Opiranserin (VVZ-149): what’s new in analgesics

Abstract

Opiranserin (VVZ-149) is a novel non-opioid, non-steroidal intravenous analgesic with triple antagonistic activity at glycine transporter 2 (GlyT₂), purine 2 receptor 3 (P₂X₃), and serotonin receptor (5-HT_2A). Its half-maximal inhibitory concentrations are 0.86, 0.87, and 1.3 μM for GlyT₂, P₂X₃, and 5-HT_2A, in the order of strength of inhibition. GlyT₂ is a sodium- and chloride-dependent transporter that recycles Gly from the synaptic cleft into the presynaptic Gly terminals in the spinal cord, brainstem, and cerebellum. Inhibition of GlyT₂ allows Gly to remain longer in the synaptic cleft and bind to postsynaptic Gly receptors, thereby enhancing inhibitory neurotransmission and potentially relieving chronic neuropathic pain. P₂X₃ antagonists are being investigated for refractory chronic cough, overactive bladder, endometriosis, and chronic pain, especially diabetic neuropathic pain. A 5-HT_2A antagonist is used to treat psychiatric disorders, cardiovascular disorders, and nausea/vomiting. It also attenuates pain-related behavior and suppresses 5-HT_2A expression in the dorsal root ganglion. Based on the triple analgesic mechanisms, opiranserin is mainly suitable for neuropathic pain which can contribute to pain chronification and partially helpful for nociceptive pain. Among the three proposed analgesic targets of opiranserin, published studies have focused on the effects mediated by GlyT₂ and 5-HT_2A antagonism, whereas the contribution of P₂X₃ antagonism has not been adequately investigated. Therefore, therapeutic effects and adverse events related to P₂X₃ cannot be fully anticipated. The major clinical concern is that opiranserin cannot be added to disposable intravenous patient-controlled analgesia devices due to their limited volume. Repeated administration may accumulate its active metabolite, VVZ-368 (N-desmethyl-VVZ-149).

INTRODUCTION

Opiranserin (VVZ-149, Unafra®; Vivozon Inc.) has triple antagonistic effects for the glycine transporter type 2 (GlyT₂), serotonin receptor 2A (5-HT_2A), and purine 2 receptor 3 (P₂X₃) [1]. It is composed of a molecular formula of C₂₁H₃₄N₂O₅ and has a molecular weight of 394.512 g/moL. The half-maximal inhibitory concentration (IC₅₀) of opiranserin is 0.86, 0.87, and 1.3 μM for antagonistic effects of the GlyT₂, P₂X₃, and 5-HT_2A, respectively [2].

The GlyT₂ inhibitors increase the inhibitory neurotransmitter Gly from preventing reuptake of Gly from the synaptic cleft into presynaptic inhibitory glycinergic neurons in the dorsal horn of the spinal cord, thereby presenting a reduced ascending pain pathway. They are helpful in the condition of reduced inhibitory pain pathway in chronic neuropathic pain [3]. The P₂X₃ antagonists bind to their receptors which are located in the sensory nerve fibers, thus preventing adenosine triphosphate (ATP) which is released from injured or inflamed tissue and activates the nerve fibers, finally reducing the ascending pain signal to the brain. The P₂X₃ antagonists are suitable for treatment for postoperative inflammatory/nociceptive pain and chronic neuropathic pain [4]. The 5-HT_2A antagonists provide pain relief mainly by facilitating the descending pain modulation system, especially in neuropathic pain and inflammatory pain [5].

Opiranserin is permitted to be used for postoperative pain control in South Korea as of December 2024. Postoperative pain, similar to the definition of pain, has sensory and emotional components. The sensory component of pain includes nociceptive pain, inflammatory pain, and neuropathic pain. The nociceptive pain (sharp, aching, or throbbing) results from the stimulation of nociceptors by tissue trauma from surgical incision and tissue retraction. Inflammatory pain occurs from sensitized nociceptive fibers by released inflammatory mediators at the surgical site. It shows classic signs of inflammation, such as pain, heat, redness, and swelling, which lasts for hours to days. Neuropathic pain arises from direct injury of neuronal structures, such as peripheral nerves, and becomes a main cause of chronification of pain, developing chronic persistent postsurgical pain (CPSP) and new persistent opioid use after surgery. The emotional component of postoperative pain includes anxiety, depression, and the pain panic (fear) of surgery, which provokes a reduced pain threshold, finally contributing to chronification of postoperative pain [6].

Neuropathic pain component in CPSP is more often reported in amputation, inguinal herniotomy, mastectomy, cesarean section, thoracotomy, knee arthroplasty, hip arthroplasty, and nuclectomy [7].

Even though limited studies are found, this paper provides a review of appropriate therapeutic effects for pain and known adverse events based on the supposed analgesic mechanisms from the available articles.

MAIN BODY

1. Previous studies related to opiranserin (VVZ-149)

Only eight published studies, including 1 clinical trial protocol, 4 clinical trials, and 3 review articles, were found in PubMed at the end of 2025 (Table 1). The first clinical trial protocol for the analgesic efficacy and safety of opiranserin was published by Nedeljkovic et al. [1]. Of the 120 patients who underwent laparoscopic colorectal surgery, 80 and 40 patients received intravenous opiranserin/hydromorphone and placebo/hydromorphone, respectively. Their primary outcome was the difference in the sum of pain intensity over 8 hours. Secondary outcomes included opioid consumption (mg) for 24 hours, pain intensity (numeric rating scale score 0–10), categorized pain relief score (0–5) and total pain relief over 8 and 24 hours, patient’s satisfaction (1–4), and adverse reactions. Findings and conclusions were excluded from this publication, which focused exclusively on the study’s rationale and methods [1].

Table 1.

Previous studies related to opiranserin (VVZ-149)

Author	Title	Summary of the study	Type of the article
Nedeljkovic et al. [1] (2017)	Randomised, double-blind, parallel group, placebo-controlled study to evaluate the analgesic efficacy and safety of VVZ-149 injections for postoperative pain following laparoscopic colorectal surgery	Additional intravenous administration of opiranserin in patients who underwent laparoscopic colorectal surgery (a loading dose of 1.8 mg/kg for 0.5 hours followed by a maintenance dose of 1.3 mg/kg/hour for 7.5 hours	Clinical trial protocol without results
Oh et al. [9] (2018)	Safety, tolerability, and pharmacokinetic Characteristics of a novel nonopioid Analgesic, VVZ-149 injections in healthy Volunteers: a first-in-class, first-in-human Study	Opiranserin was tolerated at the single dose of up to 8 mg/kg and multiple doses of up to 7 mg/kg. Over 28% (13 of 46) participants experienced adverse events such as somnolence, nausea, dizziness, and/or headache in the single-ascending-dose group; 30% (6 of 20) participants complained of dizziness, headache epistaxis, hypoesthesia, and/or presyncope in the multiple-ascending dose group.	Phase 1 clinical trial with results
Song et al. [11] (2021)	Role of VVZ-149, a novel analgesic molecule, in the affective component of pain: results from an exploratory proof-of-concept study of postoperative pain following laparoscopic and robotic-laparoscopic gastrectomy	Opiranserin was helpful in patients who required rescue dosing during the first 2 hours post-emergence by alleviating the affective component of pain.	Phase 2b clinical trial
Nedeljkovic et al. [8] (2022)	Exploratory study of VVZ-149, a novel analgesic molecule, in the affective component of acute postoperative pain after laparoscopic colorectal surgery	Even though pain intensity of the opiranserin group did not show the difference compared to the placebo group, opioid consumption for 24 hours postoperatively was lower (34.2%) with fewer patient-controlled analgesia demands. In patients with high level of negative affect including anxiety, depression, and pain panic, opioid consumption was much lower (40%) compared to placebo group. The most frequent adverse reactions were somnolence and headache.	Phase 2a clinical trial
Lee et al. [12] (2025)	Reduction of postoperative pain and opioid consumption by VVZ-149, first-in-class analgesic molecule: a confirmatory phase 3 trial of laparoscopic colectomy	The authors did not mention where the pain relief came from (emotional component or sensory component) and why they had changed the pain intensity score from numeric rating scale into SPID (to express pain intensity difference to be exaggerated).	Phase 3 clinical trial
Zhen et al. [13] (2025)	Discovery of a novel multitarget analgesic through an in vivo-guided approach	Opiranserin is a promising candidate for diverse pain sources.	Review
Cioffi et al. [14] (2025)	Current nonopioid small molecule approaches toward the treatment of neuropathic pain	The authors considered it as a good candidate for neuropathic pain.	Review
Lee et al. [15] (2025)	Opiranserin injection (Unafra®; Vivozon Inc.) as a first-in-class, non-opioid analgesic for the treatment of acute postoperative pain	Even though this paper was a well-described review article describing from the preclinical study to the phase 3 trial systemically, they did not mention about the mechanism of analgesic therapeutic action or adverse reactions related to P2X3 antagonistic effect (IC50 = 0.87).	Review

SPID: sums of pain intensity difference, P₂X₃: purine 2 receptor 3, IC₅₀: half-maximal inhibitory concentration.

The results of the phase 2a clinical trial was published in 2022 with the total number of participants reduced to 60. The final number of analyzed patients was 36 in the opiranserin group and 16 in the placebo group. The opiranserin group reported slightly lower pain intensity compared to the placebo group. The intervention significantly reduced 24-hour postoperative opioid consumption by 34.2% and lowered patient-controlled analgesia demands. Notably, in patients with a high preoperative negative affectivity (anxiety, depression, or pain panic), opioid reduction reached 40% compared to the placebo. Adverse reactions were mild, with somnolence and headache being frequent [8].

The results of the phase 1 study for safety, tolerability, and pharmacokinetics of opiranserin injection was published in 2018. A total of 66 patients were divided into 46 participants of the single-ascending-dose group (0.25, 0.5, 1, 2, 4, 6, or 8 mg/kg) and 20 participants of the multiple-ascending-dose group (4 or 7 mg/kg via 4 hours if a continuous intravenous infusion twice a day, separated by 8 hours) with the placebo groups (10 and 6 participants, respectively). In the single-ascending-dose group, the plasma concentration of opiranserin and its active metabolite (VVZ-368) increased proportionally with dose increase. In the multiple-ascending-dose groups, opiranserin did not accumulate in the plasma; VVZ-368 showed a 1.23- to 2.49-fold accumulation. The plasma concentrations of VVZ-149 and VVZ-368 were best described by a model with 2 parent compartments and a metabolic compartment. The loading dose (2.6 mg/kg/hour for 30 minutes) followed by the maintenance dose (0.9 mg/kg/hour) was considered to be the proper dose regimen for achieving the effective concentration. Opiranserin was tolerated at a single dose of up to 8 mg/kg and multiple doses of up to 7 mg/kg. Over 28% (13 of 46) of the participants experienced adverse events such as somnolence, nausea, dizziness, and/or headache in the single-ascending-dose group; 30% (6 of 20) of the participants complained of dizziness, headache, epistaxis, hypoesthesia, and/or presyncope in the multiple-ascending dose group. The adverse events were mild, transient, and self-limiting after discontinuation of administration, without changes in electrocardiogram, vital signs, physical examination, or clinical laboratory tests. However, these mild adverse reactions disappeared after discontinuation of administration [9].

Opiranserin has an IC₅₀ = 0.86 μM for the GlyT₂; ORG25543 is more selective and irreversible than GlyT₂ inhibitor (IC₅₀ = 0.016 μM) [9,10].

Both these compounds had undesirable dose-limiting toxicity, such as tremor and stereotypy, due to complete blockage of GlyT₂ and coinhibition of GlyT₁. Opiranserin showed moderate GlyT₂ inhibition compared to ORG25543; however, it also has another two P₂X₃ and 5-HT_2A antagonistic effects for pain relief. Opiranserin is mainly excreted by hepatic metabolism. Cytochrome P450 3A4 (CYP3A4) and CYP2D6 are the major and minor metabolizing enzymes, respectively [9].

A study of the analgesic efficacy and safety of opiranserin regarding the affective component of pain in laparoscopic and robotic-laparoscopic gastrectomy (phase 2b study) was published in 2021. The primary outcome, average pain intensity (numeric rating scale) over the 24-hour post-emergence period, was generally lower in the opiranserin group compared to the control group. Notably, pain scores were statistically significantly lower at 4 hours post-emergence in the opiranserin group (1.93 ± 0.98) compared to the control group (2.72 ± 1.89). Upon review, the 1-point difference in the numeric rating scale score does not meet the threshold for a minimal clinically important difference, suggesting the opiranserin is not superior to the placebo. Additionally, the observed reduction in rescue opioid consumption may stem from the sedative effects of opiranserin. The secondary outcomes were opioid consumption, patient-controlled analgesia demands, rescue dosing, and plasma exposure. In the opiranserin group, opioid consumption was significantly lower during the 24 hours following emergence. To compare analgesic efficacy, this study employed an equianalgesic dosing model, utilizing 30 mg of intravenous ketorolac, 22 μg of fentanyl, or 25 mg of meperidine, notwithstanding the differing pharmacological pain pathways targeted by non-opioid and opioid agents. Significantly fewer patient-controlled analgesia demands and lowered rescue analgesic doses were observed in the opiranserin group. At 8 hours post-emergence, the mean plasma concentrations of opiranserin and VVZ-368 were 1,421 and 421 ng/mL, respectively. Among a total number of 59 subjects, 48 cases of adverse reactions were reported (26 cases from 16 subjects [53.3%] and 22 cases from 16 subjects [55.2%] in the opiranserin and placebo group, respectively). The common adverse reactions were nausea, hypertension, headache, dizziness, chest discomfort, pruritus, and postoperative fever. Other adverse reactions were reported once, such as vomiting, musculoskeletal pain, insomnia, and hematuria. The authors concluded that opiranserin was helpful in patients who required rescue dosing during the first 2 hours post-emergence by alleviating the affective component of pain [11].

A phase 3 trial of opiranserin for reduction of postoperative pain and opioid consumption in patients receiving laparoscopic colectomy was published in 2025. The sums of pain intensity difference (SPID) from baseline over 12 hours after infusion of opiranserin, as a primary outcome, were 26.8 and 19.9 in the opiranserin and placebo groups, respectively. Opioid consumption, total amount and number of patient-controlled analgesia request, and rescue medication consumption, as secondary outcomes, were reduced during the first 12 hours post-dose compared with the placebo group. No differences were observed in SPID and the percentage of patients with a 40% decrease in maximal pain area remained similar between the groups. The most frequent adverse reactions were nausea (34%), post procedural fever (31.9%), and vomiting (13%) [12]. The authors did not specify whether the pain relief was emotional or sensory in nature, nor did they justify the transition from the numeric rating score to the SPID.

There are three review articles related to opiranserin. Zhen et al. [13] described opiranserin as a multi-target analgesic: GlyT₂ blocking with an IC₅₀ = 0.86 μM inhibiting the reuptake of Gly followed by inhibition of spinal pain processing, P₂X₃ antagonist with an IC₅₀ = 0.87 μM inhibiting nociceptive signaling in peripheral sensory neurons, and 5-HT_2A antagonist with an IC₅₀ = 1.3 μM modulating central serotonin pathways related to pain perception. The authors concluded that opiranserin is a promising therapeutic candidate for the management of various pain etiologies [13].

Cioffi et al. [14] described opiranserin being introduced as a successful reversible GlyT₂ inhibitor, developed from the ORG25543 scaffold. The authors regarded opiranserin as a viable option for neuropathic pain.

While Lee et al. [15] focused on opiranserin’s antagonism of GlyT₂ and 5-HT_2A, it is important to note its additional potent activity at the P₂X₃. The authors reported that opiranserin significantly reduced opioid consumption by targeting specific nociceptive pathways. They also highlighted that opiranserin demonstrates how ex vivo phenotypic screening, combined with a bait-target approach, can identify multi-target agents for precision analgesia. While this review systematically covers the progression from preclinical studies to phase 3 trials, it fails to address the analgesic mechanism of action or the adverse reactions associated with P₂X₃ antagonism (IC₅₀ = 0.87) [15].

2. Mechanisms of analgesic action

Opiranserin has triple antagonistic effects for the GlyT₂, 5-HT_2A, and P₂X₃. Therapeutic effects and adverse reactions, originating from the triple antagonistic effects, can be speculated on. In addition, current clinical applications of each of the GlyT₂ inhibitors, 5-HT_2A antagonists, and P₂X₃ antagonists are helpful to suppose the analgesic effect and adverse reactions of opiranserin. It is also helpful to know where GlyT₂, 5-HT_2A, and P₂X₃ are distributed in the human body (Table 2, Fig. 1) [9,10,13,16].

Table 2.

Triple antagonistic effects of opiranserin for analgesia and their biological activities, main distribution, biological effects, representative antagonists, clinical uses [9,10,13,16]

Mechanisms of analgesic action	Biological activity	Main distribution GlyT2 transporter, 5-HT2A receptor, and P2X3 receptor in the human body			Biological effects	Representative antagonists	Targeting clinical use
GlyT2 antagonist	IC50 = 0.86 μM	Central nervous system: spinal cord, especially dorsal horn, brain stem, and cerebellum		Peripheral tissues: pancreas	Increases Gly levels in the spinal cord, enhancing inhibitory synaptic transmission to reduce pain signals to the brain	ORG25543	Neuropathic pain
5-HT2A antagonist	IC50 = 1.3 μM	Central nervous system: cerebral cortex, hypothalamus, spinal cord, and brain stem		Peripheral tissues: platelets, vascular endothelial cells, and vascular smooth muscle cells	Decreases descending facilitatory modulation of pain from the brain and reduces nociceptor activation in peripheral nerves	Atypical antipsychotics: clozapine, olanzapine, and risperidone	Psychosis, migraine prophylaxis, and insomnia
P2X3 antagonist	IC50 = 0.87 μM	Central nervous system: central projections of primary sensory neurons within the dorsal horn of the spinal cord and brain stem	Sensory ganglia: dorsal root ganglia, trigeminal ganglia, and nodose ganglia	Peripheral nerve terminal: skin, viscera, airways/lungs, dental pulp, and carotid body	Blocks P2X3 receptors (IC50 = 0.87 μM) to further inhibit peripheral sensitization and nociceptive signaling	Gefapixant, eliapixant, sivopixant, filapixant, and camlipixant	Neuropathic pain, cough, overactive bladder, and endometriosis

5-HT_2A: serotonin receptor, GlyT₂: glycine transporter 2, P₂X₃: purine 2 receptor 3, IC₅₀: half-maximal inhibitory concentration.

Fig. 1.

Mechanism of analgesic action of opiranserin. Opiranserin produces its analgesic effects or adverse reactions through triple antagonistic effects on the GlyT₂, 5-HT_2A, and P₂X₃. (A) The Gly, a major inhibitory neurotransmitter, is concentrated in the dorsal horn (especially in the lamina II, substantia gelatinosa) and in the ventral horn. It is released by small interneurons, such as Renshaw cell, and acts on the Gly receptors, thus reducing excitability, reflexes, and controlling sensory/motor signals. The Gly is released from presynaptic terminals and binds to the Gly receptor on the postsynaptic neurons. The binding opens chloride channels, allowing the chloride ions to cause hyperpolarization, thus reducing the pain signaling. The GlyT₂ is located in the glycinergic neurons and recycles the Gly to the presynaptic terminals to refill synaptic vesicles. The postsynaptic Gly receptors, composed of α and β subunits, lead to open chloride influx that hyperpolarize neurons, resulting in reduction of ascending pain signals to the brain. GlyT₂ inhibitors block reuptake of Gly into the presynaptic nerve terminals in the spinal cord, finally increasing in the extracellular concentration of Gly in the synaptic cleft enhances inhibitory neurotransmission. However, GlyT₁ is mainly located on the glial cells which regulates overall synaptic Gly level, affecting N-methyl-D aspartate receptors. (B) P₂X₃ receptors are mainly located in the C-fibers of the primary afferent fibers in the dorsal horn which are kinds of ligand-gated ion channels. When tissue injury, inflammation, or nerve damage occurs, a large amount of ATP is released into the synapse of the dorsal horn, finally activating P₂X₃ leading to calcium influx. P₂X₃ antagonists bind competitively to the P₂X₃ and prevent ATP binding. Thus, they finally inhibit transmission and sensitization of pain. (C) 5-HT_2A is located in the dorsal horn, especially in the laminae I to III, and has seven-transmembrane receptors which are kinds of GPCRs. The Descending pain modulation starts from the rostroventral medulla and releases a family of 5-HT, including 5-HT_2A, into the dorsal horn, especially the primary afferent fibers, projective neurons, excitatory interneurons, and inhibitory interneurons. 5-HT_2A antagonists block their receptors, thus reduce the activation of 5-HT_2A receptors by serotonin. GlyT₂: glycine transporter 2, 5-HT_2A: serotonin receptor, P₂X₃: purine 2 receptor 3, GPCRs: G-protein-coupled receptors, 5-HT: 5-hydroxytryptamine, ATP: adenosine triphosphate, GPCRs: G-protein-coupled receptors, IC₅₀: half-maximal inhibitory concentration.

1) GlyT₂ antagonist

Gly, an amino acid, is known as a major inhibitory neurotransmitter, concentrated in the spinal cord, brain stem, and peripheral nervous system. The inhibitory glycinergic neurotransmission is impaired in chronic pain status. Presynaptic Gly is released into the synaptic cleft and attaches to the postsynaptic receptor, expressing reduced pain signaling. GlyT₂, located on the presynaptic terminal, reuptakes the synaptic Gly in order to refill the presynaptic vesicle. GlyT₂ antagonist increases synaptic Gly and activates the postsynaptic receptor, thus suppressing pain signals. The postsynaptic Gly receptor contains two transmembrane subunits of alpha (48 kDa) and beta (58 kDa) and exhibits a heterogenicity from 7 different alpha subunits [16,17]. Both GlyT₁ and GlyT₂ are mainly distributed in the spinal cord, especially the lamina III of the dorsal horn. GlyT₂ is also located in the brain stem; GlyT₁ is also distributed in the higher brain regions and peripheral tissues, including the pancreas and liver [18]. The GlyT₂ inhibitors enhance inhibitory neurotransmission in chronic neuropathic pain, characterizing allodynia and hyperalgesia [19].

GlyT₂ is known as a protein encoded by the SLC6A5 gene, and acts as a sodium- and chloride-dependent Gly transporter. Its dysfunction leads to hyperekplexia, which is a sensorimotor syndrome of perinatal clinical relevance, leading to an energic startle reflex in response to certain trivial stimuli, finally causing death due to apnea episodes [20].

There is no U.S. Food and Drug Administration-approved drug that is currently used as a GlyT₂ antagonist. The known representative GlyT₂ inhibitors are ALX1393 and ORG25543, with IC₅₀ of 100 nM and 16 nM, respectively [19]. ALX1939 has not progressed to clinical use due to poor central nervous system penetration (with only 5% crossing the blood-brain barrier following intravenous administration), an inadequate pharmacokinetic profile, and dose-limiting off-target effects. Specifically, high doses inhibit GlyT₁, leading to respiratory depression and motor impairment [21]. Despite its high selectivity, ORG25543 is unsuitable for clinical development due to its pseudo-irreversible binding to GlyT₂. Its high affinity and slow off-rate lead to a narrow therapeutic window, with animal studies reporting severe on-target toxicity, including tremors, seizures, and mortality [22].

2) 5-HT_2A antagonist

Seven families have been identified in neurotransmitter 5-hydroxytryptamine (5-HT or serotonin) receptors: 5-HT_{1A, B, D, E, F}; 5-HT_{2A, B, C}; 5-HT₃; 5-HT₄; 5-HT_{5A, B}; 5-HT₆; and 5-HT₇. All serotonergic receptors mediate their actions via guanine nucleotide-binding (G) proteins (Gα_i, Gα_q/11, or Gα_s), except 5-HT₃ which operates as a ligand-gated ion channel [23].

The 5-HT_2A is found in both the central nervous system and peripheral tissues. In the brain, the receptors are concentrated in the frontal and parietal cortex, hippocampus, basal ganglia, and amygdala. In the spinal cord, 5-HT_2A is also found in the dorsal root ganglia which are deeply related to pain perception and descending pain modulation. In addition, they are also found in the peripheral tissues, such as the smooth muscles of the blood vessels, bronchi, intestines, platelets, and buccal muscles [23].

The most common clinical application of 5-HT_2A antagonists is currently for schizophrenia and bipolar disorder as a fundamental part of the pharmacology of atypical antipsychotics (clozapine, olanzapine, risperidone, and quetiapine) and some antidepressants, such as tricyclic antidepressants and psilocybin. Atypical antipsychotics, unlike typical antipsychotics, which block D₂ receptors reducing positive symptoms of psychosis, antagonize 5-HT_2A which is expressed on the prefrontal cortex neurons that project to the dopamine-producing area, such as the ventral tegmental area, reducing negative symptoms of psychosis (flat affect, alogia, avolition, anhedonia, asociality, and apathy). Atypical antipsychotics can be divided into strong (risperidone, ziprasidone, paliperidone, and aripiprazole) and weak (clozapine and quetiapine) D₂ antagonists [24–27]. Common adverse reactions to 5-HT_2A antagonists include drowsiness, fatigue, weight gain, gastrointestinal upset, constipation, headache, and pruritus [25].

Nortriptyline, a representative tricyclic antidepressant, exerts its therapeutic effect by inhibiting the uptake of norepinephrine and serotonin (5-HT_2A and 5-HT_2C). Increased norepinephrine and serotonin levels in the central nervous system are believed to be central to its role in mood regulation and pain modulation. Tricyclic antidepressants are the main analgesics for negative symptoms of neuropathic pain, such as hypoesthesia and anesthesia. Its analgesic action results not only from the central nervous system but also from peripheral and descending pathways in neuropathic pain. In neuropathic pain, it relieves pain via a peripheral mechanism on the β_2-adrenoreceptor on the non-neuronal satellite cells within the dorsal root ganglion, thus reducing production of local tumor necrosis factor alpha. It is also related to descending pain inhibition from the periaqueductal gray through the rostral ventromedial medulla to the dorsal root ganglion. Pain relief from nortriptyline is largely attributed to increased availability of norepinephrine and serotonin, which leads to the downregulation of adrenergic and serotonergic receptors [26,28,29].

As a 5-HT_2A antagonist, opiranserin may exhibit therapeutic effects and adverse reactions similar to those of atypical antipsychotics and tricyclic antidepressants. Pain physicians frequently use these drug classes to manage pain with negative symptoms, insomnia, depression, and panic.

3) P₂X₃ antagonist

Purinergic receptors (purinoceptors), a family of plasma membrane proteins, can be divided into P₁ receptors (selectively activated by adenosine) and P₂ receptors (selectively activated by extracellular nucleotides like ATP, adenosine diphosphate, uridine-5’-triphosphate, and uridine-5’-diphosphate). P₁ receptors can be divided into A1, A2A, A2B, and A3. All P₁ receptors are G-protein-coupled receptors (GPCRs). P₂ receptors can also be divided into P_2X (ligand-gated ion channels) and P_2Y (GPCRs). P₂X₃ among the seven P₂XR families (P₂XR_1–7), is an ATP-dependent non-selective membrane cation channel. They play a key role in the development of neuropathic pain in relation to nerve transmission and sensitization of the central nervous system [30].

P₂X₃ is mainly found in the small-diameter neurons in the dorsal root ganglia, trigeminal ganglia, and nodose ganglia (a sensory cluster in the vagus nerve), lamina II of the dorsal horn in the spinal cord, peripheral tissues (skin, viscera, and heart), and motor neurons/ secretomotor neurons in the colon [31].

ATPs are released from injured and inflamed tissues. The P₂X₃ in the sensory neurons can detect the ATP even at low concentration. This sensory neuron activation leads to neuronal hypersensitivity resulting in chronic pain status [32]. Increased P₂X₃ activity and membrane expression contributed to development of chronic pain with mechanical allodynia in diabetic rats [33].

Representative P₂X₃ antagonists include gefapixant, eliapixant, sivopixant, filapixant, and camlipixant. The most common clinical application of P₂X₃ antagonists is unexplained chronic cough or refractory chronic cough. Gefapixant showed favorable results with the highest antitussive effectiveness, but showed adverse events with the highest prevalence being taste disturbance (hypogeusia, ageusia, and dysgeusia), and the highest prevalence of discontinuation [34]. Gefapixant is a first-in-class P₂X₃ antagonist which is approved for the treatment of unexplained chronic cough or refractory chronic cough in Japan, the European Union, and Switzerland. P₂X₃ antagonists inhibit ATP-mediated activation of P₂X₃ receptors on C and Aδ primary afferent fibers during airway inflammation, thereby reducing cough. Its usual regimen for dosage was 45 mg twice daily [35].

Eliapixant has been tried to treat overactive bladder, based on the mechanism of action which reduces abnormal ATP signaling (afferent impulses), which causes urgency and frequency. However, it also produces taste disturbance [36].

Eliapixant and gefapixant have been tried to treat endometriosis, based on the idea of reducing elevated levels of P₂X₃ from activation of extracellular ATP released from a chronic inflammatory condition. However, there was no significant symptom improvement in endometriosis-associated pelvic pain [37,38].

The P₂X₃ antagonists prevent ATP release from damaged cells, thus the reduced ATPs reduce the chance of sensitizing or activating C-fiber sensory neurons. Finally, the P₂X₃ antagonists can be used for neuropathic pain, cough, overactive bladder, and endometriosis. However, the representative adverse event, taste disturbance, should not be overlooked.

P₂X₃ antagonists are currently being evaluated in human subjects for other conditions, but only for endometriosis for pain conditions [39].

3. Pharmacokinetics

1) Absorption

After a 4-hour intravenous continuous infusion of opiranserin, the blood concentration showed continuous incremental increase, reaching maximal blood concentration (Cmax = 1,684.72 ± 601.15 ng/mL) at 3 to 4.3 hours after cessation of the infusion. Elimination half-life (t_1/2) was 1.5 to 2.1 hours after cessation of infusion. Opiranserin (VVZ-149) and VVZ-368 showed a dose-dependent increase. VVZ-368, unlike opiranserin, accumulated in the plasma after the fifth and sixth doses in healthy male volunteers. Opiranserin showed linear pharmacokinetic characteristics and can be safely administered at the dose of between 0.5 and 8 mg/kg [9].

2) Distribution

The plasma protein binding rate is known to be 64%–78% and 63%–69% for opiranserin and VVZ-368, respectively. The brain tissue binding rates of opiranserin and VVZ-368 are 92.92% and 93.02%, respectively [15]. In an animal study using rats, maximal concentration was found in the large intestine, followed by the small intestine and kidney. Maximal concentration was reached 1 to 2 hours after administration and disappeared completely after 8 hours [9].

3) Metabolism

Opiranserin is mainly metabolized in the liver by the human CYP3A4 enzyme system [15]. The primary active metabolite of N-desmethyl-VVZ-149 is VVZ-368. VVZ-368 has identical pharmacological properties to the parent compound, opiranserin. It also shows low oral bioavailability due to extensive first-pass metabolism [13,15]. Both opiranserin and VVZ-368 showed linear pharmacokinetic characteristics and dose-proportional increase in plasma exposure [15].

4) Excretion

Opiranserin is primarily excreted via the kidneys into the urine or into the bile for elimination in the feces [15].

4. Clinical application

1) Dose and dosage

One thousand mg of opiranserin in 100 mL is recommended to be mixed in a diluted solution of 400 mL of normal saline. A loading dose of 160 mg of opiranserin in 80 mL of the diluted solution is also recommended to inject into a peripheral vein continuously for 30 minutes. A maintenance dose of 840 mg of opiranserin in 420 mL of the diluted solution is recommended to inject for 9.5 hours. Maximal daily dose is 1,000 mg. The diluted solution should be used within 48 hours. It is not permitted to administer into the epidural or subarachnoid space [15].

2) Contraindications and cautions

The manufacturer’s contraindications for opiranserin include hypersensitivity, heart diseases, such as unstable angina, congestive heart failure, QRS > 200 msec or corrected QT interval for heart rate (QTcF) > 450 msec for male/QTcF > 470 msec for female patients, patients who receive medications which prolong PR or QRS interval, moderate to severe hepatorenal failure, and patients who receive potent CYP3A4 inhibitors. In addition, children under 18 years old, pregnant women, and breast-feeding mothers, who were not part of the study for safety of opiranserin, should be excluded from use [40].

The cautions require mild hepatorenal disorders, mild heart dysfunction, and patients who receive organic cation transporter 2 (OCT2) or multidrug and toxin extrusion 1-K and 2-K (MATE 1-K and 2-K) substrates [40].

In addition, PR and QRS prolongations were observed during intravenous administration. However, the prolongations were recovered within 24 hours after cessation of the administration [40].

3) Drug interactions

Opiranserin is mainly metabolized by the CYP3A4/5. Opiranserin and its active metabolite VVZ-368 have a mild to moderate inhibitory effect for the CYP3A4/5, OCT2, and MATE 1/2K [40].

4) Adverse events

The opiranserin group, compared to the placebo group, showed that nausea (45.1% vs. 38.1%), vomiting (15.6% vs. 8.8%), headache (14.5% vs. 13.4%), dizziness (10.5% vs. 5.6%), somnolence (6.0% vs. 2.9%), and itching (5.1% vs. 2.9%) were more frequent. Postoperative fever was a frequent objective finding, but the incidence was lower than the placebo group (11.5% vs. 12.0%) [40].

In a study in laparoscopic colectomy, the common adverse reactions included nausea (34%), fever (31.9%), and vomiting (13.5%). The other, less frequent, common adverse reactions were hypertension (8.5%), bloody stool (7.1%), vasculitis (7.1%), headache (5%), dry mouth (3.5%), back pain (3.5%), increased blood pressure (3.5%), dizziness (2.8%), arthralgia (2.1%), and itching (2.1%) [40].

CONCLUSIONS

As a first-in-class analgesic, opiranserin should be administered with a clear understanding of its potential therapeutic effects and adverse reactions. Given its triple analgesic mechanisms, it is primarily indicated for neuropathic pain—which often facilitates pain chronification—while providing partial relief of nociceptive pain. Consequently, opiranserin may be particularly effective in procedures prone to neuropathic triggers, such as amputation, inguinal herniotomy, mastectomy, cesarean section, thoracotomy, knee arthroplasty, hip arthroplasty, and nuclectomy, potentially reducing postoperative CPSP.

While studies on opiranserin have highlighted the analgesic effects of GlyT₂ and 5-HT_2A antagonism, the role of its P₂X₃ activity remains under-researched. Consequently, the therapeutic potentials and safety profile associated with its P₂X₃ antagonism cannot yet be fully characterized.

A significant challenge in clinical practice is the difficulty of incorporating opiranserin into limited-volume, disposable intravenous patient-controlled analgesia devices, which typically hold 100 to 300 mL and last 3 to 9 days. Furthermore, repeated administration may lead to the accumulation of its active metabolite, VVZ-368. While VVZ-368 provides a similar analgesic effect, its plasma concentration increases in a dose-proportional manner, rising 1.23- to 2.49-fold after the fifth and sixth doses.