N checkY
  (verify)

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 is an opioid receptor modulator, acting as a partial agonist of the μ- and κ-opioid receptors.[2] It is a biased agonist of the μ-opioid receptor.[3][4] The drug has a similar profile of effects to related opioids acting at the μ-opioid receptor, including analgesia and euphoria.[2][5] 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.[6]

Dezocine was first synthesized in 1970.[7] It was introduced for medical use in the United States in 1986 but was not marketed in other countries.[2][8] 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).[9][10] It is a more effective analgesic than pentazocine, but causes relatively more respiratory depression than pentazocine.[11] Dezocine is a useful drug for the treatment of pain,[1] but side effects such as dizziness limit its clinical application,[12] and it can produce opioid withdrawal syndrome in patients already dependent on other opioids.[13] 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][14]
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][15][16][17] It is a biased agonist of the μ-opioid receptor and activates G protein signaling but not the β-arrestin pathway.[3][4] This may account for some of dezocine's unique and atypical pharmacological properties.[3][4] 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.[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).[14][18] 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.[14] 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.[14] 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.[19]

Pharmacokinetics

Dezocine has an bioavailability by intramuscular injection of 97%.[20] It has a mean t1/2α 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.[21]

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.[22] 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,[23] dezocine's usage is discontinued in the United States, but it is still widely used in some other countries such as China.[2][24]

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.[25][26][27][8]

Brand names

The major brand name of dezocine is Dalgan.[8]

Availability

In 2000, dezocine was listed as being marketed only in the United States.[8] It has since been marketed in China.[2] Dezocine was discontinued in the United States in 2011.[2]

As of 2011, dezocine is not used in the United States or Canada. It is not commercially available in either of these countries,[23] nor is it offered as a prescribed analgesic for postoperative care. In China however, it is commonly used after surgery.[9]

Research

Depression

Dezocine shows antidepressant-like effects in animals.[3][28][29] 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.[3][28][29] 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.[3][28][30] 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.[31] 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.[3][4]

References

  1. ^ a b c d e f 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. ^ a b c d e f g h i j k l m n o p q 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. ^ a b c d e f g Barr GA, Schmidt HD, Thakrar AP, Kranzler HR, Liu R (September 2024). "Revisiting dezocine for opioid use disorder: A narrative review of its potential abuse liability". CNS Neurosci Ther. 30 (9): e70034. doi:10.1111/cns.70034. PMC 11410865. PMID 39295098. 6.3 Antidepressant actions: In a study of postoperative depression, which is common among patients undergoing cancer surgery, patients who received dezocine in addition to a pain medication had lower scores on the Beck Depression Inventory than did patients who received the pain medication alone.32 In mouse models of "depressive-like" behaviors—the forced swim task and tail suspension task—immobility is used as a proxy for the clinical state. In both tasks, dezocine dose-dependently reduced immobility, with no other motor effects. The reduction in immobility was blocked by the serotonin 1A receptor antagonist Way100635 and by the κopioid receptor agonist U50,488, consistent with dezocine acting via serotonin and κ-opioid receptors.31 [...] Given that depression often co-occurs with OUD,55,56 these pharmacological effects of dezocine could be beneficial in treating OUD [...] Dezocine may have antidepressant activity that could be helpful in treating persons with OUD.
  4. ^ a b c d Grothusen J, Lin W, Xi J, Zanni G, Barr GA, Liu R (2022). "Dezocine is a Biased Ligand without Significant Beta-Arrestin Activation of the mu Opioid Receptor". Transl Perioper Pain Med. 9 (1): 424–429. PMC 9097853. PMID 35572183. Dezocine has been found to inhibit both the serotonin and norepinephrine uptake transporters [1]. This led to the investigation and discovery that dezocine has antidepressant activity in patients treated post-operatively for pain [22]. Anti-depressant activity of dezocine was also verified in a rodent model [23]. It has been known that depression is a major comorbidity in chronic pain and opioid use disorder [24]. Substituting dezocine for methadone or buprenorphine for opioid use disorder would have the added benefit of treating the major comorbidity depression along with its other favorable properties of reduced respiratory depression and lack of addiction.
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  15. ^ 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.
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  18. ^ 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.
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  23. ^ a b "FDA Drugs". Archived from the original on 2013-01-27. Retrieved 2012-11-01.
  24. ^ 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.
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  28. ^ a b c Vázquez-León P, Miranda-Páez A, Valencia-Flores K, Sánchez-Castillo H (May 2023). "Defensive and Emotional Behavior Modulation by Serotonin in the Periaqueductal Gray". Cell Mol Neurobiol. 43 (4): 1453–1468. doi:10.1007/s10571-022-01262-z. PMID 35902460. Treatment with dezocine combined with sufentanil can signifcantly reduce the symptoms of postoperative depression and improve sleep quality in patients (Zhao et al. 2020), because of the antidepressant efects of dezocine that appear to be mediated by 5-HT1A receptors and κ-opioid receptors (Shang et al. 2021).
  29. ^ a b Shang L, Duan C, Chang S, Chang N, Jia S (September 2021). "Antidepressant-like effects of dezocine in mice: involvement of 5-HT1A and κ opioid receptors". Behav Pharmacol. 32 (6): 472–478. doi:10.1097/FBP.0000000000000641. PMID 34101632.
  30. ^ Zhao P, Wu Z, Li C, Yang G, Ding J, Wang K, Wang M, Feng L, Duan G, Li H (2020). "Postoperative analgesia using dezocine alleviates depressive symptoms after colorectal cancer surgery: A randomized, controlled, double-blind trial". PLOS ONE. 15 (5): e0233412. Bibcode:2020PLoSO..1533412Z. doi:10.1371/journal.pone.0233412. PMC 7250456. PMID 32453759.
  31. ^ Wang H, Lyu N, Zhao Q (2024). "Case report: Dezocine's rapid and sustained antidepressant effects". Front Pharmacol. 15: 1411119. doi:10.3389/fphar.2024.1411119. PMC 11291242. PMID 39092225.