With emergence of biodegradable and biocompatible substances for pharmaceutical dosage forms, it has become possible to develop controlled release drug delivery, which is essential for improving the therapy and disease status. This is based on the fact that controlled release delivery is available via diverse routes of administration and is advantageous over immediate release delivery [1]. It remains a challenge, however, to design the appropriate drug delivery system (DDS). While designing sustained released formulation for high molecular weight drugs, academic researchers are interested to achieve maximum drug loading for prolonged therapeutic effect [2].

Sustained-release medications are used for pharmacotherapy over several days, weeks or months. They have advantages over conventional preparations; these include long-lasting curative effects, and lower toxicity, dosage and frequency of administration [3].

Pain has been considered as a critical factor that is closely associated with physical and mental human health [4]. To avoid opioid crisis during traditional pain control, a concept of multimodal analgesia has emerged. Use of local anesthetics is one of the most popular, safest multimodal analgesic regimen [5,6]. Local anesthetics are disadvantageous, however, in that their duration of effect is limited (<24 hours) and they may cause potential toxicity to the cardiovascular and central nervous system. It is therefore imperative that their disadvantages be avoided [7-9]. From this context, sustained-release local anesthetics compensate for their disadvantages by not only continuously releasing a safe dose with single administration to minimize the systemic toxicity but also achieving a prolonged duration of nociceptive block [10].

Use of biodegradable and injectable DDS for sustained release of local anesthetics to the surgical site may be a viable option for both effective and safe control of acute postoperative pain during the first few days. Such DDSs can be made in the form of microspheres or temperature-responsive hydrogels [11]. Of the two, a temperature-responsive hydrogel with great potential as a DDS for the effective control of postoperative pain for about 3 days has been well described in the literature [12,13].

PF-72 (TGel Bio Co. Ltd., Seoul, Korea) is referred to as a temperature responsive hydrogel-based DDS [11]. Indeed, it is a powder obtained from lyophilization of a reverse thermal hydrogel (poloxamer 407 [20% wt/v] and sodium hyaluronate [0.5% wt/v] in a sterilized saline); it is a medical device that has been designed for a sustained-release DDS. PF-72 is used to deliver ropivacaine to the surgical site for the efficient management of postoperative pain. When mixed with a drug solution, it is transformed into a drug containing reverse thermal hydrogel, a viscous fluid at room temperature. Moreover, when injected into the target area in the body, it is also transformed into a gel containing a drug because of body temperature. Bang JY, et al. performed an animal experiment to assess the population pharmacokinetic profile of 0.75% ropivacaine combined with PF-72, thus showing that there was an increase in the duration of absorption in the blood. These authors suggested that PF-72 combined with 0.75% ropivacaine might sustain effects of 0.75% ropivacaine at the surgical site [14]. Moreover, Oh KS, et al. conducted a preclinical study to assess the pharmacokinetic, distribution and efficacy of PF-72 containing 0.75% ropivacaine for extended relief of postoperative pain by allowing the prolonged release of ropivacaine. These authors showed that PF-72 was effective in retaining 0.75% ropivacaine at the site of injection for a prolonged period of time [11]. Furthermore, Choi SW, et al. conducted a pilot clinical trial to assess the efficacy and safety of PF-72 combined with 0.75% ropivacaine hydrochloride. According to these authors, PF-72 combined with 0.75% ropivacaine hydrochloride had an effect in relieving the postoperative pain up to 72 hours in patients undergoing posterior spinal surgery without serious adverse events [15]. Along the continuum of these previous published literatures, we conducted this study to assess the efficacy and safety of PF-72 combined with 0.75% ropivacaine hydrochloride in relieving the postoperative pain in patients undergoing single-level lumbar discectomy.

1. Trial design and setting

The current single-center, single-blind, randomized, confirmatory, controlled trial was conducted at Daejeon Woori Hospital in Daejeon, Korea between March 1 and September 30, 2023.

Inclusion criteria for the current study are as follows:

(1) Korean adult men or women aged between 19 and 70 years old

(2) The patients with American Society of Anesthesiologists (ASA) scores 1-3

(3) The patients planned for elective single-level lumbar discectomy for herniated intervertebral disc or spinal stenosis

(4) The patients with preoperative 100 mm visual analogue scale (VAS) scores 0.

Exclusion criteria for the current study are as follows:

(1) The patients with no preoperative 100 mm VAS scores 0

(2) The patients with inflammation or acute porphyria at the site of surgery or its adjacent regions

(3) The patients with cognitive dysfunction that may affect the subject pain assessment

(4) The patients with body weight <50 kg in men and <45 kg in women

(5) The patients with hypersensitivity reactions to sodium hyaluronate and those with a past history of it

(6) Women with confirmed pregnancy on urine human chorionic gonadotropin test

(7) The patients with preoperative estimated glomerular filtration rate <60 ml/min

(8) The patients with preoperative serum alanine aminotransferase levels >100 IU/L

(9) The patients who were currently participating in other clinical trials and those who participated in them within 30 days of baseline screening

(10) The patients who were deemed ineligible for study participation according to the investigators’ judgment.

2. Ethics statement

The current study was approved by the Internal Institutional Review Board (IRB) of National Bioethics Policy and then conducted in compliance with the relevant ethics guidelines. All the study treatments and procedures described herein were performed in accordance with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. All the patients submitted a written informed consent. The current study was conducted in compliance with the International Conference of Harmonization - Good Clinical Practice (ICH-GCP).

3. Trial methods

After submitting a written informed consent, all the eligible patients were randomized to either the trial group or the control group. According to the standard treatment protocol of our medical institution, they were hospitalized at least one day preoperatively and received a preoperative work-up. Then, they underwent single-level lumbar discectomy and received treatment before suturing at the site of surgery according to the randomization procedure.

The patients of the trial group received PF-72 combined with 0.75% ropivacaine hydrochloride (Nacain Injection; Huons, Seoul, Korea). But the patients of the control group received an intravenous injection of ramosetron hydrochloride 0.3 mg (Ramea Injection 0.3 mg; Kwangdong Pharm., Seoul, Korea) for the prevention of postoperative nausea and vomiting (PONV) before suturing has been completed without the application of PF-72 combined with 0.75% ropivacaine hydrochloride and local anesthetics. Postoperative pain was managed with patient-controlled analgesia (PCA) delivering fentanyl 3,000 µg (Fentanyl Citrate Inj.; Hana Pharm., Seoul, Korea) mixed with a saline 200 ml.

4. Application of PF-72 combined with 0.75% ropivacaine hydrochloride to the surgical site

At least 8-24 hours preoperatively, 0.75% ropivacaine hydrochloride was taken using a disposable sterilized syringe according to the manufacturer’s instructions. It was placed in a vial containing freeze-dried powder of PF-72 and then slightly shaken. Then, it was stored in a frozen state (2-8°C) for approximately eight hours. This was followed by dissolution of freeze-dried powder. When it was transformed into a transparent solution in a vial, it was transferred to another disposable sterilized syringe. Before suturing the site of incision, it was homogeneously injected into the soft tissue on both sides of it. The sites of incision at operation include the skin or fascia, for which the dose of administration per the length of incision was set at 1 ml/1 cm, as previously described [15]. Application of PF-72 combined with 0.75% ropivacaine hydrochloride to the surgical site is displayed in Fig. 1.

Figure 1. Application of PF-72 combined with 0.75% ropivacaine hydrochloride to the surgical site.

5. Use of rescue analgesics

Rescue analgesics were additionally provided for the patients, if necessary; these include fentanyl citrate in a recovery room and tramadol hydrochloride in a ward. In more detail, rescue analgesics were administered via an intravenous route at a dose of 50 mg in the patients with postoperative NRS pain scores ≥4 points.

The dose of rescue analgesics was determined according to established principles of acute pain management.

6. Efficacy and safety outcome measures

For the assessment of the efficacy of PF-72 combined with 0.75% ropivacaine hydrochloride, the patients were monitored at 3, 6, 24, 48 and 72 hours postoperatively. Then, the amount of rescue analgesics used was measured, and numeric rating scale (NRS) pain scores were measured when the suture was compressed at 3, 6, 24, 48 and 72 hours postoperatively, for which the cumulative area under the curve (AUC_0-72) of NRS pain scores was plotted. Moreover, the Rhodes index of nausea, vomiting and retching (RINVR) were measured at 6, 24, 48 and 72 hours or 24, 48 and 72 hours postoperatively.

For the assessment of the safety of PF-72 combined with 0.75% ropivacaine hydrochloride, incidences of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) were analyzed. To do this, any TEAEs and SAEs were categorized by the system organ class and then coded by preferred terms using the Medical Dictionary for Regulatory Activities (MedDRA) version 19.

7. Statistical analysis of the patient data

For the current trial, we estimated the sample size using G* Power (Heinrich-Heine-Universität, Düsseldorf, Germany). To do this, we performed a repeated-measures analysis of variance and used a type I error of 0.05, an effect size of 0.25, a statistical power of 0.9, and a drop-out rate of 10%. Moreover, we conservatively set the correlation between the repeated measures at 0. Therefore, we estimated the sample size to be a minimum of 100.

All data was expressed as mean ± standard deviation or the number of the patients with percentage, where appropriate. Kruskal-Wallis or Fisher’s exact test were used to compare outcome measures between the two groups. Statistical analysis was performed using the Statistical Analysis Software Version 9.4 (SAS Institute Inc, Cary, North Carolina, USA). A P-value of <0.05 was considered statistically significant.

1. Baseline characteristics of the patients

A total of 95 patients were enrolled in the current study, 47 and 48 of whom were assigned to the trial group and the control group, respectively. There were no significant differences in the age, sex, height, weight, ASA physical status and length of hospital stay between the two groups (P > 0.05) (Table 1).

Table 1 . Baseline characteristics of the patients (n = 95).

Variables	Values		P-value
	Trial group (n = 47)	Control group (n = 48)
Age (years old)	55.1 ± 3.7	56.6 ± 4.8	0.105
Sex			0.218
Men	24 (51.1)	18 (37.5)
Women	23 (48.9)	60 (62.5)
Height (cm)	163.3 ± 4.6	164.9 ± 4.5	0.078
Weight (kg)	63.4 ± 5.4	63.5 ± 3.8	0.916
ASA physical status			0.449
I	6 (12.8)	9 (18.8)
II	40 (85.1)	39 (81.3)
III	1 (2.1)	0 (0.0)
Length of hospital stay (days)	5.6 ± 0.6	5.4 ± 0.5	0.109

Values are mean ± standard deviation or the number of the patients with percentage, where appropriate..

ASA: American Society of Anesthesiologists..

2. Efficacy outcomes

The amount of analgesics used was significantly smaller in the trial group as compared with the control group at 3, 6, 24, 48 and 72 hours postoperatively (P < 0.05) (Table 2). Moreover, the NRS pain scores were significantly lower in the trial group as compared with the control group at 3, 6, 24, 48 and 72 hours postoperatively (P < 0.05) (Table 3). In addition, the AUC_0-72 of the NRS pain scores was significantly smaller in the trial group as compared with the control group (P < 0.05) (Table 4). Furthermore, there was no significant difference in the number of the patients presenting with no pain (NRS pain scores ≤ 3) was significantly greater in the trial group as compared with the control group at 3, 6 and 24 hours postoperatively (P < 0.05). But there was no significant difference in it between the two groups at 48 and 72 hours postoperatively (P > 0.05) (Table 5).

Table 2 . The amount of analgesics used (n = 95).

Variables	Values		P-value
	Trial group (n = 47)	Control group (n = 48)
Time points (postoperative hours)
3	0.99 ± 1.43	5.86 ± 0.71	0.000*
6	1.47 ± 1.43	12.42 ± 2.55	0.000*
24	4.40 ± 1.54	19.58 ± 4.13	0.000*
48	7.30 ± 1.95	23.41 ± 4.44	0.000*
72	10.98 ± 2.07	27.61 ± 4.77	0.000*

Values represent (the amount of rescue analgesics) × 0.01 in the trial group and (the amount of patient-controlled anesthesia) × 0.01 and (the amount of rescue analgesics) × 0.01 in the control group. The unit is mg..

*Statistical significance at P < 0.05..

Table 3 . Time-dependent changes in the numeric rating scale pain scores (n = 95).

Variables	Values		P-value
	Trial group (n = 47)	Control group (n = 48)
Time points (postoperative hours)
3	2.7 ± 0.8	5.8 ± 0.9	0.000*
6	2.5 ± 0.5	5.8 ± 0.9	0.000*
24	1.7 ± 0.5	4.7 ± 1.4	0.000*
48	1.5 ± 0.5	2.9 ± 0.9	0.000*
72	1.2 ± 0.4	2.3 ± 0.7	0.000*

*Statistical significance at P < 0.05..

Table 4 . The area under the curve of the numeric rating scale pain scores (n = 95).

Variables	Values		P-value
	Trial group (n = 47)	Control group (n = 48)
AUC0-6	15.4 ± 3.2	34.6 ± 5.3	0.000*
AUC0-24	46.4 ± 9.1	119.8 ± 30.3	0.000*
AUC0-48	81.6 ± 18.6	188.3 ± 49.1	0.000*
AUC0-72	109.7 ± 24.2	242.8 ± 63.8	0.000*

AUC: area under the curve..

*Statistical significance at P < 0.05..

Table 5 . The number of the patients presenting with no pain (numeric rating scale pain scores ≤ 3) (n = 95).

Variables	Values		P-value
	Trial group (n = 47)	Control group (n = 48)
Time points (postoperative hours)
3	43 (91.5)	0 (0.0)	0.000*
6	47 (100.0)	0 (0.0)	0.000*
24	47 (100.0)	11 (22.9)	0.000*
48	47 (100.0)	44 (91.7)	0.117
72	47 (100.0)	48 (100.0)	1.000

Values are the number of the patients with percentage..

*Statistical significance at P < 0.05..

3. Safety outcomes

In both groups, TEAEs include mild nausea and vomiting. But there were no cases of SAEs. Moreover, there were no significant differences in the incidences of TEAEs and SAEs between the two groups (P > 0.05) (Table 6).

Table 6 . Incidences of adverse events and serious adverse events (n = 95).

Variables	Values		P-value
	Trial group (n = 47)	Control group (n = 48)
TEAEs	4 (8.5)	9 (18.8)	0.232
SAEs	0 (0.0)	0 (0.0)	1.000

Values are the number of the patients with percentage..

TEAEs: treatment-emergent adverse events; SAEs: serious adverse events..

Aside from some exceptions, spinal surgeries are mostly elective in nature [16]. They may often involve extensive dissection of subcutaneous tissues, bones and ligaments; this eventually causes a considerable degree of postoperative pain that arise from the skin, muscle, vertebrae, intervertebral discs, facet joints and neural tissue and may be severe and typically lasts for 3 days [17,18]. Postoperative pain after spinal surgeries is a common complaint, with persistent pain even after the immediate convalescent period, and it may have a negative impact on physical, social and emotional health [19]. Adequate pain relief would therefore be an essential factor of postoperative care of patients undergoing spinal surgeries. But it may also be disturbed by the underlying presence of chronic pain that had been treated with conventional analgesics or narcotics. Moreover, it may also be complicated by the alteration in pain perception due to the preexisting pain along with long-term use of analgesics and/or opioids [20,21]. In this regard, adequate pain relief promotes early mobilization and shortens the length of hospital stay [22,23]. This may eventually lead to favorable outcomes, such as faster recovery, a lower risk of complications and a higher level of patient satisfaction [24-26].

The PF-72 is a DDS that effectively delivers ropivacaine to the surgical site. It is composed of a mixture of poloxamer 407 and sodium hyaluronate, which are mixed with sterile injection water, freeze-dried into a powder, and then reconstituted with a drug solution. It has the characteristic of transforming into a viscous liquid state at room temperature. Once injected into the body and reaching the target site, it undergoes a gel-forming transformation due to body temperature [15].

According to the current trial, the total pain score was significantly lower in the trial group, maintained up to 72 hours postoperatively as compared with the control group. This implies sustained relief of postoperative pain. However, there was no significant difference in the number of the patients presenting with no pain (NRS pain scores ≤ 3) between the two groups at 3, 6 and 24 hours postoperatively.

But our results cannot be generalized; there are limitations of the current study. First, we enrolled a small number of the patients. Second, we failed to directly compare the effects between PF-72 and ropivacaine because of diverse variables, such as general anesthesia and standardized analgesics.

In conclusion, our results indicate that PF-72 combined with 0.75% ropivacaine hydrochloride is an effective, safe DDS in patients undergoing single-level lumbar discectomy.

This study was sponsored by Reanzen Co., Ltd. (Anyang, Gyeonggi, Republic of Korea), the distributor of PF-72.

No potential conflict of interest relevant to this article was reported.