Dezocine, sold under the brand name Dalgan, is an atypical

opioid Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use ...

analgesic which is used in the treatment of pain. It is used by

intravenous infusion Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

and intramuscular injection. Dezocine is an

opioid receptor Opioid receptors are a group of inhibitory G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin ...

modulator In electronics and telecommunications, modulation is the process of varying one or more properties of a periodic waveform, called the ''carrier signal'', with a separate signal called the ''modulation signal'' that typically contains informatio ...

, acting as a

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonis ...

of the μ- and

κ-opioid receptor The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP, is a G protein-coupled receptor that in humans is encoded by the ''OPRK1'' gene. The KOR is coupled to the G protein Gi/G0 and is one of four related receptors that bind op ...

s. It has a similar profile of effects to related opioids acting at the μ-opioid receptor, including

analgesia Pain management is an aspect of medicine and health care involving relief of pain (pain relief, analgesia, pain control) in various dimensions, from acute and simple to chronic and challenging. Most physicians and other health professional ...

and euphoria. Unlike other opioids acting at the κ-opioid receptor however, dezocine does not produce

side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

s such as

dysphoria Dysphoria (; ) is a profound state of unease or dissatisfaction. It is the semantic opposite of euphoria. In a psychiatric context, dysphoria may accompany depression, anxiety, or agitation. In psychiatry Intense states of distress and uneas ...

hallucination A hallucination is a perception in the absence of an external stimulus that has the qualities of a real perception. Hallucinations are vivid, substantial, and are perceived to be located in external objective space. Hallucination is a combinati ...

s at any therapeutically used dose. Dezocine was first synthesized in 1970. It was introduced for medical use in the

United States The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territori ...

in 1986 but was not marketed in other countries. Dezocine was discontinued in the United States in 2011 with no official reason given. However, it has become one of the most widely used analgesics in China. In light of the

opioid epidemic The opioid epidemic, also referred to as the opioid crisis, is the rapid increase in the overuse, misuse/abuse, and overdose deaths attributed either in part or in whole to the class of drugs opiates/opioids since the 1990s. It includes the sign ...

, dezocine has seen a resurgence in use and interest.

Medical uses

Dezocine is generally administered

intravenously Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

(as Dalgan) to relieve post-operative pain in patients. It can also be administered in

intramuscular Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles have ...

doses, and is given once rather than continuously. It is often administered in post-operative

laparoscopy Laparoscopy () is an operation performed in the abdomen or pelvis using small incisions (usually 0.5–1.5 cm) with the aid of a camera. The laparoscope aids diagnosis or therapeutic interventions with a few small cuts in the abdomen.Medlin ...

patients as an alternative to

fentanyl Fentanyl, also spelled fentanil, is a very potent synthetic opioid used as a pain medication. Together with other drugs, fentanyl is used for anesthesia. It is also used illicitly as a recreational drug, sometimes mixed with heroin, cocain ...

. Dezocine has potent analgesic effects, and comparable or greater pain-relieving ability than

morphine Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies (''Papaver somniferum''). It is mainly used as a pain medication, and is also commonly used recreationally, or to make other illicit opioids. T ...

, codeine, and

pethidine Pethidine, also known as meperidine and sold under the brand name Demerol among others, is a synthetic opioid pain medication of the phenylpiperidine class. Synthesized in 1938 as a potential anticholinergic agent by the German chemist Otto Eis ...

(meperidine). It is a more effective analgesic than

pentazocine Pentazocine, sold under the brand name Talwin among others, is a painkiller used to treat moderate to severe pain. It is believed to work by activating (agonizing) κ-opioid receptors (KOR) and μ-opioid receptors (MOR). As such it is called an ...

, but causes relatively more respiratory depression than pentazocine. Dezocine is a useful drug for the treatment of pain, but

s such as

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a common medical c ...

limit its clinical application, and it can produce

opioid withdrawal syndrome Opioid use disorder (OUD) is a substance use disorder characterized by cravings for opioids, continued use despite physical and/or psychological deterioration, increased tolerance with use, and withdrawal symptoms after discontinuing opioids. Op ...

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

of dezocine, reaches a ceiling at 0.3 to 0.4 mg/kg.

Side effects

Side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

s at lower doses include mild gastrointestinal discomfort and dizziness. Because decozine has mixed agonist/antagonist effects at the

s, 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 Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, one of which is the usage of a drug, despite substantial harm and other negative consequences. Repetitive drug use o ...

. 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

receptor modulator. It is specifically a mixed agonist–antagonist or

of the μ- and

s. Dezocine could also act as a

biased agonist Functional selectivity (or “agonist trafficking”, “biased agonism”, “biased signaling”, "ligand bias" and “differential engagement”) is the ligand (biochemistry), ligand-dependent selectivity for certain signal transduction pathway ...

of the μ-opioid receptor, although more research is needed to confirm this. The

binding affinity In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a m ...

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 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 lig ...

. In addition to its opioid activity, dezocine has been found to act as a

serotonin–norepinephrine reuptake inhibitor Serotonin–norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant drugs used to treat major depressive disorder (MDD), anxiety disorders, obsessive–compulsive disorder (OCD), social phobia, attention-deficit hyperactivity di ...

(SNRI), with pIC₅₀ values of 5.86 for the

serotonin transporter The serotonin transporter (SERT or 5-HTT) also known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a protein that in humans is encoded by the SLC6A4 gene. SERT is a type of monoamine transporter protein tha ...

(SERT) and 5.68 for the

norepinephrine transporter The norepinephrine transporter (NET), also known as noradrenaline transporter (NAT), is a protein that in humans is encoded by the solute carrier family 6 member 2 (SLC6A2) gene. NET is a monoamine transporter and is responsible for the sodium- ...

(NET). These actions theoretically might contribute to its analgesic efficacy. Dezocine is five times as potent as

and one-fifth as potent as

butorphanol Butorphanol is a morphinan-type synthetic agonist–antagonist opioid analgesic developed by Bristol-Myers. Butorphanol is most closely structurally related to levorphanol. Butorphanol is available as the tartrate salt in injectable, tablet, and ...

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 agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the a ...

s of the receptor such as

. Moreover, dezocine is not a

controlled substance A controlled substance is generally a drug or chemical whose manufacture, possession and use is regulated by a government, such as illicitly used drugs or prescription medications that are designated by law. Some treaties, notably the Single ...

and there are no reports of

related to its use, indicating that, unlike virtually all other clinically-employed μ-opioid receptor agonists (including weak partial agonists like

buprenorphine Buprenorphine 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 (intravenous and subcutaneous), as a skin patch (transdermal ...

), 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 an

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. Ho ...

by intramuscular injection of 97%. It has a mean t_1/2α of fewer than two minutes, and its

biological half-life Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...

is 2.2 hours.

Chemistry

Dezocine is a member of the

benzomorphan Benzomorphan is a chemical compound that is the base for a series of drugs which variably act on the opioid kappa and sigma receptors, including the following compounds: * 5,9-DEHB * 8-CAC * Alazocine * Anazocine * Bremazocine * Butinazoc ...

group of opioids. It is related to other benzomorphan opioids such as

. Dezocine is unusual among opioids as it is one of the only

primary amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent such ...

s known to be

active Active may refer to: Music * ''Active'' (album), a 1992 album by Casiopea * Active Records, a record label Ships * ''Active'' (ship), several commercial ships by that name * HMS ''Active'', the name of various ships of the British Royal ...

as an opioid (along with bisnortilidine, an

active metabolite An active metabolite is an active form of a drug after it has been processed by the body. Metabolites of drugs An active metabolite results when a drug is metabolized by the body into a modified form which continues to produce effects in the body ...

of tilidine).

Synthesis

Dezocine −)-13β-amino-5,6,7,8,9,10,11,12-octahydro-5α-methyl-5,11-methanobenzocyclodecen-31-ol, hydrobromideis 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 Potassium ''tert''-butoxide is the chemical compound with the formula K+(CH3)3CO−. This colourless solid is a strong base (pKa of conjugate acid around 17), which is useful in organic synthesis. It exists as a tetrameric cubane-type cluster. ...

. 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 Hydroxylammonium chloride is the hydrochloric acid salt of hydroxylamine. Hydroxylamine is a biological intermediate in nitrification (biological oxidation of ammonia with oxygen into nitrite) and in anammox (biological oxidation of nitrite and am ...

, to yield an

oxime In organic chemistry, an oxime is a organic compound belonging to the imines, with the general formula , where R is an organic side-chain and R’ may be hydrogen, forming an aldoxime, or another organic group, forming a ketoxime. O-substituted ...

. A

reduction reaction Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...

hydrogen gas Hydrogen is the chemical element with the symbol H and atomic number 1. Hydrogen is the lightest element. At standard conditions hydrogen is a gas of diatomic molecules having the formula . It is colorless, odorless, tasteless, non-toxic, a ...

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 The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(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

. 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

Canada Canada is a country in North America. Its ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, covering over , making it the world's second-largest country by tot ...

. 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.

References

{{Sigma receptor modulators Analgesics Kappa-opioid receptor antagonists Opioids Serotonin–norepinephrine reuptake inhibitors