“I’ll Be Back”: The Resurrection of Dezocine

Abstract

Beginning with opium itself, natural and synthetic opioids have been used as analgesics for over 8000 years and were likely abused as drugs of recreation for that long as well. However, the “opioid crisis” resulted in attempts to avoid or limit opioid analgesics in favor of other therapies and methods. Mu opioid agonists can be effective analgesics but suffer from addiction, tolerance, and dangerous, sometimes fatal, side effects. One exception to this generalization is dezocine (Dalgan), a mixed mu/kappa opioid partial agonist. Dezocine is at least as effective as morphine in reducing acute pain in animal models and clinical applications such as postoperative pain. And while dezocine was discontinued in western markets in 2011, it has become the favored opioid analgesic in China, capturing over 40% of the market. Additionally, dezocine possesses norepinephrine uptake inhibitory activity, which may synergize with mu agonism in the case of acute pain treatment and possibly endow the drug with antinociceptive activity in neuropathic pain conditions. This Innovations article summarizes the history and properties of dezocine and presents evidence and rationale for why dezocine has undergone a resurrection.

Pain is defined as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or is described in terms of such damage”.¹ In its most simple form, pain can be classified into two major categories depending on how long it lasts (acute and chronic) as well as four types, based on the location of the pain and how the pain is being caused. Nociceptive pain usually results from tissue injury.² Inflammatory pain is caused by a reaction from the body’s immune system.³ Neuropathic pain results from nerve injury or a change in neuronal signaling.⁴ Functional pain occurs without obvious origin and includes conditions such as fibromyalgia and the visceral pain caused by irritable bowel syndrome.⁵ The estimated global market for prescription and over-the-counter pain management drugs was valued at over $71 B in 2019 and estimated to grow to over $91 B by 2027.⁶

Today, pain management is accomplished through a number of methods, including medication, devices, physical methods (heat, electrotherapy, physical therapy/exercise), acupuncture, interventional procedures (surgery, pulsed radiofrequency, nerve ablation), and psychological techniques (cognitive behavioral therapy, hypnosis, meditation, etc.). However, arguably, one of the more controversial methods for the relief of moderate to severe pain is the use of opioid analgesics. The Centers for Disease Control and Prevention estimates that in 2019 over 153 million prescriptions for opioids were written in the United States (US) alone.⁷ Interestingly, that number has steadily declined since its height in 2012 (>255 million prescriptions in the US), due in part to the “opioid crisis”. This term is given to the waves of abuse of natural and synthetic opioids as recreational drugs and the resulting addictions, overdoses, and deaths that have occurred since 1991.⁸ The scope and impact of this crisis, described in 2017 by US Food and Drug Administration Commissioner Scott Gottleib as ”the toughest public health challenge we face at the FDA”, resulted in the passage of the 21st Century Cures Act by the US Congress, which allocated $1 B over 2 years to enhance US states’ response to the epidemic.⁹ The danger is not limited to the US. Opioid abuse has become a global problem, and the United Nations and World Health Organization have mobilized similar international responses.¹⁰

Currently used analgesic opioids such as morphine (1, Figure 1), whose origins derive from the opium poppy Papaver sominferum, share a common pharmacological mechanism, namely agonist activity at the mu opioid receptor.¹¹ Mu receptors (one of three opioid receptor subtypes: mu, delta, and kappa) are found throughout the central and peripheral nervous systems as well as non-nervous tissues. The endogenous ligand for the mu opioid receptor is β-endorphin, a member of a family of peptides that includes endorphins, enkephalins, and dynorphins. Mu receptors mediate pain and analgesic effects but are also involved in the common side effects of mu agonists, including respiratory depression, sedation, nausea and vomiting, constipation, urinary retention, and bradycardia. In addition, chronic stimulation of the mu receptor can lead to dependence and addiction. However, more recent work has shown that analgesia is modulated by all three opioid receptors as well as the norciceptin receptor (opioid receptor-like 1).¹² In particular, the kappa receptor has received significant attention as an alternative analgesic mechanism, although stimulation of that receptor is associated with its own collection of undesirable side effects.¹³

Figure 1.

Structures of morphine, (R)-pentazocine, and dezocine (Dalgan, WY-16,255).

Dezocine (3) is an aminotetralin derivative that is structurally related to the benzomorphan opiate pentazocine (2). It was discovered at the Wyeth Division of American Home Products and labeled WY-16,225. The molecule was first disclosed as an analgesic in 1973.¹⁴ As the most potent analogue of the 49 derivatives disclosed in that 1973 paper, dezocine was 2.77 times more potent than morphine in the rat tail flick model when given intraperitoneally. The compound was unique among opioid analgesics in that it possessed a primary amine rather than the more typical tertiary amine. Dezocine was approved by the US Food and Drug Administration in 1986 with the trade name Dalgan. Its use in the US was discontinued in 2011, although no official reason for its termination was given. However, dezocine’s use in China (the world’s second largest analgesic market) has flourished. Until recently, its use in that country was limited to postsurgical pain, but increases in cancer in China have resulted in a growing market for analgesics to treat moderate to severe pain. Sales of dezocine in China exceeded $630 M in 2016 and occupied over 45% of that nation’s opioid analgesic market.^15,16 In this Innovations article, we present the interesting history and pharmacological profile of dezocine and conclude with a discussion of some recent findings on the molecule that may open up new uses and indications.

The original synthesis of dezocine is shown in Scheme 1. Treatment of 1-methyl-7-methoxytetralone (4) with 1,5-dibromopentane followed by base-catalyzed cyclization gave the octahydro[10]annulen-13-one 5. Compound 5 was converted to oxime 6, which was then reduced by hydrogenation over Raney Nickel to give the mixture of diastereomers 7a and 7b in a ratio of 5:95. Conversion of the mixture of oximes to their hydrochloride salts and recrystallization from water followed by acetone/methanol provided the sterically favored beta-epimer 7b in 54% yield. The structure of 7b was assigned by ¹H NMR. Treatment of 7b with refluxing 48% aqueous HBr provided racemic 8, which was isolated as the hydrobromide salt. Yield was not provided for this final step in the synthesis. Compound 3 was obtained as the chirally pure (−)-isomer by kinetic crystallization of the d-tartaric acid salts of 8.¹⁷

Scheme 1. Synthesis of Dezocine.

Reagents and conditions: (a) NaH, benzene/DMF, 20°C; (b) NaH, 85°C, 3 h; (c) NH₂OH·HCl, pyridine, reflux, 24 h; (d) H₂/Raney Nickel, EtOH/conc. NH₄OH, 50°C, 45 psi; (e) HCl/Et₂O, recrystallize from H₂O; (f) 48% HBr, reflux, 30 min; (g) (d)-tartaric acid, methanol.

The concomitant loss of material that comes with using kinetic resolution made dezocine a fairly expensive drug. Fueled by renewed interest in dezocine in China and a desire to reduce the cost of production, a number of Chinese patents have appeared that disclose improvements to the original synthetic method.¹⁸⁻²⁰ More recently, a chiral synthesis of dezocine was described which involves an enantioselective phase-transfer alkylation of tetralone 4.²¹

During the development of dezocine, three degradation products were identified in the scaled-up synthesis (Figure 2). These compounds were synthesized to confirm their structure and assess their potential analgesic activity.²² While 9 and 10 were significantly less potent than dezocine in the rat tail flick test, 11 was shown to be only four times less potent than dezocine and equipotent with morphine.

Figure 2.

Structures of dezocine degradation products 9–11.

A detailed presentation of dezocine’s in vivo analgesic pharmacology was published in 1975.²³ Dezocine was more potent than morphine, codeine, and pentazocine in a number of pain models, regardless of the route of administration. It was less potent than morphine in causing respiratory depression, constipation, and adverse cardiovascular effects. Dezocine antagonized morphine-induced loss of righting reflex and precipitated withdrawal symptoms in morphine-dependent rhesus monkeys but did not induce the stereotypical jumping behavior in morphine-treated mice caused by the mu opioid antagonist naloxone. These data, along with results from isolated guinea pig ilium, suggested that dezocine might be a partial mu opioid agonist. Interestingly, the analgesic effect of dezocine was found to be additive with that of morphine rather than antagonistic, indicating that other mechanisms in addition to mu opioid agonism contribute the dezocine’s analgesic effect. It was later found that dezocine interacted with kappa opioid receptors.^24,25 There was disagreement in the literature for several years on whether dezocine was a kappa agonist or antagonist. However, recent studies from Wang et al.¹⁶ suggest that dezocine possesses similar potent affinity and selectivity for mu and kappa opioid receptors (Table 1) to that demonstrated by morphine and that it is a kappa opioid partial agonist. This paper nicely summarizes the historical work that ultimately identified dezocine as a partial agonist for both mu and kappa opioid receptors.

Table 1. Opioid Affinities for Morphine and Dezocine^a.

	Ki (nM)
	mu opioid	delta opioid	kappa opioid
morphine	2.8 ± 0.2	648.8 ± 59.7	55.96 ± 6.99
dezocine	3.67 ± 0.7	527 ± 70	31.9 ± 1.9

^aData were generated by the Psychoactive Drug Screening Program.²⁶ Standard ligands: mu opioid, ³[H]-DAMGO; delta opioid, ³[H]-DADLE; kappa opioid, ³[H]-U69593. Data were taken from ref (16).

Early clinical studies indicated that dezocine was more effective than morphine in preventing experimental pain as measured by the submaximal tourniquet ischemia test and that the analgesic effects for the two opioids were additive.²⁷ The first report of dezocine’s analgesic activity in an actual pain scenario described its efficacy against postsurgical pain,²⁸ and that indication has prevailed as dezocine’s primary usage until recently. A number of clinical trials quickly followed that confirmed dezocine’s efficacy as a postoperative analgesic (summarized by Hoskins and Hanks in 1991²⁹). While its use was discontinued in the US in 2011, continuing clinical studies demonstrated dezocine to be an excellent postoperative analgesic with a superior side effect profile compared to morphine and other opioids (summarized by Xi et al. in 2015³⁰). Starting in 1978,³¹ clinical data also suggested that dezocine was superior to morphine and butorphenol in relieving mild to moderate cancer pain (summarized by Hoskins and Hanks²⁹). The growing use of dezocine for treating cancer pain in China prompted a meta-analysis of published studies comparing the use of dezocine and morphine in Chinese cancer patients in 2017.³² The conclusions, based on 9 studies involving over 300 dezocine patients and 300 morphine patients, were that while there was no significant difference between dezocine and morphine in terms of antinociceptive efficacy, the rate of adverse reactions reported for dezocine was 55% less than that reported for morphine.

Respiratory depression is a well-documented side effect of opioid analgesics and is caused by stimulation of mu opioid receptors in specific regions of the CNS such as the pre-Botzinger complex. Like morphine, dezocine produced respiratory depression, described as being well-tolerated.³³ However, unlike morphine, dezocine displayed a ceiling effect for respiratory depression that did not increase when the drug was administered at higher than its maximal effective dose. Administration of morphine following dezocine failed to produce additional respiratory depression, indicating that dezocine antagonized morphine’s effects. This profile was also observed in animal studies³⁴ and is similar to other mixed opioid agonist/antagonists such as pentazocine that display partial agonist activity at the mu opioid receptor.²⁹ While dezocine’s mu opioid partial agonist profile could explain the ceiling effect that the drug displays for respiratory depression, another unexplored possibility exists.³⁵ G-protein coupled receptor (GPCR) signaling is thought to be associated with mu agonists’ analgesic properties, while respiratory depression and other side effects are thought to be mediated through β-arrestin signaling. Biased mu opioids such as Trevena’s oliceridine display improved side effect profiles compared to unbiased ligands such as morphine. While no information on dezocine’s association with β-arrestin signaling has been published, a recent patent application³⁶ disclosed GPCR-biased mu opioid analgesics whose structures bear some resemblance to that of dezocine. The exploration of dezocine as a potential biased signaling ligand would be of great interest.

Clinical reports of dezocine’s effects on constipation (another common side effect seen with opioid analgesics) are not prevalent, but animal studies indicate that dezocine had significantly less effects on intestinal smooth muscle contraction than morphine or sufentanil.³⁷ Acute administration of morphine, dezocine, and ciramidol (another mu opioid partial agonist) had no significant effects on cardiac parameters such as cardiac index, stroke volume, or pulmonary vascular resistance.³⁸ Some studies suggest that chronic use of opioids may lead to an increase in adverse cardiac events, although the evidence is not unequivocal.³⁹ The use of certain opioids such as methadone and buprenorphine in combination with other drugs can be risky due to their ability to prolong QT_C, but that is a structurally related liability. Dezocine did reduce the minimal alveolar concentration (MAC) of enfluorane in dogs, leading to reduced hemodynamic parameters and death at the high dose of 20 mg/kg.⁴⁰ These data are pertinent because opioid analgesics are often used as combination agents in general anesthesia to provide analgesia and supplement sedation.

Addiction is arguably the most politically charged side effect of opioid analgesics and is the driving force for the opioid crisis. Dezocine is not a scheduled medication classified by the World Health Organization, and no addiction related to its use has been reported.⁴¹ As described above, dezocine did not display typical behavioral patterns associated with addiction and withdrawal in animal models and even antagonized some addictive behaviors induced by morphine. However, while potentially nonaddictive, dezocine was shown to generalize to morphine and other mu agonist opioid agonists in drug discrimination studies,⁴² and the drug is claimed to cause a euphoria that is similar to that felt under the influence of morphine. Human drug abusers have described dezocine as feeling “similar to dope” (a slang term for substances of abuse, specifically morphine in this study).⁴³ Thus, while the addictive liability of dezocine may be low, there is still the risk of abuse. In this aspect, dezocine may differentiate itself from other mixed mu agonist/kappa partial antagonists such as pentazocine. Pentazocine was touted as being “nonaddictive” when first introduced in the 1960s.^44,45 However, since that time, reports have appeared describing patients who were addicted to pentazocine and experienced withdrawal symptoms following discontinuation after chronic use.^46,47 Methadone and buprenorphine, agents commonly used to treat mu opioid withdrawal, are also used to treat pentazocine withdrawal.⁴⁸ This lack of addictive potential and reduced side effects of dezocine compared to other opioid analgesics have contributed to its growing use in China in the last 20 years.

According to Drugs.com, dezocine displays the potential for drug–drug interactions with 333 other medications, 119 of which are classified as major interactions.⁴⁹ Drugs that interact with dezocine include other opioid analgesics; CNS depressants such as hypnotics, barbiturates, anticonvulsants, and benzodiazepines; muscle relaxants (especially those used to treat irritable bowel syndrome); some calcium channel blockers; drugs that can induce drowsiness and dizziness like antihistamines; anticholinergics; and agents that increase serotonin levels and serotoneric tone such as tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRI), nonselective serotonin/norepinephrine reuptake inhibitors (SNRI), serotonin agonists, and monoamine oxidase inhibitors (which can lead to Serotonin Syndrome). Its use is also cautioned in disease states that involve limited gastrointestinal motility, renal insufficiency, liver disease, and respiratory depression.

Starting in 2014, a series of publications revealed an additional layer of complexity to dezocine’s antinociceptive pharmacology. Dezocine was screened for its affinity at forty-four G-protein coupled receptors and transporters (Table 2).⁵⁰ For most of the targets, dezocine demonstrated little to no affinity, displacing less than 50% of the standard ligands at a concentration of 10 μM. As expected, dezocine demonstrated affinity for the mu, kappa, and delta opioid receptors that was in agreement with previously reported levels and confirmed by Wang et al. in 2018.¹⁶ The study also revealed that dezocine bound to the norepinephrine (NET) and serotonin (SERT) transporters with pK_i values equal to 6.00 and 6.96, respectively.⁵⁰ It was 2 orders of magnitude less potent at inhibiting norepinephrine uptake (pIC₅₀ = 5.68) and equipotent at inhibiting serotonin uptake (pIC₅₀ = 5.86) compared to the standard NET/SERT uptake inhibitor nisoxetine (NET pIC₅₀ = 7.57; SERT pIC₅₀ = 5.99). Docking calculations reported by Liu et al.⁵⁰ based on published crystal structures^51,52 suggested that dezocine may bind at a site on the NET that is near the binding site predicted for nisoxetine and located in the vicinity of TRP103, TYR127, GLU281, and LEU368 (Figure 3). These results are intriguing in light of the evidence that supports the use of norepinephrine uptake inhibitors in the treatment of pain,^53,54 including neuropathic pain.⁵⁵ Clinical data indicate that norepinephrine uptake inhibitors such as duloxetine and milnacepran are effective at treating chronic and neuropathic pain conditions such as diabetic neuropathy and fibromyalgia.^56,57 Furthermore, there is evidence that mu opioid receptors and the NET may exert additive or synergistic effects on pain pathways,⁵⁸ and support for this concept can be seen in the case of the benzenoid class mu opioid agonist/norepinephrine uptake inhibitor tapentadol discovered in the 1980s by Helmut Buschmann and collaborators.^59,60 In addition, pentazocine was reported to reduce phantom limb pain in an amputee,⁶¹ and data show that pentazocine can reduce norepinephrine uptake by reducing cell surface expression of the transporter protein through an opioid-independent mechanism.⁶² In 2014, dezocine was shown to demonstrate inhibitory effects on mechanical allodynia and thermal hyperalgesia in a rat chronic constriction injury (CCI) model of neuropathic pain.⁶³ A study published in 2017 confirmed the antiallodynic and antihyperalgesic effects of dezocine in another neuropathic pain model involving L4/L5 spinal nerve ligation in rats.⁶⁴ In that study, the antinociceptive effects of dezocine could be partially reversed by intrathecal injection of an α2 adrenergic antagonist (yohimbine) and completely reversed by intrathecal injection of a combination of a mu antagonist (CTAP) and an α2 antagonist (yohimbine) or by depletion of spinal norepinephrine through intrathecal administration of 6-hydroxydopamine. A recently posted manuscript awaiting peer review suggests that the antinociceptive effects of dezocine in the CCI model are at least partially mediated through the mTOR/ERK1/2 signaling pathway.⁶⁵

Table 2. List of Receptors and Transporters Examined in the Dezocine Receptor Screening Panel^a.

serotonin receptors		adrenoreceptors		dopamine receptors
5-HT1A	5-HT2C	α1A	α2C	D1
5-HT1B	5-HT3	α1B	β1	D2
5-HT1D	5-HT5A	α1D	β2	D3
5-HT1E	5-HT6	α2A	β3	D4
5-HT2A	5-HT7	α2B		D5
5-HT2B

GABA receptors	sigma receptors	muscarinic receptors
GABA-A	sigma 1	M1
rat benzodiazepine site	sigma 2	M2
		M3
		M4
		M5

histamine receptors	opioid receptors	biogenic amine transporters
H1	μ-receptor	serotonin
H2	κ-receptor	norepinephrine
H3	δ-receptor	dopamine

^aTaken from Liu et al., 2014.⁵⁰

Figure 3.

Docking model of dezocine (gray) and nisoxetine (green) with the norepinephrine transporter. Nearby NET residues are shown in yellow. Coordinates for NET were taken from the model⁵³ based on the crystal structure of A. aeolicus LeuT, RCSB 2A65⁵⁴). Chemical structures were sketched and then prepared with LigPrep (Schrodinger, New York, NY). Coordinates were downloaded and prepared with Protein Preparation Wizard (Schrodinger, New York, NY). Receptor Grid Preparation (Schrodinder, New York, NY) was used to create the docking sites. Standard Precision (Schrodinger, New York, NY) was employed for the docking steps.

The role of dezocine’s potent serotonin uptake inhibition in its ability to reduce neuropathic pain is less certain. Serotonin receptors in the dorsal horn of the spinal cord are thought to play a role in pain modulation, especially 5-HT_1A, 5-HT_2A/C, 5-HT₃, and 5-HT₇ receptors (summarized by Obata⁶⁶). Intrathecal administration of serotonin⁶⁷ or meta-chlorophenylbiguanide (m-CPBG),⁶⁸ an allosteric 5-HT₃ agonist, inhibited allodynia in a rat spinal nerve ligation model. Systemic administration of the highly SSRI paroxetine produced an antihyperalgesic effect in a rat spinal ligation model indirectly through the effect of increased serotonin levels on 5-HT₃ receptors.⁶⁹ Clinical trials examining SSRIs in neuropathic pain conditions (paroxetine, citalopram) found that the drugs did exert a modest effect. However, the “number needed to treat” (NNT, the number of treated patients required to show a statistically significant difference from placebo) was higher for SSRIs compared to agents that possessed both serotonin and norepinephrine reuptake inhibition such as tricyclic antidepressants and mixed serotonin/norepinephrine reuptake inhibitors.⁷⁰ SSRIs are not thought to be nearly as effective at treating pain as norepinephrine reuptake inhibitors, and SSRIs are not recommended for treating neuropathic pain.^70,71 That being said, there are reports of SSRIs relieving acute inflammatory pain.⁷² Thus, dezocine’s serotonin uptake inhibitory activity, while not sufficient to exert robust antinociceptive activity, may synergize with and enhance its less potent norepinephrine uptake inhibition to provide good potency against neuropathic pain.⁷³

The reasons for discontinuation of dezocine in the US have never been officially disclosed, and we may never know those reasons. What is certain is that dezocine has become an important and exciting analgesic medication in China. The combination of potent, effective analgesic effects, lower risk of adverse events and tolerance, and apparent lack of addictive potential have sparked growing interest and enthusiasm and made it the best-selling painkiller in that market, accruing over 40% of the market share for the drug’s current owners, Yangtse River Pharmaceutical Group. The campaign to further expand dezocine’s use and indications continues. A recent survey of the Chinese Clinical Trial Registry (chictr.org.cn) shows that over 30 clinical trials studying dezocine have been registered in China since 2014, the most recent being in February 2021. Thirteen of these trials are listed on Clinicaltrials.gov (Table 3). Indications include cancer pain, additional postoperative analgesic applications, fentanyl-induced cough, and prevention of myoclonus following anesthesia.

Table 3. Clinical Trials Involving Dezocine Currently Listed on Clinicaltrials.gov^a.

NCT no.	title	status
03147066	Dezocine for prevention of catheter-related bladder discomfort	completed
02768168	The effects of dezocine pretreatment on dexamethasone-induced perineal irritation	completed
03014713	Effect of dexmedetomidine for postoperative intravenous patient controlled analgesia	unknown
04111302	Cohort study of auricular acupressure for postoperative pain after hemorrhoidectomy	not yet recruiting
02673723	The application of dezocine combined with sufentanil for awake tracheal intubation	completed
03221491	Comparison of patient-controlled analgesia with different background infusion	completed
03823846	The effect of doctor-nurse-patient cooperative analgesic linkage program on movement evoked pain	unknown
02114463	Comparison of two kinds of postoperative analgesia after amputation	unknown
04513808	Total intravenous anesthesia and recurrence free survival	recruiting
02094339	Comparison of three kinds of postoperative analgesia after total knee arthroplasty	unknown
02289586	Interventional bronchoscopy under noninvasive ventilation	unknown
04386603	Risk factors for postoperative shoulder-tip pain after laparoscopic surgery undergoing anesthesia	completed
02619513	Effects of dexmedetomidine used in continuous thoracic paravertebral blocks	completed

^aLast accessed April 13, 2021.

Another motivator of renewed interest in dezocine is its potential for treating neuropathic and chronic pain. Traditional opioids are not particularly effective for treating neuropathic pain and suffer from the addiction, tolerance, and the potentially lethal side effects discussed above. Certain anticonvulsants such as carbamazepine, oxycarbazepine, topiramate, gabapentin, and pregabalin are often the first line of treatment for neuropathic conditions. But these drugs also suffer from numerous side effects, including chest pain, confusion, sedation, constipation, and serious allergic reactions and are contraindicated in pregnant women. Antidepressants such as duloxetine, venlafaxine, imipramine, and amitriptyline, particularly those possessing NET inhibition, are used to treat neuropathic pain, but these drugs also display a host of undesirable side effects, and patients who take them chronically can develop dependence. There are also topical options such as the sodium channel blocker lidocaine and the TRPV1 agonist capsaicin, but their use is limited due to the need for topical delivery. As mentioned above, pentazocine, which indirectly inhibits the NET by reducing cell surface expression, was reported to provide analgesic efficacy in a patient with phantom limb pain.⁶¹ Dezocine’s unique combination of mu opioid partial agonism and NET inhibition, its lack of addiction and tolerance, reasonable side effect profile, and its encouraging results in multiple animal models of neuropathic pain certainly recommend it for clinical assessment in various neuropathic and chronic pain conditions (e.g., postherpetic and diabetic neuralgia, fibromyalgia, etc.). That effort has already begun in China. In one clinical trial, dezocine was found to significantly reduce hyperalgesia (as assessed with Von Frey filaments), perception of pain (lower pain scores), and the request for rescue analgesics and patient-controlled intravenous analgesia compared to placebo in patients undergoing gastrectomy with no significant adverse effects reported during the 48-h study period.⁷⁴ In addition, a recently registered clinical trial listed in the Chinese Clinical Trial Registry (ChiCTR20000034774; initiated 07/18/2020) involves the study of dezocine in the prevention of hyperalgesia induced by anesthesia that includes the use of the short-acting opioid remifentanil.⁷⁵

Since its discontinuation in the western hemisphere in 2011, dezocine has experienced a resurrection in China, capturing over 45% of what many describe as a “booming opioid market”. It appears that the Chinese government, which historically expressed a conservative view on the use of opioids and pain killers in general, has become open to the notion of expanding the use of dezocine to indications other than postoperative analgesia. Dezocine’s unique collection of activities represent an innovative profile for an analgesic agent, combining the efficacy and safety that comes from mu and kappa opioid partial agonism with the synergy that arises from its inhibition of norepinephrine uptake. While it is still too early to tell, some preclinical and clinical data hint at the possibility that dezocine might be repositioned as a drug for neuropathic pain conditions, something that traditional mu agonist opioids do not do very well. Given the expiry of patent coverage on dezocine, the stigma of being discontinued and the current political climate around the “opioid crisis”, it is not clear whether dezocine will ever find increased use in western markets. But, at least for China, dezocine is “back” and “back” to stay.

Glossary

Abbreviations

CCI

chronic constriction injury

CTAP

d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH₂ (disulfide bridge: 2–7)

DADLE

d-Ala²,d-Leu⁵]-enkephalin

DAMGO

d-Ala²,N-MePhe⁴, Gly-ol]-enkephalin

FDA

United States Food and Drug Administration

GPCR

G-protein coupled receptor

MAC

minimal alveolar concentration

m-CPBG

meta-chlorophenylbiguanide

NET

norepinephrine transporter

NNT

number needed to treat

SERT

serotonin transporter

SNL

spinal nerve ligation

SNRI

serotonin/norepinephrine reuptake inhibitor

SSRI

selective serotonin reuptake inhibitor

TRPV1

transient receptor potential cation channel subfamily V member 1

U69583

(+)-(5α,7a,8b)-N-methyl-N-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]-benzeneacetamide

The authors declare no competing financial interest.