Buprenorphine for acute post-surgical pain: A systematic review and meta-analysis

Abstract

Our study was designed to evaluate the efficacy of buprenorphine for the management of acute post-surgical pain reported in published studies in the years 2015–2022. Comprehensive research was performed by using online resources like PUBMED and the Wiley Library database to gather the relevant literature. Two authors were assigned to independently collect the information. Cochran's Q-test and I square statistic were used to determine the heterogeneity across the studies. Publication bias was estimated by using the Egger regression analysis and found to be significantly present once the P value <0.05. In this review, 15 studies were included. The pooled ratio of pain reduction after 12 hours of surgery was reported as 11.2% with 97% heterogeneity. Day one shows 5.9 reductions in pain with 98% heterogeneity. The 3% more pain was reduced on day 2. The day 3 pooled pain reduction score was observed as 1.9%. The overall pool prevalence of pain reduction was noted as 6.2% at different time duration with significant heterogeneity of 100%. Buprenorphine transdermal and sublingual both have significant pain relief scores. The analgesic drug consumption was reduced at the end of the follow-up duration.

Introduction

Post-surgical pain is still very common globally despite many treatments that have been introduced in markets. Patients reported moderate-to-severe pain during a postoperative hospital stay. An estimated 20–40% of patients suffered from severe postoperative pain.[1] The pain reported on the day first of surgery can cause delayed ambulation and raised cardiopulmonary and thrombotic morbidity.[1,2] Chronic pain can also be seen if day first pain is not treated well.[2] Currently, multimodal analgesia is considered the best suitable method of pain relief; however, opioid therapy is still most practiced in many clinical settings.[3,4] Despite effective outcomes, these therapies also become a reason for adverse drug effects with frequently reported cases of nausea, vomiting, constipation, and urinary retention. High doses of opioids enhanced the risk of drug side effects and were vastly reported in previous studies.[5,6]

Effective management of early postoperative acute pain is highly associated with patient satisfaction, early mobilization, and reduced duration of hospital stay. Oral opioids are widely used for early management.[5] Recently, in acute pain settings, buprenorphine gained attention due to its full-agonist analgesic and partial-agonist respiratory depression properties.[6] Research revealed that buprenorphine has a ceiling effect and is 75 to 100 times more potent than morphine.[7,8] It can be used for renal dysfunction cases but need special attention when used for patients impaired with liver functions.[5,7,9] This systematic review and meta-analysis were designed to evaluate the efficacy of buprenorphine for the management of acute post-surgical pain reported in published studies in the years 2015–2022.

Methodology

This systematic review and meta-analysis were conducted according to the PRISMA guideline.[10] This study aimed to evaluate the effect of buprenorphine on acute post-surgical pain.

Literature sources

Comprehensive research was performed by using online resources like PUBMED and the Wiley Library database to gather the relevant literature produced from the years 2015–2022.

Search strategy

The following guideline keywords with various combinations were used to access the data: pain score, analgesic score, acute pain, sublingual buprenorphine, transdermal buprenorphine, etc. To identify the additional studies, we also hand-searched the reference list of selected articles.

Inclusion and exclusion criteria

All the studies exploring the effect of buprenorphine before or after surgery were included. Studies considering patients aged above 18 years were included. No restriction was made on surgery type. Both prospective and retrospective studies were included. Studies using fentanyl and tramadol in the control group were considered eligible as fentanyl and tramadol are well studied in clinical trials and understood opioids. Studies investigating the use of buprenorphine for the management of chronic pain or opioid substitution were excluded. Case reports and previous systematic reviews were excluded.

Data extraction

Authors XYZ and MO were assigned to collect the relevant information including the author's name, region of study, study design, dosage, publication year, sample size, postoperative pain, postoperative analgesia, and drug-related side effects. In case of disagreement, third reviewer was asked to resolve the matter with consensus. After the data collection process, two independent authors processed the quality assessment of included articles.

Risk of bias

Cochran's risk of bias was used to assess the quality of included studies. The main items of this scoring include title, abstract, sample size calculations, allocation of patients, and allocation concealment.

Statistical analysis

Excel sheets were formed. Meta-Mar software was used for data analysis. Mean and standard deviations were used to describe the parameters. Pool prevalence was estimated by using the Wald test with a fixed-effects model. Pool prevalence was used to generate proportions with 95% confidence intervals (CI) and model-fitted weights. Cochran's Q test and I square statistic were used to determine the heterogeneity across the studies. I² > 50% and P < 0.10 were considered significant. Publication bias was estimated by using the Egger regression analysis and found to be significantly present once the P value <0.05.

Results

During the study timeframe, a total of 390 potential studies were found. In the final stage, 15 studies were included. Out of these 15, four studies were on sublingual buprenorphine [Figure 1]. Five studies were reported from India while three were from Iran, three were from the Chinese region, and a single study was reported from Mexico, Korea, UK, and Australia while in one study the region was unclear. Most of the studies used a double-blind procedure. Five studies performed abdominal surgeries while 10 orthopedic-related types of research were included (lower limb, spinal surgery, knee arthroplasty, lumber discectomy, hip fractures, and hallux valgus surgery). The sample size of included studies ranged from 50 to 150 patients with an average age of 18 to 75 years. In the control group, tramadol, fentanyl, celecoxib, and midazolam were used. Buprenorphine was induced before the surgical intervention for an average of 10 days. Table 1 shows detailed information.

Figure 1.

Flowchart on PRISMA guidelines

Table 1.

Characteristics

Author (Year)	Region	Study type	Surgery type	Sample size	Age in years	Intervention group (buprenorphine)	Control group	Form of buprenorphine intervention
Soltani et al. (2015)[11]	Iran	Triple-blind controlled trial	Closed Reduction Orthopedic Surgery	90	37.7±16.2	4.5 µg/kg up to 1 mg (Sublingual)	Midazolam 0.03mg/kg Fentanyl 1-2µcg/kg	A half-hour before induction of anesthesia
Arshad et al. (2015)[12]	India	Prospective randomized double-blind comparative	Major abdominal surgery	60	20-50 years	10 mcg h-1	25 mcg h-1 Transdermal fentanyl	6 h before surgery and until 3 days of postoperative
Kumar et al. (2016)[13]	India	Prospective randomized double-blind	Elective abdominal surgery	90	18 to 55 years	*10 mcg h-1 *20 mcg h-1	Placebo	A night before surgery until 7 day after surgery
Desai et al. (2017)[14]	India	Prospective, randomized clinical trial	Hip surgery	50	59.9±12.8	10 mcg h-1	50 mg tramadol after every 8 hours	Before the day of surgery until 7 days after surgery
Kim et al. (2017)[15]	Korea	Prospective, randomized controlled non-inferiority trial	Spinal fusion	69	-	*5 mcg h-1 *10 mcg h-1 *15 mcg h-1 *20 mcg h-1	Oral tramadol tablets 150-300 mg every day	After 36 h until 28th day
Niyogi et al. (2017)[16]	India	Prospective randomized double-blind comparative	Spinal surgery	70	38±4.49	10 mcg h-1	Placebo	Before 24 h until 48 h after surgery
Tang et al. (2017)[17]	China	Randomized controlled trial	Lumbar discectomy	96	18-75 years	5 mcg h-1	40 mg Parecoxib (two times a day) 200 mg celecoxib	Two days before surgery and 5 POD
Rivera-Ruiz et al. (2018)[18]	Mexico	Controlled clinical trial	Abdominal hysterectomy	45	25-60 years	*17.5 mcg h-1 *26.25 mcg h-1 *35 mcg h-1	Placebo	24 h before and 24 h before the postoperative day
Xu et al. (2018)[19]	China	Randomized controlled trial	Hallux valgus surgery	90	49.2±13.7	10 mcg h-1	50 mg flurbiprofen 200 mg celecoxib orally Twice a day	2 days before surgery until 5 postoperative day
Xu X et al. (2020)[20]	China	Randomized controlled trial	Knee arthroplasty	160	64.8±8.2	TDB Patch	200 mg celecoxib orally	After 6 h of surgery
Narozi et al. (2021)[21]	Iran	Double-blind, randomized clinical trial	Open cholecystectomy	80	20-50 years	Sublingual buprenorphine tablet 0.4 mg	2 ug/kg fentanyl	After 6 h of surgery
Farshad et al. (2021)[22]	Iran	Controlled double-blind randomized clinical trial	Lumbar discectomy	78	18-35 years	Sublingual buprenorphine tablet	2 mc/kg fentanyl	1 h before surgery
Khandelwal et al. (2021)[23]	India	A randomized double-blind prospective study	Lower limb surgery	150	43±7.8 45±9.2	10 μg·h-1 20 μg·h-1	25 μg·h-1 fentanyl patch	12-16 h before surgery
Heldreich et al. (2022)[24]	Australia	Retrospective cohort study	Abdominal surgery	146	> 18	Sublingual buprenorphine	30 mg/day fentanyl	-
Davies et al. (2022)[25]	United Kingdom	A retrospective randomized controlled trial	The neck of femur fracture	148	-	5 mcg/h buprenorphine patch	-	Before surgery

Characteristics of individual studies

Side effects like nausea, vomiting, headache, sedation, and urinary retention were observed. Table 2 reflects the outcomes of included studies. Table 2 presents the complete outcomes of included studies.

Table 2.

Outcomes of included studies

Author (Year)	Postoperative pain	Postoperative analgesia	Side effects
Soltani et al. (2015) [11]	Reduction in pain score of the buprenorphine group was observed with significant differences during 12 days follow-up	-	The placebo group reported more sedation than buprenorphine
Arshad et al. (2015)[12]	At 1, 2, and 3 POD higher VAS score was observed in the buprenorphine group	Insignificant difference	At 1, 2, and 3 POD sedation ratio was elevated in the buprenorphine group
Kumar et al. (2016)[13]	Both 10 mg and 20 mg buprenorphine show lower pain scores from end of surgery to the 7th day follow-up	Placebo group required more analgesia consumption than buprenorphine	More sedation was reported in buprenorphine until 12 h
Desai et al. (2017)[14]	Until 12 hours no significant differences were observed while the pain score reduced after 1st day of surgery up to 7th day	During 7-day follow-up low buprenorphine analgesia consumption was observed	Nausea and vomiting were high in the tramadol group
Kim et al. (2017)[15]	During 14-day follow-up no significant difference was observed	14-day follow-up observed insignificant difference	Insignificant difference
Niyogi et al. (2017) [16]	Lower pain score in intervention group after 0-48 h of surgery	Right after surgery, the analgesia consumption was higher in buprenorphine group which reduce in 48 hours	Insignificant difference
Tang et al. (2017)[17]	No difference	Analgesic consumption of buprenorphine was better until day 1; however, no significant difference was found on days 3 and 5	No difference
Rivera-Ruiz et al. (2018)[18]	Placebo reported higher VAS scores without significant differences between groups	Higher buprenorphine dose raised somnolence
Xu et al. (2018)[19]	VAS score after 3 days of surgery 1.5±0.5	After 3 days of surgery, buprenorphine had lower analgesia consumption with a significant difference of 0.04	No significant difference between both groups in terms of nausea, vomiting, dizziness, headache, constipation, etc.
Xu X et al. (2020)[20]	VAS score 115.3±9.9 No significant association was found between both groups.	-	Nausea, dizziness, vomiting, headache, and urinary retention without significant difference between both groups
Narozi et al. (2021)[21]	A significant difference was found among both groups with P of 0.002	-	Nausea and vomiting are insignificant even after 24 h P=0.314
Farshad et al. (2021) [22]	VAS score 0.744±0.23 without any significant difference between both groups	-	Nausea, pain itching without significant difference among both groups
Khandelwal et al. (2021)[23]	Lower NRD score found in 20 mg patch group No significant association between NRS scores between groups	Lowest consumption of rescue analgesic in 20 mg group without any significant difference between groups	Not mentioned
Heldreich et al. (2022)[24]	Statistical significant NRS pain score between both groups after 24 h P<0.0001	Reduced analgesic consumption after 24 h of surgery with a significant difference P<0.0001	-
Davies et al. (2022) [25]	Unclear	Unclear	Nausea, urinary retention

A study by Soltani et al. reported significantly high pain in the morphine group when compared to buprenorphine (P < 0.001). However, the buprenorphine group reported four beats lower pulse rate than morphine along with a high level of sedation. No significant difference was reported between both groups in terms of side effects. Arshad's study reported no significant difference in incidents of nausea, urinary retention, and constipation between both groups (p-value = 1.0000). Kumar's study measured the systolic and diastolic blood pressure in both the placebo and treatment groups. They divided their treatment group into two main categories of low- and high-dose transdermal buprenorphine (10 mg vs. 20 mg). High systolic blood pressure was reported in the low-dose group than high dose while diastolic blood rate was observed high in the placebo group along with a high pain score. On the other side, the Desai study reported acute pain in patients with hip fractures. They reported significantly lower side effects of transdermal buprenorphine than oral tramadol (P < 0.01). No case of skin rash was reported in the buprenorphine group. Kim's study observed no significant difference between both groups when comparing back pain [Table 2].

Risk of bias

Cochran risk of bias was used to assess the quality of included studies. The main items of this scoring include title, abstract, sample size calculations, allocation of patients, and allocation concealment. The risk of bias was low in all studies; only sample size calculation was performed in a study of Desai et al. only while other lacked this point of interest [Table 3]. Desai study scored 6 points while study conducted by Narozi et al., and Nayogi et al. scored 5 points. Both of these studies not reported their sample size calculation format. Two studies scored lowest 2 points.

Table 3.

Subgroup analysis of pain reduction score

Variables	Estimate	Standard error	Student's t-test	P
At 12 h	-2.3293	1.3537	-1.7207	0.1133
At day one	1.8195	2.0304	0.8961	0.3894
At day 2	1.1907	2.2134	0.5380	0.6013
At day 3	0.94	2.2109	0.4293	0.6760

Meta-analysis

For conducting a meta-analysis, standard mean difference was used to evaluate the 12-hour, 24-hour, 48-hour, and 3^rd-day pain. Only six studies represented the mean score. Study by Kumar evaluates two different dosages of buprenorphine (10 mg and 20 mg). The pooled ratio of pain reduction after 12 hours of surgery was reported as 11.2% with 97% heterogeneity. Day one shows 5.9 reductions in pain with 98% heterogeneity. The 3% more pain was reduced on day 2 [Figure 2]. The day 3 pooled pain reduction score was observed as 1.9%. The overall pool prevalence of pain reduction was noted as 6.2% at different time duration with significant heterogeneity of 100%. However, Egger regression analysis for publication bias was insignificant a P value observed as 0.1 > 0.05 [Figure 3]. A complete subgroup analysis is described in Table 3.

Figure 2.

Wald test of pain score at the different time duration

Figure 3.

Egger regression asymmetry funnel plot

Discussion

To our knowledge, this is the first systematic review and meta-analysis which evaluate the efficacy of transdermal buprenorphine and sublingual buprenorphine for postoperative pain management. Transdermal buprenorphine was initiated 6–48 hours before surgery in majority consistent with the previous studies using transdermal buprenorphine patch prior to 12–24 hour latency time.[5,6,9] Preoperative achievement of stable plasma concentrations is considered ideal; however, ethical concerns (in terms of unnecessary usage before pain stimuli) occur when it comes to preoperative usage of opioids. Large variation was observed in buprenorphine dosage ranges from 5 mcg h⁻¹ to 52.5 mcg h⁻¹. Many studies used 5–10 mg patches with oral doses of up to 30 mg day⁻¹. The quantity of these dosages is in agreement with the postoperative opioid protocol and can be attained even after using weak opioids.[26,27] Comparative cases control placebo clinical trials observed a significant decline in pain score and lower postoperative analgesic consumption in the buprenorphine groups.[13,16,18] Meanwhile, somnolence[13] and nausea[16] incidents were increased in two studies while one study[18] reported no difference in drug-related side effects. Pain relief and reduction in analgesic consumption are common outcomes of opioids with high drug-related side effects.[26,27] The present review also demonstrates that buprenorphine reduces pain more efficiently than the placebo with documented side effects like nausea, vomiting and somnolence, and sedation without any significant difference between both groups. Placebo groups also reported cases of respiratory depression, urinary retention, vomiting, and constipation.

Studies also reported patient satisfaction and significant pain relief in the buprenorphine group when compared with weak opioid tramadol.[14,15] Moreover, buprenorphine-favoring studies were reported in this analysis. One study initiates a patch before 12 hours of surgery while another initiated it after 36 hours of surgical procedure. Both of these studies used patient-controlled analgesia with fentanyl. The analgesia onset of buprenorphine was slower than tramadol; however, the similar pain score favored the buprenorphine opioid.

Comparing the results of two studies[17,19] using NSAIDS control and buprenorphine, similar postoperative outcomes were observed in terms of pain. Meanwhile, the consumption of celecoxib reported less pain relief than buprenorphine. Postoperative analgesic consumption was also similar in both groups; except in one study low dosage of buprenorphine was consumed.[19] The drug effect was also similar in both groups; however, both studies reported higher satisfaction in the buprenorphine group. These results indicate that buprenorphine has equivalent or superior analgesic efficacy than flurbiprofen, parecoxib, and celecoxib.

Despite the significant outcomes, one study[12] failed to reduce the pain score. This study used 10 mcg h⁻¹ buprenorphine compared with 25 mcg h⁻¹ fentanyl. This study also reported high sedation scores, while postoperative opioid consumption was similar in both groups. In two studies, patches were applied before 6 hours while previous studies also reported non-equivalent dosages of buprenorphine and fentanyl.[28,29,30] Three studies[13,16,18] consumed different dosages of buprenorphine while in one study[13] that used 10 mg and 20 mg buprenorphine researchers observed more pain scores in the 10 mg group than in the other. Out of these three, two studies used a high buprenorphine dosage of 17.5 mcg h⁻¹ to 52.5 mcg h⁻¹ but failed to observe any significant difference in pain score and patient satisfaction.[16,18] Higher buprenorphine dosages reported an increased rate of somnolence[13] and sedation.[16] All these results indicate that transdermal buprenorphine provides pain relief and reduces postoperative analgesic requirements. Results also summarize that the higher doses do not provide increased analgesic benefits. Moreover, no life-threatening adverse side effects were observed in the literature.

Conclusion

In conclusion, buprenorphine either transdermal or sublingual both have significant pain relief scores. The analgesic drug consumption was reduced at the end of the follow-up duration. However, buprenorphine had more adverse effects than other NSAIDs and placebo which may irritate patients and affect their surgical experience of patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.