Postoperative pain remains a substantial clinical and economic burden, contributing to delayed recovery, increased opioid use, and a higher risk of developing chronic postsurgical pain [1-3]. Despite decades of research and drug development, currently available pharmacological options—primarily opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), and anticonvulsants—often fail to provide adequate analgesia without causing significant side effects [4-7]. Opioids remain the mainstay of therapy; however, they are also associated with respiratory depression, ileus, nausea, dependence, and paradoxical hyperalgesia. Non-opioid analgesics, such as acetaminophen, NSAIDs, gabapentin, and dexmedetomidine, are commonly included in multimodal analgesia and Enhanced Recovery After Surgery (ERAS) protocols [8]. However, these agents carry serious risks of gastrointestinal bleeding, hepatic and renal dysfunction, and cardiovascular adverse events (AEs) during the perioperative period [9-11].

Moreover, most currently available analgesic agents act through a single molecular mechanism, which limits their effectiveness against the complex and multifactorial nature of pain. Numerous promising drug candidates identified through single-target approaches have failed in clinical trials because of their insufficient efficacy. For example, selective neurokinin-1 (NK1) receptor antagonists [12-15], transient receptor potential vanilloid 1 antagonists [16-19], and cannabinoid receptor modulators have shown robust preclinical results but consistently fail to produce clinically meaningful analgesia in humans. Therefore, a paradigm shift is needed to improve the translation of analgesic drugs—from pursuing highly potent or selective single-target agents to developing multi-target agents with therapeutic efficacy.

Opiranserin injection (Unafra®) addresses the unmet need for a multi-target, non-opioid analgesic that offers opioid-comparable efficacy with an improved safety profile. It was recently approved by the Korean Ministry of Food and Drug Safety (MFDS) for the short-term management of moderate-to-severe postoperative pain. The active ingredient, opiranserin, is a dual antagonist of glycine transporter 2 (GlyT2) [20,21] and serotonin 2A receptors (5-HT2A) [22]. Vivozon Inc. established a strategic, feasible, multitarget drug discovery platform to identify antinociceptive targets with potential synergistic activity using ex vivo efficacy-based screening with a bait–target approach [23]. To discover opiranserin, GlyT2 blockers were selected as bait targets because of their role in transmitting pain signals in both the peripheral and central nervous systems. These compounds were optimized to simultaneously antagonize 5-HT2A, which contributes to pain transmission and amplification via the descending facilitatory pain pathway. To confirm phenotypic efficacy, acute rat tissue samples were maintained in culture, and pain-related neural activity was monitored. Phenotypic screening results were validated using morphine- and gabapentin-comparable analgesic or anti-allodynic effects in in vivo efficacy studies using rat models of postoperative, formalin-induced, and neuropathic pain. Through this rational, mechanism-based, multitarget drug discovery and development approach, opiranserin successfully translated its preclinical efficacy, with a reliable pharmacokinetic-pharmacodynamic (PK–PD) correlation, into meaningful decreases in pain and opioid use among patients undergoing major surgery.

In this review, in order to refine the clinical utility of opiranserin injection in the perioperative setting, we aimed to summarize its pharmacological profile including its proposed mechanism of action, in vivo efficacy studies within the multitarget drug discovery platform [23], progressive clinical development including a pivotal Korea-based Phase 3 study in laparoscopic colectomy (VVZ149-POP-P3-K301), and future research directions.

Opiranserin is a small synthetic molecule derived from the benzamide family [23]. Its analgesic effects rely on the selective and simultaneous modulation of two distinct targets, GlyT2 and 5-HT2A, both of which are involved in nociceptive processing. GlyT2 inhibitors have been studied as promising analgesic candidates because of their role in glycine-mediated inhibitory modulation and regional specificity [22]. Because GlyT2 mediates glycine reuptake in the spinal cord, its blockade amplifies inhibitory neurotransmission at glycinergic synapses in the dorsal horn, thereby attenuating the transmission of nociceptive inputs to higher centers [20,21]. Thus, GlyT2 antagonism is particularly relevant for suppressing spinal sensitization, which underlies persistent pain.

Another pain-related target of opiranserin is 5-HT2A, a serotonin-receptor subtype that plays a key role in neurotransmission, cognition, perception, and pain modulation. 5-HT2A is widely expressed in peripheral sensory neurons, primarily nociceptive neurons, and responds to serotonin released during inflammation or nociceptive stimulation [24,25]. 5-HT2A is also expressed at the termini of descending facilitatory projection neurons in the midbrain [26] and contributes to the amplification of pain signals in the spinal dorsal horn [23]. The activation of 5-HT2A enhances nociceptive transmission by modulating spinal and supraspinal circuits, thereby promoting the central facilitation of pain [27]. Opiranserin antagonizes this pronociceptive activity by reducing the excitatory serotonergic drive and peripheral nociceptor sensitization across both central and peripheral nervous systems.

Opiranserin is extensively metabolized in the liver primarily by human cytochrome P450 3A4, which produces N-desmethyl-VVZ-149 (M1). M1 is synthesized as VVZ-368, an active metabolite with pharmacological properties nearly identical to those of the parent compound. Therefore, the systemic exposure and relevant PK parameters of opiranserin and VVZ-368 have been evaluated in both animal and human plasma following opiranserin administration. A full survey of the non-clinical pharmacology and PK of opiranserin is beyond the scope of this review.

As part of a multitarget drug discovery platform, rigorous in vivo studies of opiranserin have been conducted with blinding, complete randomization, and a positive control design in rat models of postoperative pain, formalin-induced nociceptive/inflammatory pain, and neuropathic pain. The results confirmed the ex vivo phenotypic screening, demonstrating dose-dependent analgesic effects comparable to those of morphine and anti-allodynic effects comparable to those of gabapentin. In a rat formalin model, the analgesic effect of opiranserin was not blocked by pretreatment with naloxone and did not involve cyclooxygenase inhibition in in vitro assays. These findings suggest that opiranserin exerts synergistic or additive effects on nociceptive signaling cascades through dual antagonism of GlyT2 and 5-HT2A.

To evaluate the clinical efficacy and safety of opiranserin injection, 10 clinical studies (three Phase 1 studies, five Phase 2 studies, and two Phase 3 studies) have been conducted in South Korea and the USA. All trials complied with the MFDS guidelines for analgesics (August 2016) and the Food and Drug Administration (FDA) guidance for the development of non-opioid analgesics for acute pain (FDA, February 2022). In this review, we focused on the efficacy and safety of opiranserin injections in humans based on published data, along with relevant PK characteristics (Table 1).

To evaluate the safety and PK of a 4-h intravenous (IV) infusion of opiranserin injection in healthy participants, a first-in-human trial (PT-VVZ149-01, South Korea) was conducted using a randomized, double-blind, dose-escalation design [28]. In total, 46 healthy young adult males were enrolled in a single ascending dose (0.25 to 8 mg/kg) study, and 20 were enrolled in a multiple ascending dose (4 and 7 mg/kg, twice daily for 3 days) study. To determine an appropriate dosage regimen across age groups for subsequent postoperative pain studies, the second Phase 1 study (PT-VVZ149-02) evaluated PK characteristics of opiranserin injection in healthy middle-aged and older males via continuous IV infusion over 4 h at a constant rate and over 10 h as the loading/maintenance dose.

Opiranserin injection is generally safe and well tolerated, regardless of the total infusion duration and dosage regimen. No clinically significant AEs or dose-limiting toxicities were observed, except for mild nausea, dizziness, and somnolence at > 2,000 ng/mL of the pooled plasma concentration of all active moieties, that is, the parent compound (opiranserin) and its active metabolite (VVZ-368). Dose-linear PK was observed in human plasma, with no accumulation of the parent compound after repeated administration. The plasma concentrations of the active metabolite, VVZ-368, increased slightly after repeated dosing, contributing to sustained drug exposure.

A Phase 2 clinical trial (VVZ149-POP-P2-US001) evaluated the efficacy and safety of opiranserin injections in 60 patients undergoing laparoscopic colorectal surgery in the USA [29,30]. Post-surgery, patients were transferred to the post-anesthesia care unit (PACU) where the study protocol was initiated. Patients who reported a pain score of at least 5 on the 11-point Numerical Rating Scale (NRS) after regaining consciousness were randomized in a 2:1 ratio to receive either opiranserin injection or a placebo. The study drug was administered as an 8-h IV infusion (1.8 mg/kg for 0.5 h followed by 1.3 mg/kg/h for 7.5 h). All patients had access to the pro re nata dose of IV hydromorphone through patient-controlled analgesia (PCA; 0.1–0.3 mg bolus, 6-min lockout) and rescue doses (0.2–0.5 mg). Pain intensity was assessed using the NRS (0 = no pain, 10 = worst pain) 24 h after the start of the study drug infusion. The primary efficacy endpoint was the sum of the pain intensity difference (SPID) over 8 h post-dose measured at rest and during movement. The secondary endpoints included opioid consumption via PCA and rescue dosing.

The postoperative pain scores were lower in the opiranserin group than in the placebo group. Because both groups reported low levels of pain and opioid consumption post-surgery, partly because of the high utilization of opioids in the first 2 h (i.e., floor effects), the pain outcome did not significantly differ between groups. Nevertheless, pain management was considered effective following opiranserin infusion, resulting in 34.2% less opioid use and significantly fewer PCA requests for 24 h post-dose compared with the placebo.

In this study, both treatment groups showed high levels of opioid consumption for the first 2 h, with greater variability in the use of rescue medication, which was provided in addition to the PCA opioid. Additional post hoc analyses were thus conducted to evaluate pain-related and opioid-related outcomes in a subgroup of patients who have required at least one rescue analgesic in the same period (“rescued,” n = 27) or have not (“non-rescued,” n = 25). In the rescued subgroup, opiranserin injection significantly reduced postoperative pain as early as 0.5 h post-dose, with approximately 40% less opioid use for the first 9 h and 24 h. By contrast, placebo-treated patients in the rescued subgroup showed persistently elevated pain scores despite high opioid use over the 24-h period, suggesting that PCA and rescue analgesics were ineffective in patients with early opioid requirements.

The opiranserin injection administered to patients following colorectal surgery was generally safe and well tolerated. Among 60 patients, 37 (92.5%) in the opiranserin group and 16 (80.0%) in the placebo group experienced at least one treatment-emergent adverse event (TEAE). All AEs were mild or moderate in intensity. No death or serious drug-related AEs occurred in any patient. The most frequent TEAEs were nausea, somnolence, dizziness, headache, and pruritus, with a higher incidence of somnolence and headache observed in opiranserin-treated patients.

A Phase 2 clinical study (PT-VVZ149-05) evaluated the efficacy and safety of opiranserin injections in 59 South Korean patients who underwent laparoscopic or robot-assisted gastrectomy [31]. Patients were randomized 1:1 to receive either opiranserin injection or placebo, administered intraoperatively approximately 1 h before the completion of surgical suturing. The study drug was infused for 10 h (1.8 mg/kg for 0.5 h followed by 1.3 mg/kg/h for 9.5 h). Post-surgery, patients were transferred to the PACU, where IV PCA was readily available. IV fentanyl PCA boluses and fentanyl-equivalent rescue medications (fentanyl, ketorolac, and/or pethidine) were administered as required. The primary efficacy endpoint, pain intensity at rest using the NRS, was evaluated at scheduled time points 24 h post-emergence. Secondary endpoints included the total opioid consumption, number of PCA requests, and total number and amount of rescue doses over 24 h.

Overall, postoperative pain scores were lower at 24 h in the opiranserin group (n = 30) than in the placebo group (n = 29), reaching statistical significance at 4 h post-emergence. The total opioid consumption was reduced by 29.5% over 24 h, with 65.7% fewer PCA requests during the first 10 h. Considering that rescue doses were required in approximately 60% of patients in both treatment groups, additional efficacy analyses were conducted in the “rescued” (n=36) and “non-rescued” (n = 23) subgroups, as was done in the Phase 2 study in the USA (VVZ149-POP-P2-US001). There were no statistically significant differences in the pain intensity scores between opiranserin and placebo groups in the non-rescued subgroup. Conversely, in the rescued subgroup, the opiranserin group showed a 31.4% reduction in the total opioid consumption during the first 10 h post-emergence compared to the placebo group. The analgesic benefit was particularly pronounced in this subgroup of patients requiring early rescue opioids, who were previously associated with high levels of negative affect.

The opiranserin injection administered to post-gastrectomy patients was generally safe and well tolerated. Among 59 patients, 16 (53.3% in the opiranserin group and 55.2% in the placebo group) reported at least one TEAE. All AEs were mild in intensity and did not result in death or discontinuation of study drug infusion. The most common TEAEs were nausea, hypertension, headache, dizziness, and postoperative fever. The overall incidence of TEAEs was comparable between the opiranserin and placebo groups.

A pivotal Phase 3 clinical study (VVZ149-POP-P3-K301, n = 284) was conducted as a randomized, multicenter, double-blind, parallel-group, placebo-controlled trial to confirm the potential of opiranserin injection for the safe and effective management of moderate-to-severe postoperative pain following laparoscopic colectomy [32]. Patients were screened within 30 days pre-surgery and randomized in a 1:1 ratio to receive either opiranserin injection (a fixed dose of 1,000 mg) or a placebo administered postoperatively. After transfer to the PACU, patients who reported a score of ≥ 5 on the 11-point NRS after regaining consciousness were randomized in a 1:1 ratio to receive the study drug (160 mg for 0.5 h followed by 840 mg for 9.5 h). IV fentanyl was available through PCA and as rescue doses. If additional analgesia was required, patients could receive IV oxycodone, morphine, or pethidine. The primary efficacy endpoint was SPID in the first 12 h post-dose. Secondary and exploratory endpoints included SPIDs at other time points, opioid consumption (PCA and rescue medications), and the proportion of patients who did not require rescue medication during the 48 h post-dose.

The SPID over the first 12 h was significantly higher by 35% in the opiranserin group than in the placebo group. Opiranserin injection reduced pain scores as early as 4 h post-dosing, reaching mild pain levels from 8 to 48 h. During the first 12 h, opiranserin injection also significantly reduced opioid consumption by 30.8% and 60.2%, respectively, with fewer PCA requests than placebo. A higher proportion of patients treated with opiranserin injection remained free of rescue opioids on the ward between 2 and 12 h (51.4% vs. 33.3% in the placebo group). Considering the high utilization of rescue opioids in both opiranserin and placebo groups for the first 2 h in Phase 3 and other Phase 2 studies (VVZ149-POP-P2-US001 [28] and PT-VVZ149-05 [30]), the effectiveness of opiranserin injection has been demonstrated in patients requiring excessive opioid use during the first few hours of postoperative care.

Opiranserin injections administered to patients following colectomy are generally safe and well-tolerated, with no evidence of safety concerns in humans. TEAEs were reported in 101 (71.6 %) and 98 (68.5%) patients in opiranserin and placebo groups, respectively. The most frequently reported TEAEs (≥ 5% of patients) in both groups were nausea, postoperative fever, and vomiting. The incidences of common AEs were generally comparable between the groups, except for higher rates of vomiting and phlebitis in the opiranserin group. No deaths or serious TEAEs associated with the drugs were observed.

Opiranserin injection is a first-in-class non-opioid analgesic with dual antagonism against GlyT2 and 5-HT2A, which was uniquely and strategically discovered to manage pain via both the central and peripheral nervous systems. In seven Phase 2 and 3 clinical studies of postoperative pain, including a pivotal Phase 3 study (VVZ149-POP-P3-K301), the clinical efficacy of opiranserin injection for rapid pain relief and reduced opioid use in patients with postoperative pain and its excellent safety and tolerability were evaluated. In particular, opiranserin injection significantly reduced pain to a mild level (NRS PI < 4) during the first 6–12 h after the start of infusion, with a 20–60% reduction in opioid use compared to that in the placebo group. In a Phase 2 study PT-VVZ149-05, in which drug infusion was initiated intraoperatively, patients treated with opiranserin reported significantly lower pain levels at emergence (regaining consciousness) from anesthesia and reduced opioid use, supporting the prophylactic potential of opiranserin injection. The successful clinical translation of opiranserin injection provides a practical and cost-effective framework for multi-target drug development using ex vivo efficacy-based screening with a bait-target approach, followed by in vivo validation in disease models, including pain [23].

The effects of opiranserin injection for reducing pain and opioid use post-surgery were more pronounced in a subgroup of patients with severe postoperative pain (pre-dose NRS PI of ≥ 7) or those with the early use of rescue medication (≥ 1 rescue dose during the first 2 h) [30,31]. The high and early use of opioids after surgery represents a critical challenge in real-world practice, because most patients experience severe postoperative pain that often requires strong opioids for rapid pain relief. Individual differences in rescue analgesic requirements and excessive PCA demands are important with respect to the subjectivity and “unpleasantness” of pain experiences (i.e., the affective motivational component of pain [33,34]). The excessive or inefficient use of PCA [35,36] and requirements for rescue analgesics [37] have been associated with perioperative negative affect or ‘unpleasantness’ of pain, including fear/anticipatory anxiety, depression, and pain catastrophizing. Considering a stronger relationship for the pain-related cortical processes in the brain regarding the affective aspect (“pain unpleasantness”) compared to the sensory-discriminative aspect reflected in “pain intensity” [38], opiranserin injection effectively alleviates “pain unpleasantness” post-surgery that often drives excessive use of opioid analgesics with no additional pain relief.

The excessive use of opioids in surgical patients increases the risk of opioid-related AEs and delays functional recovery [10]. By reducing both pain and opioid consumption, opiranserin injection has the potential to enhance the quality of postoperative pain management when incorporated into multimodal analgesia and combined with scheduled non-opioid treatments, such as acetaminophen, NSAIDs, or regional anesthesia. Based on the consensus that opioids should be used judiciously by healthcare professionals, recent postoperative treatment regimens have focused on non-opioid multimodal analgesia. This approach may generally be implemented (e.g., Reverse Analgesic Ladder [39]) or tailored to specific surgical procedures (e.g., ERAS [8]). When non-opioid measures alone are insufficient, short-acting, immediate-release opioids are preferred for pain optimization.

Although the scheduled use of non-opioid treatments is strongly recommended for managing moderate-to-severe postoperative pain and facilitating pain relief and surgical recovery, the repeated use of currently available agents (acetaminophen, NSAIDs, gabapentinoids, ketamine, and α2-agonists) carries risks such as psychotropic and respiratory side effects, renal and cardiovascular AEs, and anastomotic leakage [40,41]. These limitations highlight the need for a new class of analgesics providing safe, effective, and opioid-sparing pain relief during surgical recovery. Opiranserin injection addresses this need as a novel non-opioid modality with no involvement of the known mechanistic pathways targeted by opioids or currently available non-opioid treatments (e.g., NSAIDs). In the pooled patient population (n = 877), no deaths or serious drug-related AEs were observed in any clinical trial. The incidences of nausea, vomiting, dizziness, and somnolence were higher in the opiranserin group than in the placebo group. Most AEs were consistent with common symptoms expected post-surgery and during recovery.

A few limitations warrant further research to elucidate the therapeutic potential of opiranserin injections in improving perioperative pain management. To date, available clinical data have been derived from 8- or 10-h IV infusions administered to patients undergoing minimally invasive colorectal and gastric procedures as well as those undergoing elective abdominoplasty and bunionectomy. Future studies should evaluate the generalizability of the observed efficacy and safety of opiranserin to other surgical domains including orthopedic, thoracic, gynecologic, and cardiovascular surgeries. Based on previous clinical studies in which opiranserin injection was administered before the induction of general anesthesia, its prophylactic potential should be further established using both visceral and non-visceral models with differing pain trajectories. To strengthen its clinical utility, long-term efficacy outcomes, such as preventing chronic postsurgical pain and reducing the risk of opioid dependence, should be investigated in future post-marketing studies.

Comparative studies examining different dosage regimens, such as continuous infusion, intermittent bolus injections, and PCA, may help optimize the analgesic efficacy of opiranserin injections while minimizing side effects. Evaluating the compatibility of opiranserin injection with IV-PCA systems may help clinicians develop patient-oriented or individualized pain management strategies. Across all clinical studies of opiranserin injection, no AEs were attributed to drug interactions with acetaminophen or regional anesthesia techniques (e.g., sciatic nerve block; unpublished data). These findings encourage further investigation into whether the concomitant use of opiranserin injections with scheduled non-opioid analgesics (NSAIDs, acetaminophen) and/or opioid-free anesthesia (e.g., ketamine and dexmedetomidine [42] and transversus abdominis plane blockade/surgical wound infiltration [43]) can improve the safety and efficacy of multimodal analgesia protocols across various surgical procedures. Furthermore, collaborative efforts to identify biomarkers and pharmacogenomic factors that influence the efficacy of opiranserin injections will advance the precision of non-opioid analgesia.

Collectively, these avenues of future research will not only refine the clinical utility of opiranserin injection by maximizing patient benefits for enhanced recovery from surgery but also provide a blueprint for future multi-target analgesic development for the central nervous system and pain therapeutics. As healthcare systems increasingly seek effective and opioid-sparing alternatives, opiranserin injections may serve as a practical model for the rational design and successful translation of multi-target drugs into routine surgical care.

Opiranserin injection (Unafra®, Vivozon Inc.) has been recently approved by the Korean MFDS in December 2024 as the first-in-class, non-opioid analgesic for the short-term treatment of moderate-to-severe postoperative pain. Strategically designed as a single synthetic molecule that simultaneously antagonizes GlyT2 and 5-HT2A, which are both involved in pain processing, opiranserin exemplifies the practical application of multitarget drug discovery and development through ex vivo phenotypic screening and a bait–target approach [20]. The clinical use of opiranserin successfully translates its preclinical efficacy into clinical benefits, demonstrating reductions in both pain and opioid consumption among surgical patients without clinically significant AEs or other safety concerns. The clinical efficacy of opiranserin injections was more pronounced in patients who required high and early postoperative opioid use—patients who are often at risk of negative affect, which can hinder effective pain management after surgery. Opiranserin injection is anticipated to provide patients and clinicians with a safe and effective treatment that minimizes opioid reliance, while improving the utility of precision analgesia to target the multifaceted nature of pain.