Sung-Woo Choi; Hae-Dong Jang; Deokwon Kang; Chung-Won Bang; Jae Chul Lee; Jae Jun Lee; Changsoon Hwang; Keun Sang Oh; Byung-Joon Shin

doi:10.4184/jkss.2019.26.1.11

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Choi, Jang, Kang, Bang, Lee, Lee, Hwang, Oh, and Shin: Comparison of the Efficacy and Safety Profiles of a Mixed ‘PF-72’ and ‘0.75% Ropivacaine HCl’ Versus a ‘0.75% Ropivacaine HCl’ and No Treatment Group: A Randomized, Single-Blind, Single-Institution Pilot Study

Original Article

Journal of Korean Spine Surg 2019;26(1):11-20.

Published online: 31 March 2019

DOI: https://doi.org/10.4184/jkss.2019.26.1.11

Comparison of the Efficacy and Safety Profiles of a Mixed ‘PF-72’ and ‘0.75% Ropivacaine HCl’ Versus a ‘0.75% Ropivacaine HCl’ and No Treatment Group: A Randomized, Single-Blind, Single-Institution Pilot Study

Sung-Woo Choi, M.D., Ph.D.^‡, Hae-Dong Jang, M.D.^∗,^‡, Deokwon Kang, M.D., Chung-Won Bang, M.D., Jae Chul Lee, M.D., Jae Jun Lee, M.D., Changsoon Hwang, Ph.D.^†, Keun Sang Oh, Ph.D.^†, Byung-Joon Shin, M.D., Ph.D.

Department of Orthopedic Surgery, College of Medicine, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea

^∗Department of Orthopedic Surgery, College of Medicine, Soonchunhyang University Bucheon Hospital, Seoul, Republic of Korea

^†TGel Bio, Co, LTD, Seoul, Republic of Korea

Corresponding author: Byung-Joon Shin, M.D., Ph.D. ORCID ID: Sung-Woo Choi: https://orcid.org/0000-0001-6263-6037 Hae-Dong Jang: https://orcid.org/0000-0002-8783-3122 Jae Chul Lee: https://orcid.org/0000-0002-8272-6723 Department of Orthopaedic Surgery, Soonchunhyang University Hospital, 59 Daesagwan-ro, Yongsan-gu, Seoul, 04401, Republic of Korea TEL: +82-2-709-9051, FAX: +82-2-796-3682 E-mail: schsbj@gmail.com

^‡ These authors contributed equally to this study as the co-first author

Received 12 March 201914 March 2019 Accepted 21 March 2019

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Study Design

Prospective pilot study

Objectives

The efficacy and safety of ‘PF-72’ for management of postoperative acute pain through a mixed ‘PF-72’ and 0.75% ropivacaine hydrochloride solution in patients with posterior spine surgery was evaluated as ‘0.75% ropivacaine’ and ‘untreated’ controls.

Summary of Literature Review

Postoperative acute pain is major surgical side effect that lead to the deterioration of the quality of life. Traditional pain control results in variable side effects, and multimodal pain management has been recommended as an alternative. Local anesthetics is a short-acting time lower than 12 hours. There is controversy about the efficiency and stability of thermoreactive hydrogel products as a drug delivery system.

Materials and Methods

Patients scheduled for posterior spine surgery were enrolled by the inclusion criteria. In the treated group, PF-72 and ropivacaine mixture was injected to the surgical wound before closure. In control group 1, only 0.75% ropivacaine hydrochloride was injected. In the control group 2, the surgical site was without injection. Ten patients were randomly assigned to each group and standardized drugs for pain control were applied postoperatively and rescue regimens were applied when necessary. Postoperative pain score and the cumulative area under the curve (AUC) of pain score were compared. The percentage of subjects who were painless (pain score ≤ 3) was examined at each observation point. The first time of injection and the total dose of the rescue regimen were examined. Postoperative nausea and vomiting (PONV) were also evaluated.

Results

There was no significant difference in demographic data. The sum AUC of pain scores in the treated group was significantly lower than that in the control group 1 and 2 at all observation times. The proportion of painless patients was significantly higher in the treated group than in the control group 2. There was no significant difference between the first administration time and the total usage of the rescue regimen, and the percentage of patients with PONV at all time points. There was no statistically significant difference in the incidence of adverse events.

Conclusion

PF-72 and ropivacaine mixture showed significant effects for pain management up to 72 hours postoperatively for the patients who underwent posterior spinal surgery without fatal complications.

Keywords: PF-72, Postoperative pain, Multimodal, Degenerative lumbar, Posterior spine surgery

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Fig. 1.

Diagram of injection sites.

Fig. 2.

The area under the curve (AUC) of numeric rating scale (NRS).

Table 1.

Inclusion and exclusion criteria

Inclusion criteria
1. 만 19세 이상 또는 만 80세 미만 성인 남녀
2. 퇴행성 질환으로 인해 L2에서 S1사이의 척추 간 협착으로 후방 척추 수술(추간판절제술 또는 후방 감압술 또는 1∼2 분절 유합술)이 필요하다고 판단된 자
3. ASA(American Society of Anesthesiologists) physical class 1-3인 자
4. 선별검사 시 수행하는 검사 결과로 시험대상자로 적합하다고 판정된 자
5. 임상시험에 자발적으로 참여를 결정하고 시험계획서를 준수할 의지가 있는 자
Exclusion criteria
1. 2 분절을 초과하는 후방 척추 유합술이 요구되는 자
2. 추간판절제술, 후방 감압술을 제외한 척추 관련 수술을 2년 이내에 시술 받은 자 ☞ 2년 이전에 수술을 받은 revision 환자의 경우 등록 가능함
3. 로피바카인(Ropivacaine) 또는 아미드계 국소마취제에 대한 과민반응 및 그 병력이 있는 자
4. 히알루론산나트륨(Sodium Hyaluronate)에 과민 자
5. NSAID에 알러지가 있는 자
6. 수술 전 3^일 ^이내에 Selective COX-2 inhibitor, Opioid, SSRI, Tricyclic antidepressant, Gabapentin, Pregabalin을 포함하는 NSAID를 투여 받은 자
7. 수술 시작 24시간 이내에 아세트아미노펜(Acetaminophen)을 복용한 자
8. 3개월 이내에 15일 이상 마약성 진통제 또는 일주일에 5번 이상 비 마약성 진통제를 복용한 자
9. 현재 글루코코르티코이드(Glucocorticoids)를 복용 중이거나 1개월 이내에 글루코코르티코이드(Glucocorticoids)를 복용한 적이 있는 자
10. 척추 수술이 아닌 타 수술이나 신체적 통증으로 진통제 치료를 받는 환자
11. 패혈증 환자
12. 신부전 또는 간부전 환자
13. 혈전 장애 또는 항 혈전 요법을 받고 있는 환자
14. 지속적인 약물 남용 및 오용, 약물 및 알코올 중독자
15. 병리학적으로 비만인 자(BMI 35 이상)
16. 조절되지 않는 당뇨가 있는 자
17. Urine HCG 검사를 통해 임신이 확인된 자
18. 중증 호흡 억제 환자
19. 두개 내압 상승 환자
20. 심각한 고혈압, 심장 판막 질환 등 심혈관계 기능 부전이 있는 자
21. MAO (MonoAmine Oxidase) 억제제 투여 중인 자
22. 뇌에 기질적 장애가 있는 자
23. 갑상선 기능 저하증이 있는 자
24. 기관지 천식 발작증의 환자
25. 명백한 척수 결함을 가진 자
26. 수술 부위 또는 그 주변에 염증이 있는 자
27. 중추 신경계 질환을 가진 자
28. 심장전도 장애가 있는 환자
29. 급성 포르피린증 환자
30. 신경병리증상(중증근무력증)의 병력이 있는 자
31. 활성 악성 종양을 가진 자 또는 종양 감압술로 척추 유합술을 시행 받은 자1
32. 신경학적 질병 등으로 통증 평가가 힘든 자
33. 현재 타 임상시험에 참여 중이거나 선별검사 전 30일 이내에 타 임상시험에 참여한 적이 있는 자
기타, 윤리적으로 또는 임상시험 결과에 영향을 줄 수 있어 임상시험의 참여
가 부적절하다고 시험자가 판단한 경우

Table 2.

Schedule table for clinical practice

Visit	1	2			3
Day	Screening D-28∼D-1	Preoperative D-1	Operative D 0	Postoperative D 0∼ D 3	Postoperative Day 14±3
관찰형태	내원		입원		내원
서면동의서	√
선정기준/제외기준^∗	√	√
인구학적 조사	√
병력 및 수술 기왕력	√
심전도 검사	√
임신검사^†	√
활력징후	√		√	√	√
신체검진	√				√
실험실적 검사^‡	√	√		√	√
임상시험 피험자 등록		√
무작위 배정		√
임상시험용 의료기기 적용			√
Rescue analgesia 투여량				√
NRS 통증 평가				√
PONV 평가				√
이상사례/중대한 이상사례		√	√	√	√
병용약물 및 병용요법^§	√	√	√	√	√

^∗ 선별검사 및 수술 전 Day–1에 선정/제외기준을 확인한다.

^† 가임 여성일 경우에만 선별검사 시 Urine HCG를 통해 임신 여부를 확인한다. 임신으로 확인된 경우, 본 임상시험 대상에서 제외한다.

^‡ 선별검사일로부터 4주 이내의 결과가 존재할 시에는 동의서를 받기 전의 결과라도 유효하게 인정할 수 있으며, 이를 선별검사 시 검사로 대체할 수 있다.일반 혈액 검사: Hemoglobin, Hematocrit, RBC count, WBC count, WBC with differential (Platelet count, MPV, MCV, MCH, MCHC, RDW, Reticulocyte count 혈청생화학적 검사: Calcium, Phosphorus, Glucose, BUN, Creatinine, Uric acid, Total protein, Albumin, Total bilirubin, ALT, AST, ALP, -GT, Total Choles-terol, Sodium, Potassium, Chloride, ESR, CRP 혈액 응고 검사: PT, aPTT, INR 뇨 검사: Protein, Glucose, Blood

^§ 본 임상시험기간 중 치료 결과에 영향을 미칠 수 있는 약물이나 대체치료는 금지되며, 선별검사 시 기저 질환으로 인해 선별검사 시점에서 과거 3개월 이내 복용하고 있는 약물/요법과 임상시험 등록 후 추가적으로 병용한 약물 및 요법을 구분하여 약물의 종류, 사용방법/횟수(투여량/투여방법), 중지여부 등을 증례기록서에 기록하도록 한다. 또한 임상시험 기간 중 병용금기 약물이나 대체치료를 받은 경우, 본 연구에서 탈락될 것이고 탈락사유를 기록한다.다만, 병용금기 약물이라 하더라도 본 연구와 관련 없이 일회성으로 투여가 필요할 경우, 시험자 판단 하에 치료 결과에 영향을 미치지 않는 범위 내에서는 사용 가능하며, 관련 내용은 증례기록서에 기록한다.

병용 허용 약물: Ramosetron HCI 등 병용 금지 약물: CYP1A2 억제제(베라파밀 (Verapamil), 플루복사민 (Fluvoxamine)), 테오필린 (Theophylline), 이미프라민 (Imipramine), Class III 항부정맥약 (아미오 다론(Amiodarone)), 아미드계 국소마취제와 구조적으로 유사한 제제, CYP3A4 억제제(케토코나졸(Ketoconazole)) 등

Table 3.

Postoperative nausea and vomiting classification

Scale	Description
0	No postoperative nausea and vomiting
1	Only nausea
2	Mild vomiting successfully treated by Ramosetron HCI
3	Heavy vomiting requiring other treatments in addition to Ramosetron HCI

Table 4.

The area under the curve of the numeric rating scale

구분		시험군 (N=10)	대조군 1 (N=10)	대조군 2 (N=10)
AUC_0-12	Median (Min∼Max)	44.00 (28.50∼67.50)	56.75 (36.50∼74.50)	58.50 (50.00∼83.00)
	p-value		<0.0001^∗
	p-value		0.0005^†	<0.0001^†
AUC_0-24	Median (Min∼Max)	82.50 (52.50∼115.50)	101.75 (66.50∼146.50)	109.25 (93.00∼159.00)
	p-value		<0.0001^∗
	p-value		0.0031^†	<0.0001^†
AUC_0-36	Median(Min∼Max)	122.00 (88.50∼158.50)	141.00 (90.50∼206.50)	160.00 (129.00∼231.00)
	p-value		<0.0001^∗
	p-value		0.0007^†	<0.0001^†
AUC_0-48	Median (Min∼Max)	161.00 (115.00∼200.50)	174.00 (114.50∼254.50)	203.25 (159.50∼281.00)
	p-value		<0.0001^∗
	p-value		0.0003^†	<0.0001^†
AUC_0-60	Median (Min∼Max)	191.00 (139.00∼236.50)	212.75 (132.50∼302.50)	239.25 (183.50∼341.00)
	p-value		<0.0001^∗
	p-value		0.0014^†	<0.0001^†
AUC_0-72	Median (Min∼Max)	215.00 (163.00∼266.50)	245.75 (144.50∼344.50)	275.25 (207.50∼395.00)
	p-value		<0.0001^∗
	p-value		0.0011^†	<0.0001^†

^∗ Kruskal-Wallis test

^† Wilcoxon rank sum test AUC: area under the curve

Table 5.

Painless patients (numeric rating scale ≤ 3)

	시험군 (N=10) N (%)	대조군 1 (N=10) N (%)	대조군2 (N=10) N (%)	p-value
1^시간	2 (20.00)	0 (0.00)	0 (0.00)	0.3103^∗
2^시간	1 (10.00)	0 (0.00)	0 (0.00)	1.0000^∗
4^시간	3 (30.00)	1 (10.00)	0 (0.00)	0.2857^∗
8 ^시간	3 (30.00)	2 (20.00)	0 (0.00)	0.3211^∗
12 ^시간	6 (60.00)	2 (20.00)	0 (0.00)	0.0109^∗
p-value		0.1698^∗	0.0108^∗
24 ^시간	6 (60.00)	5 (50.00)	3 (30.00)	0.5338^∗
36 ^시간	4 (40.00)	5 (50.00)	3 (30.00)	0.8929^∗
48 ^시간	10 (100.00)	7 (70.00)	7 (70.00)	0.1948^∗
60 ^시간	10 (100.00)	6 (60.00)	7 (70.00)	0.1512^∗
72 시간	10 (100.00)	10 (100.00)	9 (90.00)	1.0000^∗

^∗ Fisher's exact test.

Table 6.

Injection time of the first rescue analgesia

	시험군 (N=10)	^대조군 1 (N=10)	대조군 2 (N=10)
Median	7.50	10.00	11.50
(Min∼Max)	(0.00∼315.00)	(0.00∼565.00)	(0.00∼275.00)

Table 7.

Postoperative nausea and vomiting

	시험군 (N=10) N (%)	대조군 1 (N=10) N (%)	대조군 2 (N=10) N (%)
12^시간
0	9 (90.00)	10 (100.00)	9 (90.00)
1	1 (10.00)	0 (0.00)	1 (10.00)
2	0 (0.00)	0 (0.00)	0 (0.00)
3	0 (0.00)	0 (0.00)	0 (0.00)
합계	10 (100.00)	10 (100.00)	10 (100.00)
p-value		1.0000^∗
24^시간
0	9 (90.00)	8 (80.00)	10 (100.00)
1	0 (0.00)	2 (20.00)	0 (0.00)
2	1 (10.00)	0 (0.00)	0 (0.00)
3	0 (0.00)	0 (0.00)	0 (0.00)
합계	10 (100.00)	10 (100.00)	10 (100.00)
p-value		0.3103^∗
48^시간
0	8 (80.00)	9 (90.00)	9 (90.00)
1	1 (10.00)	0 (0.00)	1 (10.00)
2	1 (10.00)	1 (10.00)	0 (0.00)
3	0 (0.00)	0 (0.00)	0 (0.00)
합계	10 (100.00)	10 (100.00)	10 (100.00)
p-value		1.0000^∗
72^시간
0	10 (100.00)	10 (100.00)	9 (90.00)
1	0 (0.00)	0 (0.00)	1 (10.00)
2	0 (0.00)	0 (0.00)	0 (0.00)
3	0 (0.00)	0 (0.00)	0 (0.00)
합계	10 (100.00)	10 (100.00)	10 (100.00)
p-value		1.0000^∗

^∗ Fisher's exact test.

Table 8.

Incidence of adverse effect

항목	피험자 수(비율), N(%)
항목	시험군 (N=10)	대조군 1(N=10)	대조군 2(N=10)	전체 (N=30)
피험자 수
이상 사례	4 (40.00)	2 (20.00)	5 (50.00)	11 (36.67)
p-value	0.5101^∗
중대한 이상 사례	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)

^∗ Fisher's exact test. 의료기기 이상 사례는 임상시험용 의료기기와의 관련 가능성을 배제할 수 있는 ‘관련성이 적음’, ‘관련성이 없음’을 제외한 나머지 ‘관련성이 명백함’, ‘관련성이 많음’, ‘관련성이 의심됨’, ‘평가 불가능’ 항으로 정의.

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