Analgesic effect and safety of a half-dose transdermal buprenorphine patch after arthroscopic rotator cuff repair

Abstract

Objective

To retrospectively explore the effect of a half-dose buprenorphine transdermal patch for analgesia after arthroscopic rotator cuff repair (ARCR).

Methods

This analysis was performed with clinical data from patients who received unilateral ARCR in our hospital between October 2017 and December 2020. The patients were divided into three groups (30 cases each). In group A (control group), 100 mg flurbiprofen axetil (FA) was administered twice a day for 5 days after surgery. In group B (experimental group), 100 mg FA was administered twice a day for 5 days and half (2.5 mg) of a buprenorphine transdermal patch was applied after surgery; an additional half (2.5 mg) patch was applied 3 days later. In group C (condition control group), 100 mg FA was administered twice a day for 5 days and a 5-mg patch was applied directly after surgery. The visual analog scale (VAS) was administered repeatedly 1 day before surgery and 1, 2, 3, 5, and 14 days after surgery in each group. The simple shoulder test (SST) score, range of shoulder forward elevation (FE), and external rotation (ER) were recorded preoperatively and 12 weeks postoperatively.

Results

VAS scores on postoperative days 3 and 5 were significantly lower in groups B and C than in group A (p < 0.05). The VAS score on postoperative day 14 was significantly lower in group C than in group A (p < 0.05). The difference in VAS score between groups B and C was not significant (p > 0.05). All patients had significantly improved VAS scores, SST scores, FE, and ER at 12 weeks postoperatively.

Conclusion

The half-dose buprenorphine transdermal patch had a good analgesic effect with minimal side effects after ARCR and did not delay the recovery of shoulder joint function.

1. Introduction

Early functional exercise is related closely to the therapeutic effect after arthroscopic rotator cuff repair (ARCR); it can effectively avoid the occurrence of joint capsular contracture or adhesions and increase the movement of the shoulder joint in all directions to achieve a more satisfactory surgical effect and quality of life.¹ The primary concern of most patients after rotator cuff surgery is the long-term relief of pain; a secondary concern is pain during the postoperative period. Early functional exercise should be based on the reduction of pain or achievement of a painless condition after the operation; thus, the way in which postoperative pain can be relieved early after ARCR is very important.² Cohen et al. reported that non-steroidal anti-inflammatory drugs (NSAIDs) inhibit tendon-to-bone healing³; thus, the long-term use of such drugs is not recommended when opioids are available.⁴

Buprenorphine is a strong opioid receptor agonist, and the buprenorphine transdermal patch (BTP) provides long-lasting, low-dose sustained release of the drug. The advantages of this patch include the long analgesic period, non-oral administration, and stable blood concentration.⁵ Approved by the FDA in July 2010 and available in China in July 2013, the BTP has been used widely to treat mild, moderate, and severe orthopedic pain6. However, the main adverse reactions of this treatment, such as headache, dizziness, nausea, vomiting, drowsiness, constipation, and skin reactions, have led to criticism of the widespread use of the BTP.^5,6 Our department has used the BTP for analgesia after ARCR for more than 7 years and has achieved good results.

2. Materials and methods

2.1. Study design and subject enrollment

This study was approved by the institutional review board and followed the principles of the Declaration of Helsinki. Ninety patients undergoing unilateral ARCR in our hospital between October 2020 and October 2023 were randomly selected and divided into three groups. Group A (control group) received 100 mg FA twice a day for 5 days after surgery. Group B (experimental group) received 100 mg FA twice a day for 5 days; half (2.5 mg) of a BTP (Lohmann Therapie-Systeme AG, Andernach, Germany) was applied after surgery, and an additional half patch was applied 3 days later. Group C (control group) received 100 mg FA twice a day for 5 days and a 5-mg BTP directly after surgery. All patients (48 males and 42 females, age 27–67 years, height 150–180 cm, weight 41–82 kg) had American Society of Anesthesiologists (ASA) grades of Ⅰ–Ⅱ. Forty-six patients underwent left shoulder surgery and 44 patients underwent right shoulder surgery. The inclusion criteria were: (1) no history of chronic pain except rotator cuff injury; (2) small or moderate (<3 cm) rotator cuff tear involving only the supraspinatus muscle; (3) no history of car sickness or sea sickness; (4) no history of latent gastrointestinal discomfort; (5) no history of long-term opioid or psychotropic drug use; (6) ability to take care of themselves completely before the rotator cuff tear; (7) agreement to receive pain medication after the operation; and (8) willingness to undergo postoperative rehabilitation exercise as prescribed by a physician.

2.2. Surgical technique and postoperative management

The same surgeon performed all surgeries using the double-row suture anchor technique and the same internal fixation apparatus (Johnson & Johnson, New Brunswick, NJ, USA). The surgical method has been described previously,² and the surgical position was lateral (Fig. 1). Postoperative analgesia was applied as described above in groups A, B, and C. The effective area of the BTP was 2.5 × 2.5 cm, and the drug release rate was 0.5 μg/h. The daily dose was 0.12 mg, and each patch was applied for 7 days. As ARCR is a minimally invasive operation, the postoperative hospitalization time in our hospital is 5–7 days. Thus, all patients were given 100 mg FA twice a day for 5 postoperative days. Patients in groups B and C continued to use the BTP after discharge, until 2 weeks postoperatively (Fig. 1). The shoulder joint was fixed with an abductor postoperatively. Passive and minor rehabilitation of the shoulder joint, including anterior flexion, internal rotation, and ER, began on the first day after the operation. After 6 weeks, the sling was removed and activities were started. Muscle strength training began after 12 weeks.

Fig. 1.

Photographs of the operative setup and two methods for buprenorphine transdermal patch application. A Intraoperative photograph of a buprenorphine transdermal patch not used after the operation. B1 Half (2.5 mg) of a buprenorphine transdermal patch for postoperative application. B2 Method of applying the other half of the patch 3 days later. C A 5-mg patch for application directly after surgery.

2.3. Data collection

Data on patients’ age, height, weight, sex, course duration, surgical shoulder (left or right), ASA grade, operation time, hypertension, diabetes mellitus, smoking, and VAS scores on the day before surgery and 1, 2, 3, 5, and 14 days after the operation were collected. The function and range of the shoulder joint were evaluated by the SST and assessment of FE and ER.⁷ The VAS score, SST score, FE, and ER on preoperative day 1 and at 12 weeks postoperatively were compared. Postoperative adverse reactions (headache, dizziness, nausea, vomiting, skin allergies, and others) were recorded during the follow-up period.

2.4. Statistical methods

General patient characteristics were compared among the three groups by one-way analysis of variance (ANOVA). ANOVA was used to compare the repeated-measurement data (overall comparisons, intergroup comparisons, and intragroup comparisons at each time point), and the least significant difference method was used for multiple comparisons. Count data are expressed as rates (%) and compared using the chi-squared test. P values < 0.05 were considered to be significant.

3. Results

3.1. Patient characteristics

No significant difference was observed in the patient characteristics, except that the body mass index was significantly higher in group B than in groups A and C (p < 0.05; Table 1). We ensured that the variables of age, height, weight, sex, course duration, surgical shoulder, ASA grade, operation time, hypertension, diabetes mellitus, smoking, VAS score, SST score, FE, and ER on the day before surgery were distributed evenly among the three groups to control for confounding factors.

Table 1.

Comparison of Preoperative General Patient characteristics in Three Groups.

	Group A	Group B	Group C	P value
Age (years)	44.43 ± 11.68	45.17 ± 8.70	46.40 ± 10.87	0.765
Height (cm)	162.80 ± 8.24	164.70 ± 6.70	164.20 ± 9.41	0.650
Weight (kg)	59.90 ± 10.59	65.37 ± 7.55*	61.23 ± 11.57	0.096
BMI (kg/m2)	22.46 ± 2.58#	24.14 ± 2.85	22.55 ± 2.83#	0.033
Sex (male/female)	14/16	16/14	18/12	0.585
Surgical site (left/right)	16/14	17/13	13/17	0.561
ASA grade(Ⅰ/Ⅱ)	13/17	12/18	12/18	0.955
Course of disease(month)	5.23 ± 4.36	6.30 ± 4.22	5.73 ± 5.45	0.682
Operative time (min)	103.20 ± 19.71	109.50 ± 24.12	105.97 ± 14.67	0.472
Hypertension (yes/no)	7/23	8/22	6/24	0.830
Diabetes mellitus (yes/no)	5/25	7/23	4/26	0.591
Smoking (yes/no)	8/22	11/19	10/20	0.700
VAS (score)	5.93 ± 0.91	5.80 ± 1.81	5.70 ± 0.98	0.785
SST (score)	6.20 ± 1.73	7.00 ± 1.64	6.53 ± 1.36	0.151
FE (°)	108.57 ± 20.39	110.50 ± 19.58	103.53 ± 22.50	0.414
ER (°)	35.00 ± 8.84	34.17 ± 5.74	32.10 ± 8.11	0.326

3.2. Comparison of analgesic effects

The results of the repeated-measures ANOVA are shown in Table 2. Significant differences were observed among the three groups (P = 0.013), and five time points (P = 0.000). No significant group × time interaction effect was detected (P = 0.111). The trend in the VAS scores from preoperative and postoperative time points in the three groups is shown in Fig. 2. In all three groups, pain decreased gradually over time. The VAS scores on postoperative days 3 and 5 were lower in groups B and C than in group A (p < 0.05). The VAS score on postoperative day 14 was lower in group C than in group A (p < 0.05). The difference in the VAS score between groups B and C was not significant (p > 0.05; Table 3).

Table 2.

Repeated measures analysis of variance of VAS.

Source	SS	df	MS	F	P
Treatment group	10.031	2	5.016	4.596	0.013
Time	1698.756	3.315	512.422	791.515	0.000
Group * time	7.324	6.63	1.105	1.706	0.111
Intra-group error	188.720	288.418	0.647
Inter-group error	94.947	87	1.091

SS Sum of squares; df degree-of-freedom; MS Mean Square.

Fig. 2.

The trend in the VAS score at pre- and postoperative time points in the three groups.

* Compared with group A P < 0.05.

Table 3.

Comparison of postoperative VAS among three groups.

Group	Day 1	Day 2	Day 3	Day 5	Day 14
A	7.03 ± 0.85	5.60 ± 0.77	4.30 ± 1.15	3.20 ± 0.76	1.80 ± 0.41
B	7.07 ± 1.02	5.37 ± 0.81	3.80 ± 0.71a	2.73 ± 0.45a	1.53 ± 0.57
C	7.27 ± 0.87	5.27 ± 0.98	3.70 ± 0.99a	2.70 ± 0.75a	1.30 ± 0.60a
F	0.572	1.193	3.313	5.234	6.650
P	0.567	0.308	0.041	0.007	0.002

A:flurbiprofen axetil (FA) group B:FA + first 3 days half-dose BTP group.

C: FA + full-dose BTP group.

^aCompared with group A P<0.05.

3.3. Function score and range of movement

The VAS and SST scores, FE, and ER had improved significantly at the 12-week postoperative follow-up visit compared with the preoperative values (p < 0.05). No significant difference in these parameters was observed among the three groups (Table 4).

Table 4.

Comparison of pain and function evaluation among three groups 12 weeks after operation.

Group	VAS	SST	FE (°)	ER (°)
A	1.57 ± 0.68	9.50 ± 1.55	124.97 ± 18.99	48.40 ± 11.21
B	1.43 ± 0.57	9.27 ± 1.36	132.93 ± 14.16	49.77 ± 14.18
C	1.50 ± 0.63	9.80 ± 1.38	135.20 ± 19.34a	49.83 ± 11.44
P	0.714	0.355	0.068	0.879

A:flurbiprofen axetil (FA) group B:FA + first 3 days half-dose BTP group C: FA + full-dose BTP group.

^aCompared with group A P < 0.05.

3.4. Adverse drug reactions

Five cases of adverse drug reaction, four of which consisted of two systemic reactions, were detected in the full-dose BTP group (16.67%). Three adverse drug reactions, two of which consisted of two systemic reactions, were observed in the first 3 days in the half-dose BTP group (10.00%). Two cases of adverse drug reaction were observed in the FA group (6.67%). The frequency of adverse drug reactions did not differ significantly among the three groups (Table 5).

Table 5.

Comparison of adverse drug reactions among three groups.

		Group A	Group B	Group C	P值
ADR		2/30 (6.67%)	3/30 (10%)	5/30 (16.67%)	0.459
Manifestation	Dizziness and headache	0	2	5a
	Nausea and vomiting	2	1	4	–
	Skin allergy and others	0	0	0

ADR: Adverse drug reactions A:flurbiprofen axetil (FA) group B:FA + first 3 days half-dose BTP group C: FA + full-dose BTP group.

^a 4 cases were complicated with nausea and vomiting.

4. Discussion

The aim of ARCR is to re-anchor a rotator cuff tear from the humeral bone surface, thereby creating conditions for tendon-to-bone healing. Rotator cuff repair can be accompanied by a series of inflammatory mechanisms, osteogenesis, and osteoclastogenesis, as well as a period of inflammation, repair, and remodeling, leading to scar healing at the tendon–bone interface.⁸ As patient pain after rotator cuff repair is of long duration, long-term postoperative analgesia is very important to enable patients’ participation in rehabilitation exercises.^1,2 Buprenorphine, the active ingredient in the BTP, has affinity for some opioid receptor subtypes (μ, κ, δ, and ORL-1), with a maximum analgesic intensity ranging from 75 to 100 times that of morphine.⁹ Buprenorphine is released from the BTP continuously over 7 days of skin application; thus, the BTP has the advantages of non-oral administration, high compliance, and no need to adjust the dose for older patients or those with renal insufficiency.⁵ The BTP has become one of the most important options for orthopedic analgesia. Alemanno et al. reported that buprenorphine is more effective than tramadol hydrochloride as a nerve block for analgesia for ARCR.⁴ To our knowledge, no study has explored the analgesic and adverse effects of the BTP after ARCR.

A recent study showed that the analgesic effect of FA after ARCR was better than that of other generic NSAIDs, and its early application did not affect the healing of the rotator cuff.¹⁰ Thus, based on routine postoperative FA analgesia, the BTP was added to observe its analgesic effect and adverse reactions to it after ARCR. The three main BTP doses are 5, 10, and 20 mg⁵; the 5-mg dose is used most commonly in Asia.⁶ Although the 5-mg BTP used for postoperative orthopedic analgesia in China is a greatly reduced dose relative to the 20-mg dose used in Western countries, the incidence of adverse reactions, such as loss of appetite, dizziness, headache, irritability, and poor sleep, is about 20%.¹¹ Thus, our medical team developed the half-dose BTP by folding the anti-stick gasket for the first 3 days, and tearing off the anti-stick gasket 3 days later to give the full dose but buffer from adverse reactions to the buprenorphine component. This method was used for post-ARCR analgesia in this study. The analgesic effect was stronger in groups B and C than in group A, with no significant difference between groups B and C (Table 4, Table 5). This result indicates that the analgesic effect of the half-dose BTP during the first 3 days was considerable. The blood concentration of buprenorphine from the BTP generally peaks after 24–72 h, then remains stable for about 5 days and decreases slowly after withdrawal.¹² Our finding that the analgesic effect of the BTP improved significantly from the third postoperative day is consistent with the pharmacological properties of the BTP. However, pain from joint movement was reduced to some extent, as all patients began early functional recovery on day 1 after surgery. This is one reason for the high VAS scores during the early postoperative period and the initiation of a clear analgesic effect at 3 days after the operation in groups B and C.

Notably, patients who use the BTP are susceptible to adverse nervous and digestive system reactions. Because these multi-system adverse reactions can directly affect the analgesic effect and treatment experience, they are particularly noteworthy. According to previous reports,^11,12 adverse drug reactions to the BTP are related to its central mechanism of action, which usually occurs during the early stage of dosing. Most adverse reactions diminish after 3–4 days, and serious organic lesions have not been reported.^11,12 Buprenorphine has a high affinity for μ receptors and a slow rate of dissociation from them. Although it has long-lasting analgesic effects, it carries the risk of long-lasting adverse reactions once adverse reactions occur. In this study, the use of a half dose of the drug during the first 3 days reduced the frequency of adverse nervous- and gastrointestinal-system reactions after ARCR (Table 5).

Opioids do not directly affect healing at the bone–tendon interface after ARCR due to their central analgesic effects. A tendon repaired by ARCR can reach 60% of its normal strength 12 weeks after surgery, and the patient can carry out early muscle strength rehabilitation. Thus, we evaluate shoulder joint function in patients with shoulder cuff injuries at 12 weeks postoperatively to reflect healing at the bone–tendon interface. In this study, the VAS score, SST score, FE, and ER had improved significantly at the 12-week postoperative follow-up visit compared with the preoperative values (p < 0.05), with no significant difference observed among the three groups (Table 4). Thus, patients’ shoulder function scores and shoulder motion did not decrease 12 weeks after the operation with the addition of the BTP.

5. Limitations

Because ARCR is a minimally invasive surgery, the average postoperative hospitalization time is about 5 days, which limits drug use and the observation time in the hospital. The follow-up period for this study was only 12 postoperative weeks, and we did not perform magnetic resonance imaging to further clarify the extent of tendon-to-bone healing. The analgesic effect of the BTP over long postoperative periods needs to be studied further.

6. Conclusion

The half-dose buprenorphine transdermal patch had a good analgesic effect with minimal side effects after ARCR and did not delay the recovery of shoulder joint function.

Disclaimer

The authors, their immediate families, and any research foundations with which they are affiliated did not receive any financial payments or other benefits from any commercial entity related to the subject of this article.

Funding

This research funded from project of “3060’ young talents of Zhejiang hospital.

Ethical Approval and patient consent

The study was observational and not experimental and did not involve human tissues. The data used was collected from the hospital. All treatments were performed according to relevant guidelines and rules and informed consent was obtained from all participants through telephone follow-up. The ethics committee of Zhejiang Hospital approved the study (Approval number: 2020–96K). We followed the Declaration of Helsinki guidelines (2013).

Declaration of patient consent form

This study was a retrospective study and did not contain any identifiable information about the patients themselves, nor did it cause harm to the patients' health. No one-on-one informed consent was signed with the patient. This has been recognized and approved by the Ethics Committee of the hospital.

Financial support and suponsorship

None.

Declaration of competing interest

None.

The Author(s) declare(s) that there is no conflict of interest.

CRediT authorship contribution statement

Libin Ni: Methodology, Formal analysis, Investigation. Yingzhao Yan: Conceptualization, Writing – original draft, Writing – review & editing, Project administration. Yang Fu: Data curation, Formal analysis. Jing Sheng: Data curation, Validation. Hangbo Qu: Validation, Supervision. Xuanliang Ru: Resources, Supervision.