Buprenorphine for Pain Management in Osteoarthritis Patients Scheduled for Arthroplasty - A Randomized, Double-Blind, Placebo-Controlled Trial

Special Article - Pain Management

Austin J Anesthesia and Analgesia. 2018; 6(1): 1065.

Buprenorphine for Pain Management in Osteoarthritis Patients Scheduled for Arthroplasty - A Randomized, Double-Blind, Placebo-Controlled Trial

Härkänen L1#, Kokki M1#, Huopio J², Sjövall S³, Auriola S4, Lehtonen M4 and Pergolizzi J5, Kokki H1*

1Department of Anesthesia and Operative Services, Kuopio University Hospital, School of Medicine, University of Eastern Finland, Kuopio, Finland

²Department of Orthopaedic Surgery, Kuopio University Hospital, Kuopio, Finland

³Department of Anesthesia, Satakunta Central Hospital, Pori, Finland

4School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland

5Department of Analgesic Research, NEMA Research Inc., Naples, Florida, USA

#Both authors are equally contributed

*Corresponding author: Kokki H, Anesthesia and Operative Services, Kuopio University Hospital, Finland

Received: December 14, 2017; Accepted: January 02, 2018; Published: January 09, 2018


Background: Preoperative pain is a risk factor for persistent postoperative pain. Low-dose buprenorphine is assumed to have an antihyperalgesic efficiency and thus, started preoperatively may decrease postoperative pain.

Methods: This hypothesis was tested in a double-blind, placebo-controlled clinical trial in 117 osteoarthritis (OA) patients having hip (n=52) or knee (n=65) arthroplasty. Subjects in the buprenorphine-group (n=58) received five 7-day transdermal buprenorphine 5mcg/h patches starting 2 weeks prior to surgery, and subjects in the placebo-group (n=59) similar placebo patches. Numerical pain scores 0-10 were recorded at baseline, during the hospital stay, and four weeks after surgery. The use of analgesics, adverse drug effects and treatment satisfaction were recorded.

Results: In the buprenorphine-group the mean pain score decreased on the preoperative morning compared to pain before patch application (mean difference 0.4; 95% CI, 0.0-0.8; p=0.036). At 48 hours after surgery the average pain score was less in the buprenorphine-group than in the placebo-group (0.8; 0.0-1.5; p=0.043). Both active and placebo patches were well tolerated and satisfaction with treatment was similarly high in both groups.

Conclusion: Low-dose transdermal buprenorphine could be feasible for add-on pain management in OA and arthroplasty patients but further studies are needed to establish optimal dosage.

Keywords: Analgesics; Opioid; Buprenorphine; Arthroplasty; Replacement; Knee; Arthroplasty; Replacement; Hip; Osteoarthritis; Pain; Postoperative


Hip and knee osteoarthritis (OA) are the most common joint disease and are associated with significant pain and disability [1]. Early-stage OA treatment consists of pain management and physiotherapy, but as the condition progresses joint replacement often becomes necessary [2,3]. Preoperative pain is a risk factor for postoperative pain [4]. In a study by Gerbershagen et al [5] where data on 4000 arthroplasty patients were available, preoperative pain appeared to be a risk for early postoperative pain and for severe postoperative pain, defined as pain ≥7/10 on a numerical rating scale (NRS). After arthroplasty, 7%-23% of hip replacement and 10%- 34% of knee replacement patients have moderate or severe pain that impacts their daily life for several weeks after surgery [6,7].

Buprenorphine is a highly lipophilic thebaine derivative that has affinity for mu-, kappa-, and delta-opioid peptide receptors (MOP, KOP, DOP) and a low affinity for nociceptin receptors (NOP). It acts as an agonist at the MOP and NOP and as an antagonist at the DOP and KOP. Buprenorphine binds and dissociates from the MOP slowly and thus it has up to a two-fold duration of action and is approximately 30-fold more potent when compared to parenteral morphine [8]. Both antihyperalgesic and antinociceptive efficacy have been proposed [8]. Buprenorphine’s antihyperalgesic action has been demonstrated in a human pain model where hyperalgesia was induced by central sensitization [8].

In this prospective, randomized, double-blind, parallel-group and placebo-controlled clinical trial, we investigated the analgesic efficacy of transdermal buprenorphine initiated before elective total hip arthroscopy (THA) or total knee arthroplasty (TKA) and continued postoperatively for a total of five weeks of treatment. Our hypothesis was that add-on treatment with a transdermal buprenorphine 5mcg/h patch would decrease perioperative pain in patients scheduled for elective THA or TKA.


The study was conducted in Kuopio University Hospital (KUH), Kuopio and Satakunta Central Hospital (SCH), Pori, Finland between June 2013 and May 2014. The study protocol was approved by the Research Ethics Committee of the Hospital District of Northern Savo, Kuopio, Finland (ref. No. 113/2011), Finnish Medicines Agency (ref. 122//2011) was notified, and it was registered in the European Clinical Trials Database (ref. Eudra CT: 2011-000692-14) and in the ClinicalTrials.gov database (ref. NCT02575664). Both registering institutions approved the study. The study was conducted in accordance with the principles presented in the Declaration of Helsinki. Written informed consent was obtained from each subject.

The primary outcome measures for efficacy were the pain intensity in the preoperative morning after two weeks of patch use; consumption of rescue medication (oxycodone) during the first 24 postoperative hours; pain intensity scores; and analgesics used at four weeks after surgery. Secondary measures were postoperative pain intensity during the first two postoperative days and at four weeks after surgery; length of stay (LOS) in the hospital; patient satisfaction with pain treatment; and suspected adverse drug events (ADEs).


We recruited adult patients aged 18-75 years scheduled for primary, elective, unilateral THA or TKA due to primary OA; surgery was to be performed under spinal anesthesia. We did not enroll patients with a body-mass index (BMI) less than 18 or over 35kg/m2 or patients with ongoing buprenorphine treatment, hypersensitivity to buprenorphine or to the ingredients of the patch, a history of alcohol or narcotics abuse, treatment with MAO-inhibitors within the last four weeks, renal, hepatic or pulmonary impairment, medically treated constipation within the last three months, and those who were pregnant or lactating. A total of 160 patients were asked to participate and 126 agreed.

Patients were randomly assigned to receive either an active 5mcg/h buprenorphine or a similar placebo patch. There were two sets of patches available, one set for THA and another for TKA patients. Both sets of study patches were consecutively numbered to ensure treatment allocation was concealed from the patients, investigators, treating physicians, and data analysts. The success of blinding was tested by asking patients to guess whether they had an active or placebo patches. Concealment was ended after data analysis.

Study interventions

Patients were enrolled at the preoperative visit two weeks prior to scheduled surgery. At the preoperative visit, the first study patch was applied to those who agreed to participate and patients were instructed to change to a new patch on a different appropriate skin site after seven days. Patients were given both oral and written instructions for the change and care of the patches. Patients were instructed to contact the researchers if they had any questions, concerns, or wanted to discontinue the study treatment. Patients were treated for five weeks, starting two weeks before scheduled surgery and ending two to three weeks after hospital discharge. A total of five patches were used for each patient


Spinal anesthesia was standardized. Lumbar puncture was performed at the L4/5- or L3/4-interspace. Spinal anesthesia was induced with (levo) bupivacaine 10-15 mg with fentanyl 10-20 mcg.


A standardized surgical technique was used. The standard posterior approach was made in every THA. After skin and fascia incisions, external muscles were cut and the posterior capsule was opened. After the hip implants were installed, the posterior muscles were re-inserted in their original positions, and fascia and skin incisions were sutured. In TKA, a tourniquet was applied before the operation. Straight midline skin and medial parapatellar fascial incisions were used in approach. The patella was everted and bone cuts were made by an oscillating saw utilizing intramedullar instrumentation in the femur and extramedullar instrumentation in the tibia. Bone cement was used to fixate the components. The patella was not resurfaced. The fascia and subcutaneous tissues were sutured in layers and the skin was closed with staples. After draping the wound, the tourniquet was deflated.

Postoperative pain management

Postoperative pain was treated according to the hospitals’ standardized protocols. Local infiltration analgesia (LIA) was used for most subjects with TKA (48/51) and many with THA (23/66). All patients were administered paracetamol at a dose of 1g three times daily, with the first postoperative dose administered IV, and by mouth thereafter. If not contraindicated, patients were given an NSAID, first doses IV ketoprofen 50-100 mg, followed by meloxicam 7.5mg x 1-2 by mouth. Controlled-release oxycodone-naloxone (5/2.5mg or 10/5mg) tablets were commenced the first evening, and continued every morning and evening during the hospital stay. Rescue medication was provided as appropriate and could be 2-3 mg IV oxycodone, 5-10 mg subcutaneous oxycodone, or 5-10 mg oxycodone by mouth. At discharge, patients were prescribed paracetamol and NSAIDs for pain control, and tramadol or codeine for rescue analgesia.

Pain assessments

Pain was evaluated on an eleven-point NRS where 0=no pain, and 10=most pain. Patients were asked to rate the least, the average and the most pain at rest, during hip/knee flexion/extension, and while walking during the previous 24 hours. Pain scores were recorded at baseline before patch application (two weeks prior to scheduled surgery), on the preoperative morning, during the recovery room stay, at discharge to the surgical ward, on the first and second postoperative afternoons, at discharge from the hospital, and four weeks after surgery. All suspected ADEs were recorded at these same time points. Satisfaction with pain management was evaluated using a 5-point Likert scale where 1=very satisfied, and 5=very unsatisfied. The efficiency of pain management was rated on a scale 0-10 at baseline, on the preoperative morning, at discharge, and four weeks after surgery. In the preoperative visit patients were asked how severe postoperative pain they expected to have after surgery and how severe postoperative pain they were prepared to accept.


Sample size calculation was based on data indicating that patients waiting for arthroplasty would have a mean pain score of 53.3 (standard deviation [SD] 22.6) on a scale 0-100 [10]. To achieve a 10-point decrease in the preoperative pain score, 80 patients per group would be required to achieve a statistical significance (p-value ≤ 0.05) at a power of 0.8.

Data were entered and analysed using IBM SPSS Statistics for Window, Version 23.0. (International Business Machines Corp., Armonk, NY, USA). The normality of the data was assessed for skewness and kurtosis. The intention-to-treat population included all patients who were randomized and had at least one valid aftertreatment efficacy measurement. Binomial and categorical data were analysed using the Chi-Square test. Continuous and nominal data were analysed with an independent sample t-test or the Mann Whitney U-test or related samples t-test, as appropriate. Correlations between patients’ characteristics and analgesic efficacy were analysed using the Pearson correlation coefficient and correlations between preoperative pain and postoperative recovery with Spearman’s correlation coefficient. A two-sided p-value of < 0.05 was considered significant.


A total of 160 patients were asked to participate in the study, 126 were enrolled, of whom 9 were excluded, leaving 117 subjects for the intention-to-treat analysis. Because the study patches expired in May 2014, we did not have time to recruit new patients to replace those who declined or were excluded. The reasons for exclusion in the buprenorphine-group were withdrawn consent (n=3, one of which due to a family emergency) and cancelled surgery (n=1). In the placebo-group the reasons for exclusion were withdrawn consent (n=4, one of which was due to difficulties using transdermal system) and an acute medical condition (n=1). A flow chart is presented in Figure 1.