Dezocine

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Dezocine
Dezocine structure.svg
Dezocine 3D BS.png
Clinical data
Trade names Dalgan
Other namesWY-16,225; WY-16225
AHFS/Drugs.com Micromedex Detailed Consumer Information
Routes of
administration 		Intravenous infusion, intramuscular injection [1]
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Metabolism Hepatic
Elimination half-life 2.2 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
Formula C16H23NO
Molar mass 245.366 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 Yes check.svgY
  • Key:VTMVHDZWSFQSQP-VBNZEHGJSA-N Yes check.svgY
   (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]

Contents

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)
MOR Tooltip μ-Opioid receptor KOR Tooltip κ-Opioid receptor DOR Tooltip δ-Opioid receptor
Dezocine3.67 ± 0.731.9 ± 1.9527 ± 70
Morphine 2.8 ± 0.255.96 ± 6.99648.8 ± 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 INN Tooltip International Nonproprietary Name and USAN Tooltip 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]

Related Research Articles

<span class="mw-page-title-main">Analgesic</span> Drugs used to achieve relief from pain

An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in some instances eliminate, sensation, although analgesia and anesthesia are neurophysiologically overlapping and thus various drugs have both analgesic and anesthetic effects.

<span class="mw-page-title-main">Tramadol</span> Opioid pain medication

Tramadol, sold under the brand name Ultram among others, is an opioid pain medication and a serotonin–norepinephrine reuptake inhibitor (SNRI) used to treat moderately severe pain. When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an hour. It is also available by injection. It is available in combination with paracetamol (acetaminophen).

<span class="mw-page-title-main">Opioid</span> Psychoactive chemical

Opioids are a class of drugs that derive from, or mimic, natural substances found in the opium poppy plant. Opioids work in the brain to produce a variety of effects, including pain relief. As a class of substances, they act on opioid receptors to produce morphine-like effects.

<span class="mw-page-title-main">Buprenorphine</span> Opioid used to treat pain & opioid use disorder

Buprenorphine, sold under the brand name Subutex among others, is an opioid used to treat opioid use disorder, acute pain, and chronic pain. It can be used under the tongue (sublingual), in the cheek (buccal), by injection, as a skin patch (transdermal), or as an implant. For opioid use disorder, the patient must have moderate opioid withdrawal symptoms before buprenorphine can be administered under direct observation of a health-care provider.

Functional selectivity is the ligand-dependent selectivity for certain signal transduction pathways relative to a reference ligand at the same receptor. Functional selectivity can be present when a receptor has several possible signal transduction pathways. To which degree each pathway is activated thus depends on which ligand binds to the receptor. Functional selectivity, or biased signaling, is most extensively characterized at G protein coupled receptors (GPCRs). A number of biased agonists, such as those at muscarinic M2 receptors tested as analgesics or antiproliferative drugs, or those at opioid receptors that mediate pain, show potential at various receptor families to increase beneficial properties while reducing side effects. For example, pre-clinical studies with G protein biased agonists at the μ-opioid receptor show equivalent efficacy for treating pain with reduced risk for addictive potential and respiratory depression. Studies within the chemokine receptor system also suggest that GPCR biased agonism is physiologically relevant. For example, a beta-arrestin biased agonist of the chemokine receptor CXCR3 induced greater chemotaxis of T cells relative to a G protein biased agonist.

<span class="mw-page-title-main">Nalbuphine</span> Opioid analgesic

Nalbuphine, sold under the brand names Nubain among others, is an opioid analgesic which is used in the treatment of pain. It is given by injection into a vein, muscle, or fat.

<span class="mw-page-title-main">Tianeptine</span> Atypical antidepressant

Tianeptine, sold under the brand names Stablon, Tatinol, and Coaxil among others, is an atypical tricyclic antidepressant which is used mainly in the treatment of major depressive disorder, although it may also be used to treat anxiety, asthma, and irritable bowel syndrome.

<span class="mw-page-title-main">Opioid antagonist</span> Receptor antagonist that acts on one or more of the opioid receptors

An opioid antagonist, or opioid receptor antagonist, is a receptor antagonist that acts on one or more of the opioid receptors.

μ-opioid receptor Protein-coding gene in the species Homo sapiens, named for its ligand morphine

The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(mu)-opioid peptide (MOP) receptors. The prototypical μ-opioid receptor agonist is morphine, the primary psychoactive alkaloid in opium and for which the receptor was named, with mu being the first letter of Morpheus, the compound's namesake in the original Greek. It is an inhibitory G-protein coupled receptor that activates the Gi alpha subunit, inhibiting adenylate cyclase activity, lowering cAMP levels.

δ-opioid receptor Opioid receptor

The δ-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR or DOP, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G protein Gi/G0 and has enkephalins as its endogenous ligands. The regions of the brain where the δ-opioid receptor is largely expressed vary from species model to species model. In humans, the δ-opioid receptor is most heavily expressed in the basal ganglia and neocortical regions of the brain.

<span class="mw-page-title-main">Desmetramadol</span> Opioid painkiller medication

Desmetramadol, also known as O-desmethyltramadol (O-DSMT), is an opioid analgesic and the main active metabolite of tramadol. Tramadol is demethylated by the liver enzyme CYP2D6 to desmetramadol in the same way as codeine, and so similarly to the variation in effects seen with codeine, individuals who have a less active form of CYP2D6 will tend to have reduced analgesic effects from tramadol. Because desmetramadol itself does not need to be metabolized to induce an analgesic effect, it can be used in individuals with low CYP2D6 activity unlike tramadol.

<span class="mw-page-title-main">Tapentadol</span> Opioid analgesic of benzenoid class

Tapentadol, brand names Nucynta among others, is a centrally acting opioid analgesic of the benzenoid class with a dual mode of action as an agonist of the μ-opioid receptor and as a norepinephrine reuptake inhibitor (NRI). Analgesia occurs within 32 minutes of oral administration, and lasts for 4–6 hours.

<span class="mw-page-title-main">Ciramadol</span> Opioid analgesic drug

Ciramadol (WY-15,705) is an opioid analgesic that was developed in the late 1970s and is related to phencyclidine, tramadol, tapentadol and venlafaxine. It is a mixed agonist-antagonist for the μ-opioid receptor with relatively low abuse potential and a ceiling on respiratory depression which makes it a relatively safe drug. It has a slightly higher potency and effectiveness as an analgesic than codeine, but is weaker than morphine. Other side effects include sedation and nausea but these are generally less severe than with other similar drugs.

<span class="mw-page-title-main">Phenazocine</span> Opioid analgesic

Phenazocine is an opioid analgesic drug, which is related to pentazocine and has a similar profile of effects.

<span class="mw-page-title-main">Propiram</span> Opioid analgesic drug

Propiram is a partial μ-opioid receptor agonist and weak μ antagonist analgesic from the ampromide family of drugs related to other drugs such as phenampromide and diampromide. It was invented in 1963 in the United Kingdom by Bayer but was not widely marketed, although it saw some limited clinical use, especially in dentistry. Propiram reached Phase III clinical trials in the United States and Canada.

<span class="mw-page-title-main">RB-101</span> Chemical compound

RB-101 is a drug that acts as an enkephalinase inhibitor, which is used in scientific research.

<span class="mw-page-title-main">Opiate</span> Substance derived from opium

An opiate is an alkaloid substance derived from opium. It differs from the similar term opioid in that the latter is used to designate all substances, both natural and synthetic, that bind to opioid receptors in the brain. Opiates are alkaloid compounds naturally found in the opium poppy plant Papaver somniferum. The psychoactive compounds found in the opium plant include morphine, codeine, and thebaine. Opiates have long been used for a variety of medical conditions, with evidence of opiate trade and use for pain relief as early as the eighth century AD. Most opiates are considered drugs with moderate to high abuse potential and are listed on various "Substance-Control Schedules" under the Uniform Controlled Substances Act of the United States of America.

<span class="mw-page-title-main">Tonazocine</span> Chemical compound

Tonazocine (WIN-42,156) is an opioid analgesic of the benzomorphan family which made it to phase II clinical trials for the treatment of postoperative pain, but development was apparently ceased and ultimately it was never marketed. Tonazocine is a partial agonist at both the mu-opioid and delta-opioid receptors, but acting more like an antagonist at the former and more like an agonist at the latter. It lacks most of the side effects of other opioids such as adverse effects on the cardiovascular system and respiratory depression, but it can cause sedation, and in some patients it may induce hallucinations.

<span class="mw-page-title-main">Cebranopadol</span> Opioid analgesic drug

Cebranopadol is an opioid analgesic of the benzenoid class which is currently under development internationally by Grünenthal, a German pharmaceutical company, and its partner Depomed, a pharmaceutical company in the United States, for the treatment of a variety of different acute and chronic pain states. As of November 2014, it is in phase III clinical trials.

<span class="mw-page-title-main">PZM21</span> Chemical compound

PZM21 is an experimental opioid analgesic drug that is being researched for the treatment of pain. It is claimed to be a functionally selective μ-opioid receptor agonist which produces μ-opioid receptor mediated G protein signaling, with potency and efficacy similar to morphine, but with less β-arrestin 2 recruitment. However, recent reports highlight that this might be due to its low intrinsic efficacy, rather than functional selectivity or 'G protein bias' as initially reported. In tests on mice, PZM21 was slightly less potent than morphine or TRV130 as an analgesic, but also had significantly reduced adverse effects, with less constipation than morphine, and very little respiratory depression, even at high doses. This research was described as a compelling example of how modern high-throughput screening techniques can be used to discover new chemotypes with specific activity profiles, even at targets such as the μ-opioid receptor which have already been thoroughly investigated. More recent research has suggested however that at higher doses, PZM21 is capable of producing classic opioid side effects such as respiratory depression and development of tolerance and may have only limited functional selectivity.

References

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  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 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. 1 2 3 4 5 6 7 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. 1 2 3 4 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.
  5. ↑ 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.
  6. ↑ Westmoreland C (August 1991). "Opioid agonist-antagonists". Current Opinion in Anesthesiology. 4 (4): 556–562. doi:10.1097/00001503-199108000-00017.
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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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  22. ↑ 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.
  23. 1 2 "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.
  25. ↑ 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.
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  27. ↑ Kar A (2005). Medicinal Chemistry. New Age International. p. 268. ISBN   9788122415650.
  28. 1 2 3 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. 1 2 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.
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