Efficacy of buprenorphine added to 2% lignocaine plus adrenaline 1:80,000 in providing postoperative analgesia after lower third molar surgery

Efficacy of buprenorphine added to 2% lignocaine plus adrenaline 1:80,000 in providing postoperative analgesia after lower third molar surgery

International Journal of Oral & Maxillofacial Surgery, 2016-12-01, Volume 45, Issue 12, Pages 1644-1651, Copyright © 2016 International Association of Oral and Maxillofacial Surgeons

Abstract

A number of trials have examined the peripheral analgesic effect of opioids, known to have an anti-nociceptive effect at the central and/or spinal cord level. This study aimed to evaluate the efficacy of buprenorphine added to 2% lignocaine with adrenaline 1:80,000 in providing postoperative analgesia after lower third molar surgery. Sixty patients were randomized to three groups: group A received lignocaine 2% with adrenaline 1:80,000 for inferior alveolar nerve block (IANB), along with intramuscular (IM) injection of 1 ml saline; group B received buprenorphine mixed with lignocaine 2% with adrenaline 1:80,000 for IANB (0.01 mg buprenorphine/ml lignocaine with adrenaline), along with 1 ml saline IM; group C received lignocaine 2% with adrenaline 1:80,000 for IANB, along with 0.03 mg buprenorphine IM. Mean postoperative pain scores (visual analogue scale; when the patient first felt pain) were 6.0 for group A, 1.0 for group B, and 4.4 for group C. The mean duration of postoperative analgesia was 3.5 h in groups A and C and 12 h in group B. The mean number of postoperative analgesics consumed was 5.8 in groups A and C and 3.9 in group B. The addition of buprenorphine (0.03 mg) to 2% lignocaine with adrenaline 1:80,000 significantly reduced the severity of postoperative pain and prolonged the duration of analgesia, thereby decreasing the need for postoperative analgesics.

Effective postoperative pain control is an essential component of the management of the surgical patient. Traditionally, analgesics have been divided into centrally acting opioids (e.g. morphine) or peripherally acting non-steroidal anti-inflammatory drugs (NSAIDs; e.g. aspirin). Recent advances in pharmacology have challenged this strict distinction. Not only have local analgesic effects been recognized for opioids in peripheral tissue, but conversely NSAIDs have been shown to act within the central nervous system.

Opioid analgesics are often the first line of treatment for many painful conditions and may offer advantages over NSAIDs; for example, they have no true ‘ceiling dose’ for analgesia and do not cause direct organ damage. Morphine is a μ-agonist opioid regarded as the gold standard of opioid analgesics used to relieve severe or agonizing pain. However, it produces a wide spectrum of unwanted effects, including respiratory depression, nausea, vomiting, dizziness, mental clouding, dysphoria, pruritus, constipation, urinary retention, hypotension, and increased pressure in the biliary tract. Therefore, an opioid with greater analgesic potential than morphine but with lesser adverse effects is desirable. Buprenorphine hydrochloride is an opioid receptor μ agonist and κ antagonist, having both analgesic and anti-hyperalgesic properties. It has rapid onset and a long duration of action. It has an anti-nociceptive potency approximately 25 to 50 times greater than that of morphine. Adverse effects occur at a lower frequency than with morphine.

NSAIDs, which are used widely to treat pain and inflammation, are particularly useful in managing the pain associated with minimally invasive surgery. However, the associated side effects include peptic ulcer disease, gastrointestinal haemorrhage, renal dysfunction, altered liver function, and platelet dysfunction, which limit the use of these agents in some patients during the perioperative period. Thus, there is a need for a drug that can provide good analgesia but which is without the associated adverse effects of the opioids and NSAIDs.

The recognition of opioid ‘local analgesia’ provides an opportunity to design new analgesics that produce no central side effects but retain potent analgesic actions. Peripheral opioid effects are not obvious in normal tissue but become so within minutes to hours after the start of inflammation; this is not a limiting factor, because most common, painful conditions are associated with inflammation. Small, systemically inactive doses of exogenous opioids administered in the vicinity of peripheral nerve terminals have beneficial analgesic effects. They have been used in brachial plexus block and have been reported to provide marked prolongation of analgesia.

The aim of this prospective, randomized, double-blind clinical study was to evaluate the efficacy of buprenorphine added to 2% lignocaine with adrenaline 1:80,000 in providing postoperative analgesia after lower third molar surgery. The objectives of this study were to evaluate (1) the role of buprenorphine in the onset, duration, and depth of anaesthesia associated with lignocaine used for peripheral nerve block, (2) the severity of postoperative pain, (3) the duration of postoperative analgesia, (4) the decrease in number of rescue analgesics consumed by the patient, and (5) the adverse effects associated with buprenorphine when given with local anaesthetic used for peripheral nerve block.

Materials and methods

Sixty patients undergoing surgery for the removal of impacted mandibular third molars were selected on a random basis. Healthy patients aged 18–40 years without significant medical diseases or history of bleeding disorders, with impacted mandibular third molars, were included in the study.

The following patients were excluded from the study: those who were allergic or hypersensitive to any of the drugs used in the study; medically compromised patients with bleeding problems, diabetes, an immune-compromised status, or an osseous pathology affecting the surgical outcome and wound healing; patients with a history of asthma, neurological or psychiatric disease, or substance abuse; patients who had consumed analgesics with in the 6 hrs prior to surgical procedure; patients not returning the questionnaire given to them after the surgical procedure to assess their postoperative status; cases in which the inferior alveolar nerve block (IANB) failed.

A complete history was taken and a general physical and clinical examination was performed for all patients. This study was approved by the necessary institutional and ethics review board. All participants signed an informed consent form after which they were randomized by a dental nurse to one of the three study groups. The control group (group A) comprised patients who received lignocaine 2% with adrenaline 1:80,000 alone for IANB, along with intramuscular (IM) injection of 1 ml saline in the deltoid muscle of the arm. The first test group (group B) consisted of patients who received buprenorphine 0.01 mg per millilitre of lignocaine 2% with adrenaline 1:80,000 for IANB, along with IM injection of 1 ml saline in the deltoid muscle of the arm. The second test group (group C) consisted of patients who received lignocaine 2% with adrenaline 1:80,000 for IANB, along with IM injection of 0.03 mg buprenorphine in the deltoid muscle of the arm.

A slip system was used as the method of randomization, wherein three slips were made and labelled. The patient was asked to pick any one slip and they were allocated to the respective group accordingly.

A pulse oximeter was used during the procedure to record the patient’s oxygen saturation, heart rate, and blood pressure.

Preparation of the solution for nerve block

One millilitre of 0.3 mg buprenorphine was added to 30 ml of lignocaine 2% with adrenaline 1:80,000. Thus each millilitre of this solution contained 0.01 mg of buprenorphine. This was done by a dental nurse, who then also dispensed the solution for nerve block during the procedure. Thus, the operator remained unaware of the solution used in the patient. The formulation used in this study was buprenorphine hydrochloride 0.3 mg (Buprigesic; Neon Laboratories Ltd, Mumbai, India); this was used for peripheral block as well as for IM injection.

Intramuscular injections in the deltoid muscle of the arm

All patients were given an IM injection into the deltoid muscle of the arm immediately following the administration of the local anaesthetic (LA). While, group A and group B patients received 1 ml of saline IM, group C patients received 1 ml of a reconstituted solution of 10 ml saline and 1 ml buprenorphine, such that the dose of buprenorphine received by the patient was 0.03 mg. The dental nurse prepared and gave the IM injection. The operator was unaware of the group allocations.

Administration of local anaesthesia

The classical direct IANB technique was used. All patients received a maximum of 3 ml of the solution (2 ml for IANB, 0.5 ml for lingual nerve block, and 0.5 ml for long buccal nerve block), irrespective of the group to which they belonged. Group A and group C patients received 3 ml of lignocaine 2% with adrenaline 1:80,000, while patients in group B received 3 ml of a reconstituted solution of a mixture of 30 ml lignocaine 2% with adrenaline 1:80,000 and 1 ml buprenorphine 0.3 mg (thus receiving a total dose of 0.03 mg buprenorphine).

Surgical and post-surgical procedures

The surgical extraction of the impacted third molars was performed using the standard surgical procedure. Patients were given verbal and written postoperative instructions. Antibiotics (500 mg amoxicillin + 125 mg clavulanic acid, 400 mg metronidazole) were prescribed postoperatively for 5 days, along with a rescue analgesic (diclofenac potassium 50 mg), to be taken by the patient whenever the pain first appeared, after which the patient was advised to take the medication twice daily for 3 days. Sutures were removed on the seventh postoperative day.

After the surgery, patients were given a questionnaire which contained all the questions regarding their postoperative status (including postoperative analgesia, adverse effects associated with buprenorphine, and the timing and number of rescue analgesics consumed). The patients returned the questionnaire on the third postoperative day.

Preoperative parameters assessed

The position of the tooth was assessed clinically and categorized as follows: 0, unerupted; 1, partially erupted; 2, erupted. The tooth was also assessed radiographically and categorized according to the Pell and Gregory classification.

Electric pulp testing was performed. The preoperative baseline pulp sensitivity values were recorded using a Parkell Gentle-Pulse Pulp Vitality Tester (graded in units from 0 to 10). A conductive jelly was applied to the probe tip and this was placed on the centre of the buccal surfaces of the first premolar. The current was gradually increased until the patient felt pain.

Intraoperative parameters

The onset of anaesthesia was determined based on subjective and objective (needle stick test, test for proprioception, and electric pulp test) evaluations. For the subjective evaluation, the patients were asked for symptoms of tingling and numbness on the ipsilateral tongue and lower lip every 30 s after the nerve block had been administered. For the needle stick test, pain was assessed on insertion of a sterile 26-gauge needle into the mucosa around the mandibular first premolar at a 45° angle until the tip contacted bone; the absence of pain signified the onset of soft tissue anaesthesia. For the proprioception test, a probe was inserted into the periodontal ligament space between the two mandibular premolars on the same side; the absence of pain determined loss of proprioception. No sensation on pulp sensitivity testing of the mandibular first premolar (performed every 30 s after the administration of nerve block) was taken as the onset of pulpal anaesthesia.

The depth of anaesthesia was recorded intraoperatively using the Heft–Parker visual analogue scale (VAS) during soft tissue incision, flap elevation, osteotomy, and suturing. The Heft–Parker VAS consists of a long horizontal line of 170 mm, anchored by the verbal descriptors ‘no pain’ and ‘worst pain imaginable’. It was marked on the basis of what the patient felt best represented their perception of the intensity of current pain. The duration of anaesthesia was calculated from the time at onset of numbness and tingling post injection to the appearance of sensation in the area.

Intraoperatively, patients were also monitored for adverse effects associated with buprenorphine/lignocaine with adrenaline 1:80,000. These could be local (erythema, haematoma, pain, or burning on injection) or systemic (decrease in oxygen saturation, tachycardia/bradycardia, hypotension/hypertension, nausea, vomiting, headache, dizziness, drowsiness, confusion, tinnitus, tremors, blurred vision, or syncope).

Postoperative parameters

The duration of analgesia was calculated as the number of hours the patient was pain-free after the procedure. The pain was assessed every 2 h up to 24 h and then at 36, 48, and 72 h. The severity of postoperative pain was monitored when the patient first felt pain using a VAS after which the patient consumed the rescue analgesic prescribed. The VAS consisted of a 10-cm line with two end-points representing ‘no pain’ and ‘worst pain imaginable’. Patients were asked to rate their pain by placing a mark on the line corresponding to their current level of pain. The patient’s assessment of the severity of postoperative pain and duration of analgesia ended when the patient took the rescue analgesic, after the first perceived pain. Diclofenac potassium 50 mg was prescribed as a rescue analgesic (recommended to be taken twice a day for 3 days).

Patients were also asked to document postoperative adverse effects associated with buprenorphine, which could be local (prolonged anaesthesia or paresthesia, haematoma, cellulitis, trismus, oedema, tissue sloughing and ulceration, infection, facial palsy, or soft tissue injury) or systemic (drowsiness, nausea, vomiting, constipation, disturbed sleep, headache, sweating, shallow breathing, or reduced sexual interest).

Statistical analysis

For normally distributed data, the means of the three study groups were compared using one-way analysis of variance (ANOVA) followed by post hoc multiple comparisons test. The χ 2 test or Fisher’s exact test, as appropriate, was applied for the comparison of categorical data. As data for the severity of postoperative pain and preoperative pulp sensitivity were skewed, the Kruskal–Wallis test was applied for three groups, followed by the Mann–Whitney test for two groups.

The statistical analysis was conducted using IBM SPSS Statistics version 22.0 software (IBM Corp., Armonk, NY, USA). The confidence interval (CI) was also calculated in the present study and reported as the 95% CI (i.e. there is a 95% chance that the CI calculated contains the true population mean; thus, there is a 95% chance that the population mean lies within the interval). The CI permits a more flexible and nuanced approach to the analysis of research data.

Results

The study population consisted of 60 patients, with 20 assigned to each group. The patients were aged 18 to 40 years. Twenty-three (38.3%) were female and 37 (61.7%) were male. The three groups were matched for age and sex.

Preoperative parameters

The clinical and radiographic positions of the teeth are shown in Figs 1 and 2 . The three groups were matched for these parameters. The preoperative pulp sensitivity was a mean 3.3 in group A, 3.5 in group B, and 3.1 in group C. The minimum preoperative pulp sensitivity in all three groups was 2 and the maximum was 5. There was no significant difference between the groups with regard to this parameter.

Distribution of the study patients with regard to the clinical position of the tooth.
Fig. 1
Distribution of the study patients with regard to the clinical position of the tooth.
Distribution of the study patients with regard to the radiographic position of the tooth.
Fig. 2
Distribution of the study patients with regard to the radiographic position of the tooth.

Intraoperative parameters

The time to onset of anaesthesia is shown in Table 1 . There was no significant difference in the time to onset between the three groups ( P > 0.05). Thus, the addition of buprenorphine to the LA had no effect on the onset of anaesthesia in the present study.

Table 1
Evaluation of patients with regard to the time to onset of anaesthesia (mean ± standard deviation, seconds).
Group a Subjective Needle stick test Loss of proprioception Electric pulp test
Group A 67 ± 33.37 110.80 ± 34.24 141.00 ± 33.50 187.75 ± 37.50
Group B 63.75 ± 32.76 107.53 ± 31.40 165.25 ± 49.24 179.25 ± 47.77
Group C 55.50 ± 26.25 99.51 ± 38.87 148.25 ± 27.15 178.00 ± 43.99
P -value 0.485 0.579 0.124 0.742

a Group A = lignocaine 2% with adrenaline 1:80,000 for IANB, along with 1 ml saline IM; group B = buprenorphine mixed with lignocaine 2% with adrenaline 1:80,000 for IANB (0.01 mg buprenorphine/ml lignocaine with adrenaline), along with 1 ml saline IM; group C = lignocaine 2% with adrenaline 1:80,000 for IANB, along with 0.03 mg buprenorphine IM. IANB, inferior alveolar nerve block; IM, intramuscular.

The depth of anaesthesia was recorded intraoperatively using the Heft–Parker VAS during soft tissue incision, flap elevation, osteotomy, and suturing. No difference was found between the groups – the patients in all groups reported zero pain during the procedure. Therefore, no statistical analysis was required for this parameter and it was concluded that the addition of buprenorphine to LA had no effect on the depth of anaesthesia associated with lignocaine.

With regard to the duration of anaesthesia, this was a mean 237.75 min in group A, 244.00 min in group B, and 251.25 min in group C. The difference between the groups was found to be non-significant ( P = 0.571). Thus, the addition of buprenorphine to LA had no effect on the duration of anaesthesia in the present study.

None of the patients in the present study reported any adverse effects during the procedure.

Postoperative parameters

The severity of postoperative pain was assessed by VAS ( Table 2 ). The difference between group A and group C, and vice versa, was found to be significant ( P = 0.017), while the difference between group B and group C, and between group B and group A, and vice versa, was found to be highly significant ( P < 0.001). Thus, in the present study the addition of buprenorphine to LA decreased the severity of postoperative pain considerably, while IM injection also decreased the severity, but to a lesser extent.

Table 2
Evaluation of the severity of postoperative pain (VAS score).
Group a Number Mean SD Min. Max. Percentile
25th 50th (median) 75th
Group A 20 6.00 2.052 1 9 5.25 6.00 7.75
Group B 20 1.05 0.686 0 2 1.00 1.00 1.75
Group C 20 4.40 1.957 1 7 3.00 4.00 6.75
VAS, visual analogue scale; SD, standard deviation.

a Group A = lignocaine 2% with adrenaline 1:80,000 for IANB, along with 1 ml saline IM; group B = buprenorphine mixed with lignocaine 2% with adrenaline 1:80,000 for IANB (0.01 mg buprenorphine/ml lignocaine with adrenaline), along with 1 ml saline IM; group C = lignocaine 2% with adrenaline 1:80,000 for IANB, along with 0.03 mg buprenorphine IM. IANB, inferior alveolar nerve block; IM, intramuscular.

The duration of postoperative analgesia is shown in Table 3 . On comparison, the difference between group A and group C, and vice versa, was found to be non-significant ( P = 1.000), while the difference between group A and group B, and between group B and group C, and vice versa, was highly significant ( P = 0.000). Thus, the addition of buprenorphine to LA prolonged the duration of postoperative analgesia considerably, while IM injection had no such effect.

Table 3
Evaluation of the duration of postoperative analgesia (hours).
Group a Number Mean SD SE 95% CI for the mean Min. Max.
Lower bound Upper bound
Group A 20 3.50 1.100 0.246 2.99 4.01 2 6
Group B 20 12.00 8.730 1.95 7.91 16.09 4 36
Group C 20 3.50 1.051 0.235 3.01 3.99 2 5
SD, standard deviation; SE, standard error; CI, confidence interval.

a Group A = lignocaine 2% with adrenaline 1:80,000 for IANB, along with 1 ml saline IM; group B = buprenorphine mixed with lignocaine 2% with adrenaline 1:80,000 for IANB (0.01 mg buprenorphine/ml lignocaine with adrenaline), along with 1 ml saline IM; group C = lignocaine 2% with adrenaline 1:80,000 for IANB, along with 0.03 mg buprenorphine IM. IANB, inferior alveolar nerve block; IM, intramuscular.

With regard to the number of postoperative analgesics consumed ( Table 4 ), the difference between group A and group C, and vice versa, was not significant ( P = 1.000), while the difference between group A and group B, and between group B and group C, and vice versa, was highly significant ( P = 0.000). Thus, buprenorphine added to LA decreased the need for postoperative analgesic consumption in comparison to the LA only group and the IM buprenorphine plus LA group.

Table 4
Evaluation of the number of postoperative analgesics consumed.
Group a Number Mean SD SE 95% CI for the mean Min. Max.
Lower bound Upper bound
Group A 20 5.80 0.894 0.200 5.38 6.22 5 8
Group B 20 3.95 1.504 0.336 3.25 4.65 0 6
Group C 20 5.80 0.523 0.117 5.56 6.04 4 6
SD, standard deviation; SE, standard error; CI, confidence interval.

a Group A = lignocaine 2% with adrenaline 1:80,000 for IANB, along with 1 ml saline IM; group B = buprenorphine mixed with lignocaine 2% with adrenaline 1:80,000 for IANB (0.01 mg buprenorphine/ml lignocaine with adrenaline), along with 1 ml saline IM; group C = lignocaine 2% with adrenaline 1:80,000 for IANB, along with 0.03 mg buprenorphine IM. IANB, inferior alveolar nerve block; IM, intramuscular.

None of the patients in the present study reported any adverse effects after the procedure.

Discussion

Buprenorphine is a semi-synthetic, mixed agonist–antagonist opioid analgesic. An IM injection of buprenorphine 0.3 mg is equipotent to morphine 10 mg, but the analgesia produced lasts significantly longer. The low abuse liability of the drug has resulted in its wide use as a therapeutic agent in patients with opioid dependence. Currently, its principal clinical application is as an analgesic for moderate to severe pain in the perioperative setting.

Evidence has begun to accumulate that opioid anti-nociception can be initiated by the activation of peripheral opioid receptors. It is speculated that the peripheral administration of opioids provides stronger and longer lasting analgesia with a lower dose of opioid and without central side effects such as respiratory depression, nausea, vomiting, and pruritus. A number of trials have examined the peripheral analgesic effect of opioids in a variety of surgical settings. Recent studies have been conducted with the addition of buprenorphine to bupivacaine for nerve blocks, claiming a significant increase in the duration of postoperative analgesia compared to bupivacaine alone.

Lignocaine 2% plus adrenaline 1:80,000 was selected as the anaesthetic solution in the present study because it is easily available and produces anaesthesia for a duration sufficient to complete lower third molar surgery. Furthermore, unlike long-acting agents such as bupivacaine, its use avoids the possibility of inadvertent trauma to the oral soft tissues while chewing solid food or by the intake of hot fluids. Also, being an intermediate-acting LA, there is less chance of it masking the postoperative analgesic effects of buprenorphine.

Some of the previous studies investigating buprenorphine for postoperative analgesia have included a variety of intraoral surgical procedures, such as apicectomy, third molar surgery, enucleation of cysts, incision and drainage of abscesses, and alveoloplasty. In the present study, only patients undergoing lower third molar surgery were included so that all patients had similar levels of pain and inflammation. Furthermore, all extractions in all patients were performed by the same operator, thus eliminating a procedural bias.

The parameters of age, sex, clinical and radiographic position of the tooth ( Figs 1 and 2 ), and baseline pulp sensitivity did not differ between the groups. Therefore, the three groups were comparable, and significant differences in the other parameters assessed could not be attributed to differences in these parameters.

When the three groups were compared with each other, no significant difference ( P > 0.05) was found for the time to onset of anaesthesia associated with lignocaine. This is in agreement with other studies in which no difference in the time to onset of sensory block was found when buprenorphine was added to LA for regional block to provide postoperative analgesia in outpatients. Similarly, no statistically significant difference was found in the onset of sensory blockade in a study carried out by Mathew et al., in which one group received buprenorphine with bupivacaine (mean time of 6.31 min) and the other received bupivacaine alone (mean time of 6.17 min). In contrast, in a study by Mehta et al., the time to onset of anaesthesia was prolonged in the group receiving 25 μg fentanyl plus bupivacaine as compared to bupivacaine alone. According to the authors, this could have been due to the reduction in pH of bupivacaine due to the addition of fentanyl.

Yilmaz-Rastoder et al. conducted a study aimed to understand the mechanisms associated with the use of adjuvant drugs to prolong the duration of LA-induced block of peripheral nerves. Their results led them to conclude that the reported clinical efficacy of drugs such as buprenorphine was achieved by means of influencing the actions of LAs via indirect mechanisms that remain unidentified.

In the present study, no difference was found between the groups with respect to the depth of anaesthesia, as the patients in all groups reported zero pain during the procedure. This could be attributed to the anaesthetic effect of the LA lignocaine used in all of the patients during the procedure.

The addition of buprenorphine to 2% lignocaine solution in the present study also had no effect on the duration of anaesthesia associated with lignocaine. Similarly, Dixit et al. carried out a study in which the duration of sensory block was similar in the groups receiving bupivacaine alone, or bupivacaine with buprenorphine. In contrast to this, in a study by Vishwas et al., the addition of an opioid (fentanyl) to lidocaine significantly prolonged the duration of sensory block compared to that obtained with lidocaine alone. However, in this latter study the duration of sensory block was taken as the time between the onset of analgesia and the re-appearance of pain or request for pain relief. So, the difference could be attributed to the analgesic effect of fentanyl postoperatively.

None of the patients reported any adverse effects in any of the groups that were evaluated during the present study. This absence of adverse effects may be attributed to the fact that as little as 0.03 mg of buprenorphine was used in the study. These results are supported by those of Kumar et al., who found no adverse effects related to the addition of buprenorphine to lidocaine 2%. However, this is in contrast to the study by Paliwal and Karnawat, in which the incidence of nausea, vomiting, and sedation, although found in all groups, was greater in patients receiving buprenorphine (0.3 mg) added to bupivacaine (0.25% bupivacaine, 40 ml) as compared to those receiving bupivacaine alone or bupivacaine with clonidine (150 μg) when used for brachial plexus block. The difference was statistically non-significant. According to the authors, the increased incidence of adverse effects in their study indicated partial systemic absorption of buprenorphine.

In the present study, the addition of buprenorphine to lignocaine for regional block significantly reduced the postoperative severity of pain and significantly prolonged the duration of analgesia, while IM injection of buprenorphine also reduced the severity of pain but to a lesser extent, and slightly prolonged the duration of analgesia. One possible explanation for the failure to elicit a more full-fledged analgesia with IM injection of buprenorphine could be that a suboptimal dose of buprenorphine was used in the present study (0.03 mg as opposed to 0.3 mg). However, as the addition of a suboptimal dose of buprenorphine to LA significantly prolonged the duration of analgesia in the present study, the theory of the presence of peripheral opioid receptors is reinforced.

Thiede et al. conducted a pharmacokinetic analysis of two new long-acting formulations of buprenorphine and showed that given a therapeutic plasma buprenorphine concentration threshold of 0.1 ng/ml, a single subcutaneous injection of 0.18 mg/kg sustained release buprenorphine (SRB) lasted for 264.0 ± 32.2 h, while a single application of 30 μg/h of transdermal buprenorphine (TDB) lasted for 72 h. In comparison, 0.2 mg/kg intravenous buprenorphine achieved a therapeutic concentration for only 8 h.

These results are similar to those obtained in the present study, in which the IM injection of buprenorphine did not significantly prolong the analgesia, like the intravenous administration in the study by Thiede et al., probably because of systemic absorption and action on receptors in the central nervous system. Similarly, buprenorphine given with local nerve block prolonged analgesia (submucosal) in the present study, like the subdermal group in the study by Thiede et al., thus further strengthening the concept of the presence of peripheral mechanisms working to provide opioid analgesia. Also, the study of Thiede et al. correlated plasma buprenorphine concentrations with clinical efficacy, which has not been done in other studies including the present one.

In a study performed by Swarnkar et al., VAS scores were significantly lower in the group receiving 0.5% 40 ml lidocaine for intravenous regional anaesthesia (IVRA) and buprenorphine 0.3 mg IM (group B) and the group receiving 0.5% 40 ml lidocaine with buprenorphine 0.3 mg for IVRA (group C), as compared to the group receiving 0.5% 40 ml lidocaine for IVRA (group A). Similarly there was a highly significant difference between group C and group B when compared statistically, with group C having lower VAS scores than group B. Mehrotra and Mehrotra compared the analgesic effect of IM and perineural buprenorphine in the same patients. The verbal numeric rating scale (0 for no pain, 10 for worst pain imaginable) score was 6.3 for the IM route compared to 1.9 for regional infiltration. This was significant and reasonably excluded systemic drug absorption from the perineural tissues as the cause of analgesia. This was also the case in the present study in which the regional block produced much lower VAS scores than the lignocaine alone group and the IM buprenorphine group. The authors also reported no incidence of systemic toxicity in patients receiving buprenorphine; local reactions were limited to erythema and cellulitis in three cases, which resolved on treatment.

The prolonged duration of analgesia associated with buprenorphine may be explained by the fact that it dissociates very slowly from opioid receptors. Mathew et al. found that the duration of analgesia was longer in the group receiving 0.5% bupivacaine and 3 μg/kg buprenorphine (13.24 h) as compared to the group receiving 0.5% bupivacaine alone (6.68 h). Similarly, Candido et al. performed a study wherein buprenorphine plus LA (mixture of mepivacaine and tetracaine) produced analgesia of three-times longer duration (mean 22.3 h) than when using LA alone (mean 6.6 h) and twice as long as buprenorphine given by IM injection plus LA as the only block (mean 12.5 h). In contrast to these, a study by Flory et al. found no difference in duration, quality of postoperative analgesia, or patient satisfaction in two groups receiving brachial plexus block with 0.5% bupivacaine alone or with the addition of morphine 5 mg to 0.5% bupivacaine. According to the authors, this could be explained by the long-acting anaesthetic effect of bupivacaine, which could have masked the postoperative analgesia associated with morphine.

Various mechanisms have been proposed for the activation of opioid receptors on peripheral neurons. Peripheral opioid receptors are synthesized in the dorsal root ganglion and are transported intra-axonally to the peripheral sensory nerve endings. Opioid receptors belong to the family of seven transmembrane domain G protein coupled receptors. The binding of opioid peptides to opioid receptors will cause opioid receptor activation and coupling to inhibitory G proteins resulting in the inhibition of high-voltage activated calcium channels, tetrodotoxin-resistant sodium channels, and decreased levels of neuronal cyclic adenosine monophosphate (cAMP). This inhibits the neuronal firing and transmitter release, as well as the calcium-dependent release of excitatory proinflammatory compounds (e.g. substance P), which contributes to their analgesic and anti-inflammatory actions.

The opioid anti-nociceptive effect is particularly prominent in inflamed tissue. Inflammation enhances the peripherally directed axonal transport of opioid receptors from the dorsal root ganglion to the periphery, leading to receptor up-regulation (increase in their number in peripheral nerve terminals). Perhaps the major contributor to up-regulation in the number and efficacy of sensory neuron μ opioid receptors is nerve growth factor, which is increased in peripheral inflammation and acts on nociceptive neurons via interaction with the tyrosine kinase receptors.

In addition to opioid receptor up-regulation, inflammation also changes the environment in local tissue via a pH decrease, rendering opioid receptors more active due to an increased G protein coupling and cAMP levels. Also, the previously inactive opioid receptors become active in inflamed tissue, enhancing the analgesic potential of opioids.

Additional effects that may enhance opioid efficacy in the periphery include an increase in the number of nociceptor endings and disruption of the perineural barrier (facilitating the passage of corticotrophin-releasing hormones, interleukin 1B, and other cytokines), stimulating the release of opioid peptides from immune cells, which activate opioid receptors on the sensory nerve endings leading to anti-nociception.

Considering the presence of opioid receptors in both local and recruited immune cells, buprenorphine could be acting via a comparable mechanism.

As most of the patients in the present study reported with some level of pain before the procedure due to the erupting third molar or pericoronitis (which can be attributed to prostaglandin synthesis due to an underlying infection and accompanying inflammatory response), and were not given preoperative analgesics, it can be assumed that some level of inflammation was present at the extraction site at the time of surgery. The prolonged duration of analgesia in this study thus strengthens the hypothesis that an inflammatory process may be required for the occurrence of peripheral opioid effects.

Dionne et al. carried out a study in which low doses of morphine (0.4, 1.2, and 3.6 mg) administered into the intraligamentary space of a chronically inflamed hyperalgesic tooth produced a dose-related naloxone-reversible analgesia, whereas the subcutaneous administration of a 1.2-mg dose of morphine failed to elicit an analgesic response. According to the authors, this analgesic effect was mediated by a local mechanism in the inflamed tissue. Similarly, in a study by Likar et al., pain scores and the supplemental consumption of diclofenac were significantly lower in patients receiving morphine into inflamed submucous tissue for up to 24 h, as compared to patients receiving morphine into non-inflamed tissues or perineurally.

The present study also showed that the addition of buprenorphine to lignocaine significantly decreased the need for postoperative analgesics ( Table 4 ). This finding is supported by the study of Kumar et al., in which the number of postoperative analgesics consumed in the buprenorphine added to lignocaine group was less than that consumed in the lignocaine alone group after minor oral surgical procedures. In contrast, no difference in number of postoperative analgesics was seen in the study by Likar et al., in which one group was administered postoperative morphine sulphate plus lidocaine as a local spray and the other group received lidocaine alone. According to the authors, since the patients presented in a pain-free state at the time of surgery, no apparent activation of the peripheral opioid receptors occurred.

The present study clearly indicates that buprenorphine added to the LA injected for IANB provides prolonged postoperative analgesia and markedly decreases the need for pain medication in the postoperative period. In view of the absence of adverse effects in this small group of patients, the addition of buprenorphine to bupivacaine for IANB in patients undergoing lower third molar surgery may be a way to provide postoperative analgesia for outpatients.

The following conclusions can be drawn from this study: (1) the addition of buprenorphine (0.03 mg) to 2% lignocaine in adrenaline 1:80,000 injected to block the inferior alveolar nerve in patients undergoing lower third molar extractions, has no effect on the onset, duration, or depth of anaesthesia associated with lignocaine; (2) it significantly reduces the postoperative severity of pain and prolongs the duration of analgesia (up to a maximum of 36 h), thereby decreasing the need for postoperative analgesics; (3) IM administration of buprenorphine did not significantly prolong the duration of analgesia in this study, with the use of the same suboptimal dose (0.03 mg) of buprenorphine, thus further strengthening the concept of the peripheral action of opioids; (4) there were no adverse effects associated with the addition of buprenorphine to lignocaine for inferior alveolar nerve block.

More clinical trials with larger numbers of patients are essential to further substantiate the efficacy of buprenorphine in providing postoperative pain relief when added to local anaesthetics. Also, the correlation of plasma concentrations of buprenorphine and the route of administration should be an important aspect of future studies, and the absence of this is a weakness of the current one.

Funding

None.

Competing interests

No conflicts of interest.

Ethical approval

The study design was approved in the Minutes of the Institutional Ethics Board (F/Ethical/1593).

Patient consent

Informed consent was obtained from all patients.

References

  • 1. Ramsay M.A.: Acute postoperative pain management. Proc (Bayl Univ Med Cent) 2000; 13: pp. 244-247.
  • 2. Khanna I.K., Pillarisetti S.: Buprenorphine—an attractive opioid with underutilized potential in treatment of chronic pain. J Pain Res 2015; 8: pp. 859-870.
  • 3. Veil E.J., Eledjam J.J., De La Coussaye J.E., D’Athis F.: Brachial plexus block with opioids for postoperative pain relief: comparison between buprenorphine and morphine. Reg Anesth 1989; 14: pp. 274-278.
  • 4. Bazin J.E., Massoni C., Bruelle P., Fenies V., Groslier D., Schoeffler P.: The addition of opioids to local anaesthetics in brachial plexus block: the comparative effects of morphine, buprenorphine and sufentanil. Anaesthesia 1997; 52: pp. 858-862.
  • 5. Candido K.D., Winnie A.P., Ghaleb A.H., Fattouh M.W., Franco C.D.: Buprenorphine added to the local anesthetic for axillary brachial plexus block prolongs postoperative analgesia. Reg Anesth Pain Med 2002; 27: pp. 162-167.
  • 6. Robaux S., Blunt C., Viel E., Cuvillon P., Nouguier P., Dautel G., et. al.: Tramadol added to 1.5% mepivacaine for axillary brachial plexus block improves postoperative analgesia dose-dependently. Anesth Analg 2004; 98: pp. 1172-1177.
  • 7. Fletcher D., Kuhlman G., Samii K.: Addition of fentanyl to 1.5% lidocaine does not increase the success of axillary plexus block. Reg Anesth 1994; 19: pp. 183-188.
  • 8. Flory N., Van-Gessel E., Donald F., Hoffmeyer P., Gamulin Z.: Does the addition of morphine to brachial plexus block improve analgesia after shoulder surgery?. Br J Anaesth 1995; 75: pp. 23-26.
  • 9. Modi M., Rastogi S., Kumar A.: Buprenorphine with bupivacaine for intraoral nerve blocks to provide postoperative analgesia in outpatients after minor oral surgery. J Oral Maxillofac Surg 2009; 67: pp. 2571-2576.
  • 10. Kumar S.P., Suryavanshi R.K., Kotrashetti S.M.: Efficacy of buprenorphine added to 2% lignocaine 1:80000 in postoperative analgesia after minor oral surgery. J Maxillofac Oral Surg 2013; 12: pp. 30-34.
  • 11. Paliwal B., Karnawat R.: Comparative study of effects of buprenorphine or clonidine as adjuvants to local anesthetics (bupivacaine 0.25%) for supraclavicular brachial plexus block. IOSR J Dent Med Sci 2013; 4: pp. 30-39.
  • 12. Mathew A., Balamurugan B., Gowthaman R.: Buprenorphine as an adjuvant to bupivacaine in supraclavicular brachial plexus block. Chettinad Health City Med J 2014; 3: pp. 39-43.
  • 13. Mehta S., Dalwadi H., Shah T.D.: Comparative study of low dose bupivacaine–fentanyl vs. conventional dose of bupivacaine in spinal anaesthesia for orthopedic procedures in elderly patients. Guj Med J 2015; 70: pp. 25-28.
  • 14. Yilmaz-Rastoder E., Gold M.S., Hough K.A., Gebhart G.F., Williams B.A.: Effect of adjuvant drugs on the action of local anesthetics in isolated rat sciatic nerves. Reg Anesth Pain Med 2012; 37: pp. 403-409.
  • 15. Dixit R., Chakole V., Tadwalkar G.V.: Effect of buprenorphine on post operative analgesia in supraclavicular brachial plexus block using peripheral nerve locator. J Evol Med Dent Sci 2013; 2: pp. 114-118.
  • 16. Vishwas G.K., Kiran B.R., Sagar S.M., Shiva Kumar K.P.: Effect of fentanyl as an adjuvant to local anaesthetics in supraclavicular brachial plexus block on duration of post-operative analgesia: a prospective randomised clinical study. Int. J. Sci. Res. 2015; 4: pp. 274-276.
  • 17. Thiede A.J., Garcia K.D., Stolarik D.F., Ma J., Jenkins G.J., Nunamaker E.A.: . J Am Assoc Lab Anim Sci 2014; 53: pp. 692-699.
  • 18. Swarnkar N., Ghosh A., Yadav A.: Buprenorphine significantly prolongs postoperative analgesia in intravenous regional anesthesia: a double blind randomized clinical trial. Internet J Anesthesiol 2008; 19: pp. 1.
  • 19. Mehrotra M., Mehrotra S.: An innovative approach to nerve block analgesia. Indian J Anaesth 2002; 46: pp. 151.
  • 20. Smith H.S.: Peripherally-acting opioids. Pain Phys 2008; 11: pp. S121-S132.
  • 21. Lesniak A., Lipkowski A.W.: Opioid peptides in peripheral pain control. Acta Neurobiol Exp (Wars) 2011; 71: pp. 129-138.
  • 22. Dionne R.A., Lepinski A.M., Gordon S.M., Jaber L., Brahim J.S., Hargreaves K.M.: Analgesic effects of peripherally administered opioids in clinical models of acute and chronic inflammation. Clin Pharmacol Ther 2001; 70: pp. 66-73.
  • 23. Likar R., Koppert W., Blatnig H., Chiari F., Sittl R., Stein C., et. al.: Efficacy of peripheral morphine analgesia in inflamed, non-inflamed and perineural tissue of dental surgery patients. J Pain Symptom Manag 2001; 21: pp. 330-337.
  • 24. Likar R., Schafer M., Trampitsch E., Breschan C., Sittll R., Gaggl A., et. al.: Topical application of local anesthetics and opioids after elective tooth extraction. Schmerz 2005; 19: pp. 195-198. 200

Was this article helpful?

Efficacy of buprenorphine added to 2% lignocaine plus adrenaline 1:80,000 in providing postoperative analgesia after lower third molar surgery N. Chhabra , P. Sharma , S. Chhabra and N. Gupta International Journal of Oral & Maxillofacial Surgery, 2016-12-01, Volume 45, Issue 12, Pages 1644-1651, Copyright © 2016 International Association of Oral and Maxillofacial Surgeons Abstract A number of trials have examined the peripheral analgesic effect of opioids, known to have an anti-nociceptive effect at the central and/or spinal cord level. This study aimed to evaluate the efficacy of buprenorphine added to 2% lignocaine with adrenaline 1:80,000 in providing postoperative analgesia after lower third molar surgery. Sixty patients were randomized to three groups: group A received lignocaine 2% with adrenaline 1:80,000 for inferior alveolar nerve block (IANB), along with intramuscular (IM) injection of 1 ml saline; group B received buprenorphine mixed with lignocaine 2% with adrenaline 1:80,000 for IANB (0.01 mg buprenorphine/ml lignocaine with adrenaline), along with 1 ml saline IM; group C received lignocaine 2% with adrenaline 1:80,000 for IANB, along with 0.03 mg buprenorphine IM. Mean postoperative pain scores (visual analogue scale; when the patient first felt pain) were 6.0 for group A, 1.0 for group B, and 4.4 for group C. The mean duration of postoperative analgesia was 3.5 h in groups A and C and 12 h in group B. The mean number of postoperative analgesics consumed was 5.8 in groups A and C and 3.9 in group B. The addition of buprenorphine (0.03 mg) to 2% lignocaine with adrenaline 1:80,000 significantly reduced the severity of postoperative pain and prolonged the duration of analgesia, thereby decreasing the need for postoperative analgesics. Effective postoperative pain control is an essential component of the management of the surgical patient. Traditionally, analgesics have been divided into centrally acting opioids (e.g. morphine) or peripherally acting non-steroidal anti-inflammatory drugs (NSAIDs; e.g. aspirin). Recent advances in pharmacology have challenged this strict distinction. Not only have local analgesic effects been recognized for opioids in peripheral tissue, but conversely NSAIDs have been shown to act within the central nervous system. Opioid analgesics are often the first line of treatment for many painful conditions and may offer advantages over NSAIDs; for example, they have no true ‘ceiling dose’ for analgesia and do not cause direct organ damage. Morphine is a μ-agonist opioid regarded as the gold standard of opioid analgesics used to relieve severe or agonizing pain. However, it produces a wide spectrum of unwanted effects, including respiratory depression, nausea, vomiting, dizziness, mental clouding, dysphoria, pruritus, constipation, urinary retention, hypotension, and increased pressure in the biliary tract. Therefore, an opioid with greater analgesic potential than morphine but with lesser adverse effects is desirable. Buprenorphine hydrochloride is an opioid receptor μ agonist and κ antagonist, having both analgesic and anti-hyperalgesic properties. It has rapid onset and a long duration of action. It has an anti-nociceptive potency approximately 25 to 50 times greater than that of morphine. Adverse effects occur at a lower frequency than with morphine. NSAIDs, which are used widely to treat pain and inflammation, are particularly useful in managing the pain associated with minimally invasive surgery. However, the associated side effects include peptic ulcer disease, gastrointestinal haemorrhage, renal dysfunction, altered liver function, and platelet dysfunction, which limit the use of these agents in some patients during the perioperative period. Thus, there is a need for a drug that can provide good analgesia but which is without the associated adverse effects of the opioids and NSAIDs. The recognition of opioid ‘local analgesia’ provides an opportunity to design new analgesics that produce no central side effects but retain potent analgesic actions. Peripheral opioid effects are not obvious in normal tissue but become so within minutes to hours after the start of inflammation; this is not a limiting factor, because most common, painful conditions are associated with inflammation. Small, systemically inactive doses of exogenous opioids administered in the vicinity of peripheral nerve terminals have beneficial analgesic effects. They have been used in brachial plexus block and have been reported to provide marked prolongation of analgesia. The aim of this prospective, randomized, double-blind clinical study was to evaluate the efficacy of buprenorphine added to 2% lignocaine with adrenaline 1:80,000 in providing postoperative analgesia after lower third molar surgery. The objectives of this study were to evaluate (1) the role of buprenorphine in the onset, duration, and depth of anaesthesia associated with lignocaine used for peripheral nerve block, (2) the severity of postoperative pain, (3) the duration of postoperative analgesia, (4) the decrease in number of rescue analgesics consumed by the patient, and (5) the adverse effects associated with buprenorphine when given with local anaesthetic used for peripheral nerve block. Materials and methods Sixty patients undergoing surgery for the removal of impacted mandibular third molars were selected on a random basis. Healthy patients aged 18–40 years without significant medical diseases or history of bleeding disorders, with impacted mandibular third molars, were included in the study. The following patients were excluded from the study: those who were allergic or hypersensitive to any of the drugs used in the study; medically compromised patients with bleeding problems, diabetes, an immune-compromised status, or an osseous pathology affecting the surgical outcome and wound healing; patients with a history of asthma, neurological or psychiatric disease, or substance abuse; patients who had consumed analgesics with in the 6 hrs prior to surgical procedure; patients not returning the questionnaire given to them after the surgical procedure to assess their postoperative status; cases in which the inferior alveolar nerve block (IANB) failed. A complete history was taken and a general physical and clinical examination was performed for all patients. This study was approved by the necessary institutional and ethics review board. All participants signed an informed consent form after which they were randomized by a dental nurse to one of the three study groups. The control group (group A) comprised patients who received lignocaine 2% with adrenaline 1:80,000 alone for IANB, along with intramuscular (IM) injection of 1 ml saline in the deltoid muscle of the arm. The first test group (group B) consisted of patients who received buprenorphine 0.01 mg per millilitre of lignocaine 2% with adrenaline 1:80,000 for IANB, along with IM injection of 1 ml saline in the deltoid muscle of the arm. The second test group (group C) consisted of patients who received lignocaine 2% with adrenaline 1:80,000 for IANB, along with IM injection of 0.03 mg buprenorphine in the deltoid muscle of the arm. A slip system was used as the method of randomization, wherein three slips were made and labelled. The patient was asked to pick any one slip and they were allocated to the respective group accordingly. A pulse oximeter was used during the procedure to record the patient's oxygen saturation, heart rate, and blood pressure. Preparation of the solution for nerve block One millilitre of 0.3 mg buprenorphine was added to 30 ml of lignocaine 2% with adrenaline 1:80,000. Thus each millilitre of this solution contained 0.01 mg of buprenorphine. This was done by a dental nurse, who then also dispensed the solution for nerve block during the procedure. Thus, the operator remained unaware of the solution used in the patient. The formulation used in this study was buprenorphine hydrochloride 0.3 mg (Buprigesic; Neon Laboratories Ltd, Mumbai, India); this was used for peripheral block as well as for IM injection. Intramuscular injections in the deltoid muscle of the arm All patients were given an IM injection into the deltoid muscle of the arm immediately following the administration of the local anaesthetic (LA). While, group A and group B patients received 1 ml of saline IM, group C patients received 1 ml of a reconstituted solution of 10 ml saline and 1 ml buprenorphine, such that the dose of buprenorphine received by the patient was 0.03 mg. The dental nurse prepared and gave the IM injection. The operator was unaware of the group allocations. Administration of local anaesthesia The classical direct IANB technique was used. All patients received a maximum of 3 ml of the solution (2 ml for IANB, 0.5 ml for lingual nerve block, and 0.5 ml for long buccal nerve block), irrespective of the group to which they belonged. Group A and group C patients received 3 ml of lignocaine 2% with adrenaline 1:80,000, while patients in group B received 3 ml of a reconstituted solution of a mixture of 30 ml lignocaine 2% with adrenaline 1:80,000 and 1 ml buprenorphine 0.3 mg (thus receiving a total dose of 0.03 mg buprenorphine). Surgical and post-surgical procedures The surgical extraction of the impacted third molars was performed using the standard surgical procedure. Patients were given verbal and written postoperative instructions. Antibiotics (500 mg amoxicillin + 125 mg clavulanic acid, 400 mg metronidazole) were prescribed postoperatively for 5 days, along with a rescue analgesic (diclofenac potassium 50 mg), to be taken by the patient whenever the pain first appeared, after which the patient was advised to take the medication twice daily for 3 days. Sutures were removed on the seventh postoperative day. After the surgery, patients were given a questionnaire which contained all the questions regarding their postoperative status (including postoperative analgesia, adverse effects associated with buprenorphine, and the timing and number of rescue analgesics consumed). The patients returned the questionnaire on the third postoperative day. Preoperative parameters assessed The position of the tooth was assessed clinically and categorized as follows: 0, unerupted; 1, partially erupted; 2, erupted. The tooth was also assessed radiographically and categorized according to the Pell and Gregory classification. Electric pulp testing was performed. The preoperative baseline pulp sensitivity values were recorded using a Parkell Gentle-Pulse Pulp Vitality Tester (graded in units from 0 to 10). A conductive jelly was applied to the probe tip and this was placed on the centre of the buccal surfaces of the first premolar. The current was gradually increased until the patient felt pain. Intraoperative parameters The onset of anaesthesia was determined based on subjective and objective (needle stick test, test for proprioception, and electric pulp test) evaluations. For the subjective evaluation, the patients were asked for symptoms of tingling and numbness on the ipsilateral tongue and lower lip every 30 s after the nerve block had been administered. For the needle stick test, pain was assessed on insertion of a sterile 26-gauge needle into the mucosa around the mandibular first premolar at a 45° angle until the tip contacted bone; the absence of pain signified the onset of soft tissue anaesthesia. For the proprioception test, a probe was inserted into the periodontal ligament space between the two mandibular premolars on the same side; the absence of pain determined loss of proprioception. No sensation on pulp sensitivity testing of the mandibular first premolar (performed every 30 s after the administration of nerve block) was taken as the onset of pulpal anaesthesia. The depth of anaesthesia was recorded intraoperatively using the Heft–Parker visual analogue scale (VAS) during soft tissue incision, flap elevation, osteotomy, and suturing. The Heft–Parker VAS consists of a long horizontal line of 170 mm, anchored by the verbal descriptors ‘no pain’ and ‘worst pain imaginable’. It was marked on the basis of what the patient felt best represented their perception of the intensity of current pain. The duration of anaesthesia was calculated from the time at onset of numbness and tingling post injection to the appearance of sensation in the area. Intraoperatively, patients were also monitored for adverse effects associated with buprenorphine/lignocaine with adrenaline 1:80,000. These could be local (erythema, haematoma, pain, or burning on injection) or systemic (decrease in oxygen saturation, tachycardia/bradycardia, hypotension/hypertension, nausea, vomiting, headache, dizziness, drowsiness, confusion, tinnitus, tremors, blurred vision, or syncope). Postoperative parameters The duration of analgesia was calculated as the number of hours the patient was pain-free after the procedure. The pain was assessed every 2 h up to 24 h and then at 36, 48, and 72 h. The severity of postoperative pain was monitored when the patient first felt pain using a VAS after which the patient consumed the rescue analgesic prescribed. The VAS consisted of a 10-cm line with two end-points representing ‘no pain’ and ‘worst pain imaginable’. Patients were asked to rate their pain by placing a mark on the line corresponding to their current level of pain. The patient's assessment of the severity of postoperative pain and duration of analgesia ended when the patient took the rescue analgesic, after the first perceived pain. Diclofenac potassium 50 mg was prescribed as a rescue analgesic (recommended to be taken twice a day for 3 days). Patients were also asked to document postoperative adverse effects associated with buprenorphine, which could be local (prolonged anaesthesia or paresthesia, haematoma, cellulitis, trismus, oedema, tissue sloughing and ulceration, infection, facial palsy, or soft tissue injury) or systemic (drowsiness, nausea, vomiting, constipation, disturbed sleep, headache, sweating, shallow breathing, or reduced sexual interest). Statistical analysis For normally distributed data, the means of the three study groups were compared using one-way analysis of variance (ANOVA) followed by post hoc multiple comparisons test. The χ 2 test or Fisher's exact test, as appropriate, was applied for the comparison of categorical data. As data for the severity of postoperative pain and preoperative pulp sensitivity were skewed, the Kruskal–Wallis test was applied for three groups, followed by the Mann–Whitney test for two groups. The statistical analysis was conducted using IBM SPSS Statistics version 22.0 software (IBM Corp., Armonk, NY, USA). The confidence interval (CI) was also calculated in the present study and reported as the 95% CI (i.e. there is a 95% chance that the CI calculated contains the true population mean; thus, there is a 95% chance that the population mean lies within the interval). The CI permits a more flexible and nuanced approach to the analysis of research data. Results The study population consisted of 60 patients, with 20 assigned to each group. The patients were aged 18 to 40 years. Twenty-three (38.3%) were female and 37 (61.7%) were male. The three groups were matched for age and sex. Preoperative parameters The clinical and radiographic positions of the teeth are shown in Figs 1 and 2 . The three groups were matched for these parameters. The preoperative pulp sensitivity was a mean 3.3 in group A, 3.5 in group B, and 3.1 in group C. The minimum preoperative pulp sensitivity in all three groups was 2 and the maximum was 5. There was no significant difference between the groups with regard to this parameter. Fig. 1 Distribution of the study patients with regard to the clinical position of the tooth. Fig. 2 Distribution of the study patients with regard to the radiographic position of the tooth. Intraoperative parameters The time to onset of anaesthesia is shown in Table 1 . There was no significant difference in the time to onset between the three groups ( P > 0.05). Thus, the addition of buprenorphine to the LA had no effect on the onset of anaesthesia in the present study. Table 1 Evaluation of patients with regard to the time to onset of anaesthesia (mean ± standard deviation, seconds). Group a Subjective Needle stick test Loss of proprioception Electric pulp test Group A 67 ± 33.37 110.80 ± 34.24 141.00 ± 33.50 187.75 ± 37.50 Group B 63.75 ± 32.76 107.53 ± 31.40 165.25 ± 49.24 179.25 ± 47.77 Group C 55.50 ± 26.25 99.51 ± 38.87 148.25 ± 27.15 178.00 ± 43.99 P -value 0.485 0.579 0.124 0.742 a Group A = lignocaine 2% with adrenaline 1:80,000 for IANB, along with 1 ml saline IM; group B = buprenorphine mixed with lignocaine 2% with adrenaline 1:80,000 for IANB (0.01 mg buprenorphine/ml lignocaine with adrenaline), along with 1 ml saline IM; group C = lignocaine 2% with adrenaline 1:80,000 for IANB, along with 0.03 mg buprenorphine IM. IANB, inferior alveolar nerve block; IM, intramuscular. The depth of anaesthesia was recorded intraoperatively using the Heft–Parker VAS during soft tissue incision, flap elevation, osteotomy, and suturing. No difference was found between the groups – the patients in all groups reported zero pain during the procedure. Therefore, no statistical analysis was required for this parameter and it was concluded that the addition of buprenorphine to LA had no effect on the depth of anaesthesia associated with lignocaine. With regard to the duration of anaesthesia, this was a mean 237.75 min in group A, 244.00 min in group B, and 251.25 min in group C. The difference between the groups was found to be non-significant ( P = 0.571). Thus, the addition of buprenorphine to LA had no effect on the duration of anaesthesia in the present study. None of the patients in the present study reported any adverse effects during the procedure. Postoperative parameters The severity of postoperative pain was assessed by VAS ( Table 2 ). The difference between group A and group C, and vice versa, was found to be significant ( P = 0.017), while the difference between group B and group C, and between group B and group A, and vice versa, was found to be highly significant ( P < 0.001). Thus, in the present study the addition of buprenorphine to LA decreased the severity of postoperative pain considerably, while IM injection also decreased the severity, but to a lesser extent. Table 2 Evaluation of the severity of postoperative pain (VAS score). Group a Number Mean SD Min. Max. Percentile 25th 50th (median) 75th Group A 20 6.00 2.052 1 9 5.25 6.00 7.75 Group B 20 1.05 0.686 0 2 1.00 1.00 1.75 Group C 20 4.40 1.957 1 7 3.00 4.00 6.75 VAS, visual analogue scale; SD, standard deviation. a Group A = lignocaine 2% with adrenaline 1:80,000 for IANB, along with 1 ml saline IM; group B = buprenorphine mixed with lignocaine 2% with adrenaline 1:80,000 for IANB (0.01 mg buprenorphine/ml lignocaine with adrenaline), along with 1 ml saline IM; group C = lignocaine 2% with adrenaline 1:80,000 for IANB, along with 0.03 mg buprenorphine IM. IANB, inferior alveolar nerve block; IM, intramuscular. The duration of postoperative analgesia is shown in Table 3 . On comparison, the difference between group A and group C, and vice versa, was found to be non-significant ( P = 1.000), while the difference between group A and group B, and between group B and group C, and vice versa, was highly significant ( P = 0.000). Thus, the addition of buprenorphine to LA prolonged the duration of postoperative analgesia considerably, while IM injection had no such effect. Table 3 Evaluation of the duration of postoperative analgesia (hours). Group a Number Mean SD SE 95% CI for the mean Min. Max. Lower bound Upper bound Group A 20 3.50 1.100 0.246 2.99 4.01 2 6 Group B 20 12.00 8.730 1.95 7.91 16.09 4 36 Group C 20 3.50 1.051 0.235 3.01 3.99 2 5 SD, standard deviation; SE, standard error; CI, confidence interval. a Group A = lignocaine 2% with adrenaline 1:80,000 for IANB, along with 1 ml saline IM; group B = buprenorphine mixed with lignocaine 2% with adrenaline 1:80,000 for IANB (0.01 mg buprenorphine/ml lignocaine with adrenaline), along with 1 ml saline IM; group C = lignocaine 2% with adrenaline 1:80,000 for IANB, along with 0.03 mg buprenorphine IM. IANB, inferior alveolar nerve block; IM, intramuscular. With regard to the number of postoperative analgesics consumed ( Table 4 ), the difference between group A and group C, and vice versa, was not significant ( P = 1.000), while the difference between group A and group B, and between group B and group C, and vice versa, was highly significant ( P = 0.000). Thus, buprenorphine added to LA decreased the need for postoperative analgesic consumption in comparison to the LA only group and the IM buprenorphine plus LA group. Table 4 Evaluation of the number of postoperative analgesics consumed. Group a Number Mean SD SE 95% CI for the mean Min. Max. Lower bound Upper bound Group A 20 5.80 0.894 0.200 5.38 6.22 5 8 Group B 20 3.95 1.504 0.336 3.25 4.65 0 6 Group C 20 5.80 0.523 0.117 5.56 6.04 4 6 SD, standard deviation; SE, standard error; CI, confidence interval. a Group A = lignocaine 2% with adrenaline 1:80,000 for IANB, along with 1 ml saline IM; group B = buprenorphine mixed with lignocaine 2% with adrenaline 1:80,000 for IANB (0.01 mg buprenorphine/ml lignocaine with adrenaline), along with 1 ml saline IM; group C = lignocaine 2% with adrenaline 1:80,000 for IANB, along with 0.03 mg buprenorphine IM. IANB, inferior alveolar nerve block; IM, intramuscular. None of the patients in the present study reported any adverse effects after the procedure. Discussion Buprenorphine is a semi-synthetic, mixed agonist–antagonist opioid analgesic. An IM injection of buprenorphine 0.3 mg is equipotent to morphine 10 mg, but the analgesia produced lasts significantly longer. The low abuse liability of the drug has resulted in its wide use as a therapeutic agent in patients with opioid dependence. Currently, its principal clinical application is as an analgesic for moderate to severe pain in the perioperative setting. Evidence has begun to accumulate that opioid anti-nociception can be initiated by the activation of peripheral opioid receptors. It is speculated that the peripheral administration of opioids provides stronger and longer lasting analgesia with a lower dose of opioid and without central side effects such as respiratory depression, nausea, vomiting, and pruritus. A number of trials have examined the peripheral analgesic effect of opioids in a variety of surgical settings. Recent studies have been conducted with the addition of buprenorphine to bupivacaine for nerve blocks, claiming a significant increase in the duration of postoperative analgesia compared to bupivacaine alone. Lignocaine 2% plus adrenaline 1:80,000 was selected as the anaesthetic solution in the present study because it is easily available and produces anaesthesia for a duration sufficient to complete lower third molar surgery. Furthermore, unlike long-acting agents such as bupivacaine, its use avoids the possibility of inadvertent trauma to the oral soft tissues while chewing solid food or by the intake of hot fluids. Also, being an intermediate-acting LA, there is less chance of it masking the postoperative analgesic effects of buprenorphine. Some of the previous studies investigating buprenorphine for postoperative analgesia have included a variety of intraoral surgical procedures, such as apicectomy, third molar surgery, enucleation of cysts, incision and drainage of abscesses, and alveoloplasty. In the present study, only patients undergoing lower third molar surgery were included so that all patients had similar levels of pain and inflammation. Furthermore, all extractions in all patients were performed by the same operator, thus eliminating a procedural bias. The parameters of age, sex, clinical and radiographic position of the tooth ( Figs 1 and 2 ), and baseline pulp sensitivity did not differ between the groups. Therefore, the three groups were comparable, and significant differences in the other parameters assessed could not be attributed to differences in these parameters. When the three groups were compared with each other, no significant difference ( P > 0.05) was found for the time to onset of anaesthesia associated with lignocaine. This is in agreement with other studies in which no difference in the time to onset of sensory block was found when buprenorphine was added to LA for regional block to provide postoperative analgesia in outpatients. Similarly, no statistically significant difference was found in the onset of sensory blockade in a study carried out by Mathew et al., in which one group received buprenorphine with bupivacaine (mean time of 6.31 min) and the other received bupivacaine alone (mean time of 6.17 min). In contrast, in a study by Mehta et al., the time to onset of anaesthesia was prolonged in the group receiving 25 μg fentanyl plus bupivacaine as compared to bupivacaine alone. According to the authors, this could have been due to the reduction in pH of bupivacaine due to the addition of fentanyl. Yilmaz-Rastoder et al. conducted a study aimed to understand the mechanisms associated with the use of adjuvant drugs to prolong the duration of LA-induced block of peripheral nerves. Their results led them to conclude that the reported clinical efficacy of drugs such as buprenorphine was achieved by means of influencing the actions of LAs via indirect mechanisms that remain unidentified. In the present study, no difference was found between the groups with respect to the depth of anaesthesia, as the patients in all groups reported zero pain during the procedure. This could be attributed to the anaesthetic effect of the LA lignocaine used in all of the patients during the procedure. The addition of buprenorphine to 2% lignocaine solution in the present study also had no effect on the duration of anaesthesia associated with lignocaine. Similarly, Dixit et al. carried out a study in which the duration of sensory block was similar in the groups receiving bupivacaine alone, or bupivacaine with buprenorphine. In contrast to this, in a study by Vishwas et al., the addition of an opioid (fentanyl) to lidocaine significantly prolonged the duration of sensory block compared to that obtained with lidocaine alone. However, in this latter study the duration of sensory block was taken as the time between the onset of analgesia and the re-appearance of pain or request for pain relief. So, the difference could be attributed to the analgesic effect of fentanyl postoperatively. None of the patients reported any adverse effects in any of the groups that were evaluated during the present study. This absence of adverse effects may be attributed to the fact that as little as 0.03 mg of buprenorphine was used in the study. These results are supported by those of Kumar et al., who found no adverse effects related to the addition of buprenorphine to lidocaine 2%. However, this is in contrast to the study by Paliwal and Karnawat, in which the incidence of nausea, vomiting, and sedation, although found in all groups, was greater in patients receiving buprenorphine (0.3 mg) added to bupivacaine (0.25% bupivacaine, 40 ml) as compared to those receiving bupivacaine alone or bupivacaine with clonidine (150 μg) when used for brachial plexus block. The difference was statistically non-significant. According to the authors, the increased incidence of adverse effects in their study indicated partial systemic absorption of buprenorphine. In the present study, the addition of buprenorphine to lignocaine for regional block significantly reduced the postoperative severity of pain and significantly prolonged the duration of analgesia, while IM injection of buprenorphine also reduced the severity of pain but to a lesser extent, and slightly prolonged the duration of analgesia. One possible explanation for the failure to elicit a more full-fledged analgesia with IM injection of buprenorphine could be that a suboptimal dose of buprenorphine was used in the present study (0.03 mg as opposed to 0.3 mg). However, as the addition of a suboptimal dose of buprenorphine to LA significantly prolonged the duration of analgesia in the present study, the theory of the presence of peripheral opioid receptors is reinforced. Thiede et al. conducted a pharmacokinetic analysis of two new long-acting formulations of buprenorphine and showed that given a therapeutic plasma buprenorphine concentration threshold of 0.1 ng/ml, a single subcutaneous injection of 0.18 mg/kg sustained release buprenorphine (SRB) lasted for 264.0 ± 32.2 h, while a single application of 30 μg/h of transdermal buprenorphine (TDB) lasted for 72 h. In comparison, 0.2 mg/kg intravenous buprenorphine achieved a therapeutic concentration for only 8 h. These results are similar to those obtained in the present study, in which the IM injection of buprenorphine did not significantly prolong the analgesia, like the intravenous administration in the study by Thiede et al., probably because of systemic absorption and action on receptors in the central nervous system. Similarly, buprenorphine given with local nerve block prolonged analgesia (submucosal) in the present study, like the subdermal group in the study by Thiede et al., thus further strengthening the concept of the presence of peripheral mechanisms working to provide opioid analgesia. Also, the study of Thiede et al. correlated plasma buprenorphine concentrations with clinical efficacy, which has not been done in other studies including the present one. In a study performed by Swarnkar et al., VAS scores were significantly lower in the group receiving 0.5% 40 ml lidocaine for intravenous regional anaesthesia (IVRA) and buprenorphine 0.3 mg IM (group B) and the group receiving 0.5% 40 ml lidocaine with buprenorphine 0.3 mg for IVRA (group C), as compared to the group receiving 0.5% 40 ml lidocaine for IVRA (group A). Similarly there was a highly significant difference between group C and group B when compared statistically, with group C having lower VAS scores than group B. Mehrotra and Mehrotra compared the analgesic effect of IM and perineural buprenorphine in the same patients. The verbal numeric rating scale (0 for no pain, 10 for worst pain imaginable) score was 6.3 for the IM route compared to 1.9 for regional infiltration. This was significant and reasonably excluded systemic drug absorption from the perineural tissues as the cause of analgesia. This was also the case in the present study in which the regional block produced much lower VAS scores than the lignocaine alone group and the IM buprenorphine group. The authors also reported no incidence of systemic toxicity in patients receiving buprenorphine; local reactions were limited to erythema and cellulitis in three cases, which resolved on treatment. The prolonged duration of analgesia associated with buprenorphine may be explained by the fact that it dissociates very slowly from opioid receptors. Mathew et al. found that the duration of analgesia was longer in the group receiving 0.5% bupivacaine and 3 μg/kg buprenorphine (13.24 h) as compared to the group receiving 0.5% bupivacaine alone (6.68 h). Similarly, Candido et al. performed a study wherein buprenorphine plus LA (mixture of mepivacaine and tetracaine) produced analgesia of three-times longer duration (mean 22.3 h) than when using LA alone (mean 6.6 h) and twice as long as buprenorphine given by IM injection plus LA as the only block (mean 12.5 h). In contrast to these, a study by Flory et al. found no difference in duration, quality of postoperative analgesia, or patient satisfaction in two groups receiving brachial plexus block with 0.5% bupivacaine alone or with the addition of morphine 5 mg to 0.5% bupivacaine. According to the authors, this could be explained by the long-acting anaesthetic effect of bupivacaine, which could have masked the postoperative analgesia associated with morphine. Various mechanisms have been proposed for the activation of opioid receptors on peripheral neurons. Peripheral opioid receptors are synthesized in the dorsal root ganglion and are transported intra-axonally to the peripheral sensory nerve endings. Opioid receptors belong to the family of seven transmembrane domain G protein coupled receptors. The binding of opioid peptides to opioid receptors will cause opioid receptor activation and coupling to inhibitory G proteins resulting in the inhibition of high-voltage activated calcium channels, tetrodotoxin-resistant sodium channels, and decreased levels of neuronal cyclic adenosine monophosphate (cAMP). This inhibits the neuronal firing and transmitter release, as well as the calcium-dependent release of excitatory proinflammatory compounds (e.g. substance P), which contributes to their analgesic and anti-inflammatory actions. The opioid anti-nociceptive effect is particularly prominent in inflamed tissue. Inflammation enhances the peripherally directed axonal transport of opioid receptors from the dorsal root ganglion to the periphery, leading to receptor up-regulation (increase in their number in peripheral nerve terminals). Perhaps the major contributor to up-regulation in the number and efficacy of sensory neuron μ opioid receptors is nerve growth factor, which is increased in peripheral inflammation and acts on nociceptive neurons via interaction with the tyrosine kinase receptors. In addition to opioid receptor up-regulation, inflammation also changes the environment in local tissue via a pH decrease, rendering opioid receptors more active due to an increased G protein coupling and cAMP levels. Also, the previously inactive opioid receptors become active in inflamed tissue, enhancing the analgesic potential of opioids. Additional effects that may enhance opioid efficacy in the periphery include an increase in the number of nociceptor endings and disruption of the perineural barrier (facilitating the passage of corticotrophin-releasing hormones, interleukin 1B, and other cytokines), stimulating the release of opioid peptides from immune cells, which activate opioid receptors on the sensory nerve endings leading to anti-nociception. Considering the presence of opioid receptors in both local and recruited immune cells, buprenorphine could be acting via a comparable mechanism. As most of the patients in the present study reported with some level of pain before the procedure due to the erupting third molar or pericoronitis (which can be attributed to prostaglandin synthesis due to an underlying infection and accompanying inflammatory response), and were not given preoperative analgesics, it can be assumed that some level of inflammation was present at the extraction site at the time of surgery. The prolonged duration of analgesia in this study thus strengthens the hypothesis that an inflammatory process may be required for the occurrence of peripheral opioid effects. Dionne et al. carried out a study in which low doses of morphine (0.4, 1.2, and 3.6 mg) administered into the intraligamentary space of a chronically inflamed hyperalgesic tooth produced a dose-related naloxone-reversible analgesia, whereas the subcutaneous administration of a 1.2-mg dose of morphine failed to elicit an analgesic response. According to the authors, this analgesic effect was mediated by a local mechanism in the inflamed tissue. Similarly, in a study by Likar et al., pain scores and the supplemental consumption of diclofenac were significantly lower in patients receiving morphine into inflamed submucous tissue for up to 24 h, as compared to patients receiving morphine into non-inflamed tissues or perineurally. The present study also showed that the addition of buprenorphine to lignocaine significantly decreased the need for postoperative analgesics ( Table 4 ). This finding is supported by the study of Kumar et al., in which the number of postoperative analgesics consumed in the buprenorphine added to lignocaine group was less than that consumed in the lignocaine alone group after minor oral surgical procedures. In contrast, no difference in number of postoperative analgesics was seen in the study by Likar et al., in which one group was administered postoperative morphine sulphate plus lidocaine as a local spray and the other group received lidocaine alone. According to the authors, since the patients presented in a pain-free state at the time of surgery, no apparent activation of the peripheral opioid receptors occurred. The present study clearly indicates that buprenorphine added to the LA injected for IANB provides prolonged postoperative analgesia and markedly decreases the need for pain medication in the postoperative period. In view of the absence of adverse effects in this small group of patients, the addition of buprenorphine to bupivacaine for IANB in patients undergoing lower third molar surgery may be a way to provide postoperative analgesia for outpatients. The following conclusions can be drawn from this study: (1) the addition of buprenorphine (0.03 mg) to 2% lignocaine in adrenaline 1:80,000 injected to block the inferior alveolar nerve in patients undergoing lower third molar extractions, has no effect on the onset, duration, or depth of anaesthesia associated with lignocaine; (2) it significantly reduces the postoperative severity of pain and prolongs the duration of analgesia (up to a maximum of 36 h), thereby decreasing the need for postoperative analgesics; (3) IM administration of buprenorphine did not significantly prolong the duration of analgesia in this study, with the use of the same suboptimal dose (0.03 mg) of buprenorphine, thus further strengthening the concept of the peripheral action of opioids; (4) there were no adverse effects associated with the addition of buprenorphine to lignocaine for inferior alveolar nerve block. More clinical trials with larger numbers of patients are essential to further substantiate the efficacy of buprenorphine in providing postoperative pain relief when added to local anaesthetics. Also, the correlation of plasma concentrations of buprenorphine and the route of administration should be an important aspect of future studies, and the absence of this is a weakness of the current one. Funding None. Competing interests No conflicts of interest. Ethical approval The study design was approved in the Minutes of the Institutional Ethics Board (F/Ethical/1593). Patient consent Informed consent was obtained from all patients. References 1. Ramsay M.A.: Acute postoperative pain management. Proc (Bayl Univ Med Cent) 2000; 13: pp. 244-247. 2. Khanna I.K., Pillarisetti S.: Buprenorphine—an attractive opioid with underutilized potential in treatment of chronic pain. J Pain Res 2015; 8: pp. 859-870. 3. Veil E.J., Eledjam J.J., De La Coussaye J.E., D’Athis F.: Brachial plexus block with opioids for postoperative pain relief: comparison between buprenorphine and morphine. Reg Anesth 1989; 14: pp. 274-278. 4. Bazin J.E., Massoni C., Bruelle P., Fenies V., Groslier D., Schoeffler P.: The addition of opioids to local anaesthetics in brachial plexus block: the comparative effects of morphine, buprenorphine and sufentanil. Anaesthesia 1997; 52: pp. 858-862. 5. Candido K.D., Winnie A.P., Ghaleb A.H., Fattouh M.W., Franco C.D.: Buprenorphine added to the local anesthetic for axillary brachial plexus block prolongs postoperative analgesia. Reg Anesth Pain Med 2002; 27: pp. 162-167. 6. Robaux S., Blunt C., Viel E., Cuvillon P., Nouguier P., Dautel G., et. al.: Tramadol added to 1.5% mepivacaine for axillary brachial plexus block improves postoperative analgesia dose-dependently. Anesth Analg 2004; 98: pp. 1172-1177. 7. Fletcher D., Kuhlman G., Samii K.: Addition of fentanyl to 1.5% lidocaine does not increase the success of axillary plexus block. Reg Anesth 1994; 19: pp. 183-188. 8. Flory N., Van-Gessel E., Donald F., Hoffmeyer P., Gamulin Z.: Does the addition of morphine to brachial plexus block improve analgesia after shoulder surgery?. Br J Anaesth 1995; 75: pp. 23-26. 9. Modi M., Rastogi S., Kumar A.: Buprenorphine with bupivacaine for intraoral nerve blocks to provide postoperative analgesia in outpatients after minor oral surgery. J Oral Maxillofac Surg 2009; 67: pp. 2571-2576. 10. Kumar S.P., Suryavanshi R.K., Kotrashetti S.M.: Efficacy of buprenorphine added to 2% lignocaine 1:80000 in postoperative analgesia after minor oral surgery. J Maxillofac Oral Surg 2013; 12: pp. 30-34. 11. Paliwal B., Karnawat R.: Comparative study of effects of buprenorphine or clonidine as adjuvants to local anesthetics (bupivacaine 0.25%) for supraclavicular brachial plexus block. IOSR J Dent Med Sci 2013; 4: pp. 30-39. 12. Mathew A., Balamurugan B., Gowthaman R.: Buprenorphine as an adjuvant to bupivacaine in supraclavicular brachial plexus block. Chettinad Health City Med J 2014; 3: pp. 39-43. 13. Mehta S., Dalwadi H., Shah T.D.: Comparative study of low dose bupivacaine–fentanyl vs. conventional dose of bupivacaine in spinal anaesthesia for orthopedic procedures in elderly patients. Guj Med J 2015; 70: pp. 25-28. 14. Yilmaz-Rastoder E., Gold M.S., Hough K.A., Gebhart G.F., Williams B.A.: Effect of adjuvant drugs on the action of local anesthetics in isolated rat sciatic nerves. Reg Anesth Pain Med 2012; 37: pp. 403-409. 15. Dixit R., Chakole V., Tadwalkar G.V.: Effect of buprenorphine on post operative analgesia in supraclavicular brachial plexus block using peripheral nerve locator. J Evol Med Dent Sci 2013; 2: pp. 114-118. 16. Vishwas G.K., Kiran B.R., Sagar S.M., Shiva Kumar K.P.: Effect of fentanyl as an adjuvant to local anaesthetics in supraclavicular brachial plexus block on duration of post-operative analgesia: a prospective randomised clinical study. Int. J. Sci. Res. 2015; 4: pp. 274-276. 17. Thiede A.J., Garcia K.D., Stolarik D.F., Ma J., Jenkins G.J., Nunamaker E.A.: . J Am Assoc Lab Anim Sci 2014; 53: pp. 692-699. 18. Swarnkar N., Ghosh A., Yadav A.: Buprenorphine significantly prolongs postoperative analgesia in intravenous regional anesthesia: a double blind randomized clinical trial. Internet J Anesthesiol 2008; 19: pp. 1. 19. Mehrotra M., Mehrotra S.: An innovative approach to nerve block analgesia. Indian J Anaesth 2002; 46: pp. 151. 20. Smith H.S.: Peripherally-acting opioids. Pain Phys 2008; 11: pp. S121-S132. 21. Lesniak A., Lipkowski A.W.: Opioid peptides in peripheral pain control. Acta Neurobiol Exp (Wars) 2011; 71: pp. 129-138. 22. Dionne R.A., Lepinski A.M., Gordon S.M., Jaber L., Brahim J.S., Hargreaves K.M.: Analgesic effects of peripherally administered opioids in clinical models of acute and chronic inflammation. Clin Pharmacol Ther 2001; 70: pp. 66-73. 23. Likar R., Koppert W., Blatnig H., Chiari F., Sittl R., Stein C., et. al.: Efficacy of peripheral morphine analgesia in inflamed, non-inflamed and perineural tissue of dental surgery patients. J Pain Symptom Manag 2001; 21: pp. 330-337. 24. Likar R., Schafer M., Trampitsch E., Breschan C., Sittll R., Gaggl A., et. al.: Topical application of local anesthetics and opioids after elective tooth extraction. Schmerz 2005; 19: pp. 195-198. 200

Related Articles

Leave A Comment?

You must be logged in to post a comment.