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

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 ]. 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 IC 50 = 0.86 μM for the GlyT 2 ; ORG25543 is more selective and irreversible than GlyT 2 inhibitor (IC 50 = 0.016 μM) [ 9 , 10 ]. Both these compounds had undesirable dose-limiting toxicity, such as tremor and stereotypy, due to complete blockage of GlyT 2 and coinhibition of GlyT 1 . Opiranserin showed moderate GlyT 2 inhibition compared to ORG25543 ; however, it also has another two P 2 X 3 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: GlyT 2 blocking with an IC 50 = 0.86 μM inhibiting the reuptake of Gly followed by inhibition of spinal pain processing, P 2 X 3 antagonist with an IC 50 = 0.87 μM inhibiting nociceptive signaling in peripheral sensory neurons, and 5-HT 2A antagonist with an IC 50 = 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 GlyT 2 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 GlyT 2 and 5-HT 2A , it is important to note its additional potent activity at the P 2 X 3 . 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 P 2 X 3 antagonism (IC 50 = 0.87) [ 15 ]. Opiranserin has triple antagonistic effects for the GlyT 2 , 5-HT 2A , and P 2 X 3 . Therapeutic effects and adverse reactions, originating from the triple antagonistic effects, can be speculated on. In addition, current clinical applications of each of the GlyT 2 inhibitors, 5-HT 2A antagonists, and P 2 X 3 antagonists are helpful to suppose the analgesic effect and adverse reactions of opiranserin. It is also helpful to know where GlyT 2 , 5-HT 2A , and P 2 X 3 are distributed in the human body ( Table 2 , Fig. 1 ) [ 9 , 10 , 13 , 16 ]. 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. GlyT 2 , located on the presynaptic terminal, reuptakes the synaptic Gly in order to refill the presynaptic vesicle. GlyT 2 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 GlyT 1 and GlyT 2 are mainly distributed in the spinal cord, especially the lamina III of the dorsal horn. GlyT 2 is also located in the brain stem; GlyT 1 is also distributed in the higher brain regions and peripheral tissues, including the pancreas and liver [ 18 ]. The GlyT 2 inhibitors enhance inhibitory neurotransmission in chronic neuropathic pain, characterizing allodynia and hyperalgesia [ 19 ]. GlyT 2 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 GlyT 2 antagonist. The known representative GlyT 2 inhibitors are ALX1393 and ORG25543 , with IC 50 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 GlyT 1 , 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 GlyT 2 . 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 ]. 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-HT 3 ; 5-HT 4 ; 5-HT 5A, B ; 5-HT 6 ; and 5-HT 7 . All serotonergic receptors mediate their actions via guanine nucleotide-binding (G) proteins (Gα i , Gα q/11 , or Gα s ), except 5-HT 3 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 D 2 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) D 2 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. Purinergic receptors (purinoceptors), a family of plasma membrane proteins, can be divided into P 1 receptors (selectively activated by adenosine) and P 2 receptors (selectively activated by extracellular nucleotides like ATP, adenosine diphosphate, uridine-5’-triphosphate, and uridine-5’-diphosphate). P 1 receptors can be divided into A1, A2A, A2B, and A3. All P 1 receptors are G-protein-coupled receptors (GPCRs). P 2 receptors can also be divided into P 2X (ligand-gated ion channels) and P 2Y (GPCRs). P 2 X 3 among the seven P 2 XR families (P 2 XR 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 ]. P 2 X 3 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 P 2 X 3 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 P 2 X 3 activity and membrane expression contributed to development of chronic pain with mechanical allodynia in diabetic rats [ 33 ]. Representative P 2 X 3 antagonists include gefapixant, eliapixant, sivopixant, filapixant, and camlipixant. The most common clinical application of P 2 X 3 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 P 2 X 3 antagonist which is approved for the treatment of unexplained chronic cough or refractory chronic cough in Japan, the European Union, and Switzerland. P 2 X 3 antagonists inhibit ATP-mediated activation of P 2 X 3 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 P 2 X 3 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 P 2 X 3 antagonists prevent ATP release from damaged cells, thus the reduced ATPs reduce the chance of sensitizing or activating C-fiber sensory neurons. Finally, the P 2 X 3 antagonists can be used for neuropathic pain, cough, overactive bladder, and endometriosis. However, the representative adverse event, taste disturbance, should not be overlooked. P 2 X 3 antagonists are currently being evaluated in human subjects for other conditions, but only for endometriosis for pain conditions [ 39 ]. 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 ]. 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 ]. 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 ]. Opiranserin is primarily excreted via the kidneys into the urine or into the bile for elimination in the feces [ 15 ]. 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 ]. 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 ]. 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 ]. 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 ].

Opiranserin (VVZ-149, Unafra®; Vivozon Inc.) has triple antagonistic effects for the glycine transporter type 2 (GlyT 2 ), serotonin receptor 2A (5-HT 2A ), and purine 2 receptor 3 (P 2 X 3 ) [ 1 ]. It is composed of a molecular formula of C 21 H 34 N 2 O 5 and has a molecular weight of 394.512 g/moL. The half-maximal inhibitory concentration (IC 50 ) of opiranserin is 0.86, 0.87, and 1.3 μM for antagonistic effects of the GlyT 2 , P 2 X 3 , and 5-HT 2A , respectively [ 2 ]. The GlyT 2 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 P 2 X 3 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 P 2 X 3 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.

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 GlyT 2 and 5-HT 2A antagonism, the role of its P 2 X 3 activity remains under-researched. Consequently, the therapeutic potentials and safety profile associated with its P 2 X 3 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.