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.
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.
| 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.
| 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 |
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.
| 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 |
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