Abstract
Pain after arthroscopy is quite distressing. Intra-articular bupivacaine produces transient analgesia and reports of analgesia using intra-articular opioids have produced conflicting results. Recently, spinal administration of neostigmine was shown to produce dose-dependant analgesia. However, this was limited by adverse effects. The purpose of this study was to compare the effects on intra-articular neostigmine, bupivacaine and morphine. 75 patients were randomized to receive intra-articular saline, bupivacaine, morphine, neostigmine and bupivacaine-neostigmine after arthroscopic surgery under spinal anaesthesia. Visual analog pain scores (VAS), duration of analgesia as defined as time for first demand for parenteral opioids and the total subsequent consumption of morphine was evaluated. Intra-articular bupivacaine resulted in significant VAS reduction at one and four hours as compared to those receiving intra-articular saline and morphine. Analgesia lasted longer after 500ugm intra-articular neostigmine as compared with bupivacaine, morphine or saline. The need for supplementary analgesia was lowest in the neostigmine group as compared to the other groups. No significant difference was found if bupivacaine was added to neostigmine. Among all the groups, no significant side-effects were observed.
Key Words: Arthroscopy, Bupivacaine, Morphine, Neostigmine
Introduction
The recent growth of arthroscopic surgery has presented new challenges in the field of postoperative pain management. Although, intra-articular injection of bupivacaine following arthroscopy has been demonstrated to be safe [1, 2, 3] and effective [4, 5] in providing post-operative analgesia, the mean duration of analgesia is only 2 hours [5]. Opioids were also considered as analgesics following intra-articular surgery after opioid receptors were demonstrated not only in the brain and spinal cord, but also in peripheral tissues [6, 7, 8]. However, the results of various studies using intra-articular opioids have been equivocal, with a few studies even demonstrating higher pain scores in the immediate post-operative period [9, 10]. Since contemporary research has focused on “peripheral sites” in the region of tissue injury as potential targets of analgesic drugs, the search is on for an ideal analgesic technique that is site-specific, long lasting, easily administered and has a high therapeutic safety index.
Recently new interest has focused on the cholinergic system that modulates pain perception and transmission. The acetyl-choline esterase inhibitor neostigmine, has demonstrated a dose-dependant analgesia following spinal or epidural administration [11, 12]. However, this central delivery of neostigmine is limited by dose-related side effects such as nausea, vomiting, pruritis, caused by cephalad spread of neostigmine in the cerebrospinal fluid [13, 14].
The present study was designed to determine the efficacy of intra-arthroscopic bupivacaine, morphine and neostigmine for pain relief following arthroscopic surgery as compared to a placebo group. Since the mechanisms of action of these three drugs were different, a combination of intra-articular bupivacaine and neostigmine was also used to see whether the effects are synergistic, additive or not.
Material and Methods
75 patients from a Military Hospital ranging from 22-35 years in age in ASA I and II, were included in this study. Informed consent was obtained from all. Exclusion criteria were age less than 22 years or more than 35 years, achieved dermatome level of lower than T12, use of analgesics within 24 hours prior to surgery, conversion of arthroscopic surgery intra-operative to open surgery and any history of allergic reaction to bupivacaine or neostigmine.
Patients were prospectively studied and assigned into a randomized blind manner to one of the five treatment groups using a placebo controlled design to evaluate analgesia and adverse effects.
Group A - Intra-articular injection of 20 ml normal saline
Group B - Intra-articular injection of 20 ml 0.5% bupivacaine
Group C - Intra-articular injection of 20 ml normal saline+500 ugm neostigmine
Group D- Intra-articular injection of 20 ml 0.5% bupivacaine+500 ugm neostigmine
Group E - Intra-articular injection of 20 ml normal saline + 3 mg morphine
All solutions were free of preservatives, opened just prior to injection.
The day before surgery, the study groups were introduced to a 100 mm VAS with 0 as an indication of no pain at all and 100 as an indicator of the worst possible pain. Pre-operative pain scores at rest and on movement were recorded. The tests were subsequently performed by two interviewers who were not aware of the study-medication given.
Spinal anaesthesia was scheduled for all the patients. Premedication was given on the table in the form of Inj atropine 0.3 mg I/V repeated in aliquots of 0.3 mg I/V if the pulse rate fell below 55 beats/minute intraoperative. Inj diazepam 10 mg I/V was given to all the patients after ascertaining the level of spinal spread. The anaesthetic regimen consisted of an intrathecal injection of 60-75 mg lignocaine with dextrose, as per the built and sex of the patient. Intrathecal and parenteral opioids and NSAIDs were avoided pre-and intra-operatively. All patients underwent arthroscopic surgery after inflation of a thigh tourniquet to 300-350 mmHg.
At the conclusion of surgery, the appropriate study drug was administered in a randomized manner from a coded syringe into the joint space via a 18G needle. The tourniquet was deflated and the patient was taken into the post-operative room and subsequently to the ward. An observer, blinded to the group assigned to the patient, noted the haemodynamic monitoring, VAS scoring and the level of residual spinal blockade upon arrival in the post-operative room. He or she recorded the time the patient first requested pain medication. Analgesic rescue medication consisted of a 3 mg I/V bolus of morphine on an “SOS” basis and the number of such boluses were recorded. The duration of effective analgesia was measured from time zero until first use of parenteral morphine.
Evaluation of adverse effects included assessment of the occurrence of post-operative emesis and nausea (yes or no), pruritis, bradycardia (heart rate <55/min) and urinary retention (voiding possible unassisted after operation) by interviewing the patients after 48 hours. VAS were assessed at 1, 4, 8, 24 and 48 hours with arrival at the post-operative room taken as time zero.
Unless otherwise indicated, data was represented as mean ± SD. Statistical analysis of the data included the Kolmogorov-Smirnov test for all data. Pain scores and analgesic requirements during the first 48 hours were compared between groups using repeated measures ANOVA. Age, weight, sex, preoperative pain scores and tourniquet times were analyzed by Chi-square and one-way ANOVA where appropriate. Time for first analgesic used was studied by Kaplan-Meier survival analysis. Results were considered statistically significant when p < 0.05. The statistical packages used were MS Excel (version-2000) and SPSS for Windows 98.
Results
75 patients were enrolled in this study. There were no significant intergroup differences as regards to sex, distribution, age, weight or duration of anaesthesia (Table 1). Adverse effects were not significant in any of the groups and are listed in Table 2. Post dural puncture headache was observed in 13 patients, which responded to analgesics alone. Nausea was experienced by 12 patients in Group E, 11 patients in Group A. 7 in Group B and 5 each in Group C & D. Vomiting was observed in 4 patients in Group A and one patient in Group D after an intra-venous bolus of 3.0 mg morphine. One patient in Group B and 2 patients in Group E had urinary retention post-operative, which required “single-shot” catheterization. Out of the total 75 patients, 16 had postoperative bradycardia, which responded to atropine. These were the patients actively involved in training and other forms of strenuous exercise pre-injury and had a pre-operative heart rate of around 60/min.
Table 1.
Patient's profile
| p value | Group A (N=15) | Group B (N=15) | Group C (N=15) | Group D (N=15) | Group E (N=15) | |
|---|---|---|---|---|---|---|
| Sex (M/F) | − | 13/2 | 14/1 | 14/1 | 12/3 | 14/1 |
| Weight (kg) | − | 59.2 | 63.7 | 66.2 | 62.8 | 60.6 |
| Age | 0.08 | 28 ± 6 | 32 ± 8 | 29 ± 6 | 31 ± 5 | 27 ± 5 |
| Volume of lignocaine (ml) | 0.14 | 1.2 ± 0.3 | 1.1 ±-0.3 | 1.2 ±0.1 | 1.2 ± 0.4 | 1.2 ± 0.2 |
| No of dermatomes anaesthetized 1 hr post-operative | 0.92 | 4.8 ± 1.1 | 5.1 ± 1.0 | 4.9 ± 1.3 | 5.0 ± 1.1 | 5.0 ± 1.2 |
| Surgical time (hours) | 0.78 | 1.1 ± 0.1 | 1.2 ± 0.3 | 1.2 ± 0.1 | 1.3 ± 0.2 | 1.2 ± 0.2 |
Table 2.
Mobilization and complication rate
| Group A (N=15) | Group B (N=15) | Group C (N=15) | Group D (N=15) | Group E (N=15) | |
|---|---|---|---|---|---|
| Time to mobilization (min) | 151 | 188 | 175 | 170 | 177 |
| Noctural pain 1st post-operative day | 8/15 | 4/15 | 4/15 | 5/15 | 9/15 |
| Noctural pain 2nd post-operative day | 6/15 | 2/15 | 3/15 | 3/15 | 5/15 |
| Excessive sweating/vomiting | 4/15 | 0/15 | 0/15 | 1/15 | 5/15 |
| Nausea | 11/15 | 7/15 | 5/15 | 5/15 | 12/15 |
| Urinary retention | 0/15 | 1/15 | 0/15 | 0/15 | 2/15 |
| Pruritus | 0/15 | 0/15 | 0/15 | 0/15 | 0/15 |
| Respiratory depression | 0/15 | 0/15 | 0/15 | 0/15 | 0/15 |
| Postoperative bradycardia | 3/15 | 4/15 | 2/15 | 3/15 | 4/15 |
| Postoperative hypotension | 0/15 | 0/15 | 0/15 | 0/15 | 0/15 |
There was no significant difference in the VAS score between all the groups at one hour post-operatively. This could have been the result of residual control neuronal blockade. A significant increase in the VAS score by the first four hours post-operative (p<0.5) was observed in Group A, that is the saline group as compared to the Groups B, C, D and E. 8 hours following arthroscopic surgery, patients who had received intra-articular bupivacaine along with neostigmine (Group D) and neostigmine alone (Group C) showed a significant decrease in VAS scoring for pain as compared to the rest of the groups. Subsequently, 24 and 48 hours after operation, there was no statistically significant difference between all the groups (Fig. 1).
Fig. 1.
VAS scores in different groups
Patients who received intra-articular saline (Group A) and intra-articular morphine (Group E) had a significantly higher morphine requirement as compared to the three groups receiving bupivacaine alone, neostigmine with or without bupivacaine (Group B, C & D) with no statistically significant difference observed between the Groups C & D. Subsequently, the neostigmine alone and the neostigmine with bupivacaine groups (Group C & D) had a significant lower VAS at 8 hours, 24 hours and 48 hours as compared to the placebo, morphine and bupivacaine alone groups (Group A, B and E), with no significant discrepancy in the pain scores between the two groups, C and D (p <0.1). The total amount of rescue morphine given appeared to be significantly lower in cases receiving intra-articular neostigmine, either alone or along with bupivacaine (Group C & D) as compared to the saline, bupivacaine and morphine group (Fig. 2).
Fig. 2.
Comparative study of morphine requirement
There was no significant difference in the time for mobilization in all the groups. Incidence of nocturnal pain on the first post-operative day was significant in the saline and morphine groups as compared to the groups receiving bupivacaine, neostigmine and both bupivacaine and neostigmine. On the second night following surgery, the group receiving bupivacaine (Group B) had a higher VAS score for nocturnal pain but it was not statistically significant (p <0.1) as compared to Groups C & D.
Intra-articular administration of 500ugms neostigmine along with bupivacaine provided longer lasting analgesia as defined by the time for first use of rescue morphine as compared with the other groups. It was also significant as compared with the group receiving intra-articular neostigmine alone (Fig. 3).
Fig. 3.
Time for first morphine requirement
Discussion
Arthroscopic surgery of the knee is currently a common diagnostic and therapeutic tool. It is more so in the Armed Forces where trauma-induced injuries are quite common. Various parameters have been implicated in pain following arthroscopic surgery. These include pre-operative pain scores duration [14] and type of surgery, [15] experience of the surgeon, use of general anaesthesia vs. regional anaesthesia [9], the volume of the drug injected [16], timing of intra-articular injection relative to the deflation of tourniquet [17]. As such, post-operative pain is a complex, subjective, emotional experience of infinite range, its emotional aspect best demonstrated by the dramatic response to placebos.
Studies of intra-articular analgesia have shown only a small difference in analgesic requirement between intervention and placebo groups. Smith et al (1992) found that 63% of patients in a placebo group study required no analgesia [18] and Richmond (1994) quoted a figure of 72% [19]. This led them to conclude that pain after arthroscopy is a poor model for testing the efficacy of analgesics. Subsequently, Cook et al (1997) demonstrated that 85% of their patients needed analgesics at variable periods of time following arthroscopy and that 25% were disturbed by pain on the first two nights following arthroscopy [17]. These findings suggested that pain after arthroscopy is not significant but rather it is variable. Perhaps because of this, relief of post-operative pain following arthroscopy is often a neglected area of anaesthesia practice.
The use of peri-operative analgesia has varied widely in different studies. Few studies have assessed pain on a subjective basis and others on movement only. The techniques of statistical analysis of pain scores also have varied. This has made the comparison of the large number of studies inconclusive and difficult to compare.
Pain modulating systems such as alpha-adrenergic agonists [20] and opiates [21] were tried parenterally but were found to have a high incidence of side effects with distressing “escape” periods of time [22]. A central route of administration, spinal or epidural was also tried but was limited by dose related side-effects. The discovery of peripheral receptors of different pain-modulating systems such as opioids and alpha-adrenergic agonists led to the trials for a peripheral, site specific route of drug delivery which could reduce the incidence of centrally-mediated adverse effects.
Long acting local anaesthetics were a logical inclusion into the armamentarium. However, studies of intra-articular analgesia have revealed inconsistent findings with local anaesthetics particularly bupivacaine which was found to be either ineffective or effective only for short periods of time.
Opioid receptors and endogenous opiates have been demonstrated not only in the brain but also in the spinal cord, peripheral nerves and dorsal root ganglia. Pre-clinical trials have demonstrated a site-specific analgesia by peripherally administered opiates in models of peripheral inflammation in rats and cats [6, 7]. In various studies, opioids and their agonists were found to block thermal hyperalgesia, inhibit cutaneous vasodilatation and extravasation, block the peripheral release of substance P [5, 10]. The same dose of opioids had no effect when given systematically. It is possible that the activation of the peripheral opiate receptors depends on the presence of the chemical mediators of inflammation.
In the present study, those patients receiving intra-articular bupivacaine had good analgesia in the immediate post-operative period, lasting up to four hours. In contrast, patients receiving intra-articular morphine required a significant dose of parenteral opioids with increase in VAS score. Our observations about the lack of analgesic effect of morphine during the first four postoperative hours are similar to those of Stein et al (1991) [10] and Khoury et al (1992) [23]. However, unlike their observations and in agreement with those of Heard et al (1992) [9] and Raja et al (1992) [5], we failed to observe a prolonged and / or a delayed analgesic effect of intra-articular morphine. A possible explanation of this discrepancy could pertain to the different anaesthetic regimens in the two studies. Stein et al [5] subjected their patients to general anaesthesia for arthroscopy while the patients of Raja et al [7] underwent arthroscopy under epidural anaesthesia. If the activation of the peripheral opiate receptors depends upon neuroendocrine responses secondary to afferent impulses arising from nociceptive pathways, it is possible that epidural anaesthesia may block this effect. Our patients received spinal anaesthesia which produces a more profound and reliable block. This could account for the poor analgesic effects of intra-articular morphine in this study. Also, our patients were operated on varying periods of time following injury. The effect of time on pre-operative pain induced induction of opiate receptors and the subsequent analgesic response of intra-articular opioids was not analysed in this study.
Recently, new interest has focused on cholinesterase inhibitors for producing dose-dependant analgesia by modulating pain perception and transmission. Duarte et al showed that the intra-plantar administration of acetylcholine in animals resulted in anti-nociceptive effects [24]. In addition, there is growing evidence of the existence of choline acetyl transferase in the primary afferents and of cholinergic receptors at the central nerve endings of small afferent fibres. It is postulated that acetylcholine acts as an analgesic agonist at muscarinic receptor type I or II, similar to the spinal subtypes. The likely mechanism of action includes hyperpolarisation of neurons [14], decrease in pro-nocireceptive neurotransmitters and activation of the nitric oxide-cyclic guanosine monophosphate pathway [25]. Administration of the cholinesterase enzyme inhibitor, neostigmine will increase the endogenous acetylcholine levels at the peripheral nociceptors and may cause analgesia.
It has already been seen that intra-thecal or epidural administration of cholinesterase inhibitors such as edrophonium or neostigmine produces a dose-dependent analgesia and displays a synergistic or additive analgesia when administered simultaneously with alpha-adrenergic agonists and opioids [12, 13, 14]. However, adverse effects like vomiting, nausea, headache, bradycardia, hypotension and pruritus limited the subarachnoid administration of neostigmine.
In this study, we gave neostigmine intra-articular to one group (Group C) and a combination of neostigmine and bupivacaine to another group (Group D) to assess the efficacy of neostigmine as an analgesic. One group received only bupivacaine (Group D) while we included a placebo group (Group A) since the efficacy of bupivacaine is not irrefutably proven. Group E received intra-articular morphine.
Pain scores were assessed at rest and on movement. In the present study, the difference between the various groups in measure of pain, on movement and at night were not statistically significant. The availability of parenteral analgesia on demand could have led to this convergence of pain scores since the only statistically significant difference between the groups was for analgesic use. Patients with neostigmine either alone or with bupivacaine required significantly less parenteral morphine than the placebo, morphine and bupivacaine alone group. Time to first analgesia was also longer as compared to the other groups. When bupivacaine was added to neostigmine, there was a marginal increase in the first time analgesic use time but it was not significant.
The salient observation is that the pain following arthroscopic surgery on the knee is variable but intra-articular injection of neostigmine 500 ugm decreases the requirement of supplementary opioid analgesia significantly. Addition of bupivacaine does not prolong the duration of neostigmine analgesia significantly while intra-articular bupivacaine alone has a short but marginally more dense analgesic effect. Our study failed to demonstrate significant analgesia using intra-articular morphine, which could be due to the anaesthetic technique used or to the time difference between injury and operation in our patients.
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