Adenosine is a purine nucleoside that occurs naturally in all cells of the body. Its role in modulation of pain has been confirmed by receptor-mediated action in spinal cord . Intravenous (i.v.) and intrathecal adenosine has been found to be effective in chronic neuropathic and experimental pain [2–5]. Given as an i.v. infusion it has also shown an effect on intraoperative anaesthetic requirements and postoperative pain . Fukunaga and colleagues concluded that adenosine significantly reduced opioid requirements and minimized opioid-related adverse effects including sedation, cardiorespiratory instability, nausea and vomiting in the postoperative recovery period compared with remifentanil . In experimental pain, doses ranging from 500 to 2000 μg have been used by the intrathecal route and were found to be safe up to 1000 μg . Eisenach and colleagues observed a rise in intrathecal adenosine concentrations after the intrathecal administration of opioids (fentanyl and morphine), suggesting that local opioid receptor stimulation in the human being spinal cord may release adenosine . In another study, Eisenach and colleagues observed that intrathecal, but not i.v., adenosine reduced allodynia in patients with neuropathic pain . These studies suggest that intrathecal adenosine may play a role in pain management.
However, only two studies on intrathecal adenosine for the relief of acute pain have been published so far [10,11]. In one study, the authors concluded that intrathecal adenosine 500 μg did not influence the requirements of anaesthetics or postoperative analgesics . The other study concluded that adding 500 μg of adenosine to 10 μg of sufentanil did not prolong pain relief during labour .
Pre-emptive analgesia is thought to interrupt the transmission of noxious perioperative inputs to the spinal cord and to prevent the establishment of central sensitization, resulting in reduced pain intensity and lower analgesic requirements even after the effect of the analgesic agent has worn off . Various drugs have been administered through different routes to assess the efficacy of this technique. These include central neuraxial (epidural or intrathecal) blocks, wound infiltration with local anaesthetics, or systemic N-methyl-d-aspartate (NMDA) receptor antagonists, non-steroidal anti-inflammatory drugs (NSAIDs), and opioids. Ong and colleagues carried out meta-analysis to determine the efficacy of pre-emptive analgesia for acute postoperative pain management . They assessed pain intensity scores, supplemental analgesic consumption, and time to first rescue analgesic in 66 studies involving 3261 patients receiving various pre-emptive techniques. Central neuraxial block (epidural block) was found to significantly improve all these three variables. The study suggested that neuraxial block was a more effective technique of pre-emptive analgesia for postoperative pain management compared to other techniques.
The aim of our study was to evaluate the analgesic efficacy of intrathecal adenosine for postoperative pain relief, and to assess its potential role as a pre-emptive analgesic.
The institutional Ethics Committee approved the study and written informed consent was obtained from all the patients prior to inclusion in the study.
Ninety ASA I and II adult female patients undergoing elective abdominal hysterectomy under balanced general anaesthesia were included. Exclusion criteria included patient's refusal, consumption of analgesics, emergency surgery, abnormality of the spine or any other contraindication to an intrathecal injection, and a history of any concomitant acute or chronic pain.
The patients were visited on the day before surgery, when they were introduced to the concept of the visual analogue scale (VAS) that consisted of a 10 cm scale with 0 implying ‘no pain’ and 10 being the ‘worst possible pain’. Patients received diazepam 10 mg orally on the night before surgery and 5 mg on the morning of surgery.
Patients were randomly assigned to one of three groups (30 patients each) using a table of random numbers. Patients belonging to the ‘early adenosine’ group received 1000 μg adenosine, dissolved in 1 mL of normal saline, intrathecally 30 min before induction of anaesthesia. Patients belonging to the ‘late adenosine’ group received the same dose of adenosine intrathecally before reversal of residual neuromuscular blockade at the end of the surgical procedure. Control patients did not receive any drug intrathecally. Adenosine was injected under aseptic precautions, using a 25-G spinal needle at the L3–L4 or L4–L5 vertebral interspace with the patients in the left lateral position.
A balanced general anaesthetic technique was used in all patients. Anaesthesia was induced with i.v. thiopentone and tracheal intubation was facilitated using succinylcholine. Anaesthesia was maintained with halothane 0.5–1%, nitrous oxide 66% in oxygen and pancuronium 0.08 mg kg−1. Intravenous morphine 0.1 mg kg−1 was administered after induction. The degree of muscle relaxation was assessed using the train-of-four (TOF) response (Neurostim T4 monitor; Hugo Sachs Elektonik KG, West Germany). Top up doses of pancuronium were administered whenever there were more than two responses. Respiration was controlled using mechanical anaesthesia ventilator (Manley Servovent; Datex Ohmeda, UK) connected to the Bains breathing system. Ventilation was adjusted to maintain normocapnia. Neuromuscular blockade was reversed with i.v. neostigmine 0.05 mg kg−1 and atropine 0.02 mg kg−1 when the TOF count was two.
Monitoring included heart rate (HR), non-invasive blood pressure (BP), electrocardiograph and oxygen saturation (Propaq 102 EL monitor; Protocol Systems Inc., USA). Baseline values of the parameters were recorded preoperatively. In the ‘early adenosine’ group, HR and BP were recorded 15 and 30 min after the intrathecal administration until start of surgery. Intraoperatively, haemodynamic parameters were recorded in all patients at 0 min (time of induction), 1 min and 5 min to monitor the response to tracheal intubation, and subsequently every 15 min until the end of surgery. Initial postoperative monitoring and pain assessment was in the recovery room, and, after 2 h, in a high-dependency area. The anaesthesiologist who assessed the patients in the postoperative period was not aware of the study group assignment.
Pain intensity and pain relief were evaluated half-hourly for the first 2 h, and then 4 hourly until 24 h after surgery. Time to first rescue analgesia (i.v. morphine) was recorded. When pain intensity reached 5 or more on the 11-point VAS, or when patients requested analgesia, they received i.v. morphine 0.1 mg kg−1. No other analgesics were administered during the study period.
The degree of sedation was estimated using a 4-point scale (0: awake and alert; 1: awake but drowsy; 2: drowsy but arousable; 3: unarousable). Patients were monitored closely for any adverse effects.
Based on a previous study, a 30% reduction in total morphine requirements was considered clinically significant . To achieve this, 30 patients per group were needed (80% power and 5% significance level). Preoperative HR and BP were analysed using the paired t-test. Intraoperative HR and BP, pain and sedation scores, doses of morphine and time for first rescue analgesia were analysed by one-way analysis of variance and Tukey's tests. A P < 0.05 was considered statistically significant.
There were no dropouts during the 24-h follow-up. The three groups were comparable with respect to age and weight of the patients (Table 1). Changes in mean HR and systolic BP over time were similar among groups (P > 0.05). In the ‘early adenosine’ group, no significant changes in HR and systolic BP were observed as compared to baseline.
Pain ratings were not different among groups (P > 0.05) (Table 2). Intraoperatively all patients received one dose of morphine 0.1 mg kg−1. None of the patients required a repeated dose. Three patients in the ‘early adenosine’ group, two patients in ‘late adenosine’ group and three control patients did not require any analgesic during the 24-h follow-up period; the difference between groups was not statistically significant. Two patients in the control group required five morphine doses each. However, cumulative morphine consumption did not differ among groups (Table 3).
Mean sedation scores at 30 min were 1.0 ± 0.8 in the ‘early adenosine’ group, 1.1 ± 0.6 in the ‘late adenosine’ group and 1.2 ± 0.7 in controls. A decreasing trend was observed in all groups; however, there was no intergroup difference (P > 0.05).
Eleven, nine and fifteen patients in the ‘early adenosine’ group, the ‘late adenosine’ group and the control group, respectively, complained of postoperative nausea. Of those, two in the ‘early adenosine’ group and four in the control group also vomited. No other adverse effects were reported.
Since there was no difference in pain scores and analgesic requirements between the early and the late adenosine administration, we combined the data from both adenosine groups and compared them with the control group. There was no difference between the combined adenosine data (time to first rescue analgesia was 395 ± 429 min, morphine requirements was 11.96 ± 3.95 mg, pain scores are shown in Table 2) and the control group. As the data distribution for time to first rescue analgesia was skewed, log transformation was applied to the data. However, this also did not reveal any statistically significant difference. As the combined adenosine groups and the control group responses were moving in the same direction with skewed data, median values were also calculated and compared between different groups. Again, there was no statistically significant difference.
In the present study, 1000 μg of adenosine was used by the intrathecal route in patients undergoing abdominal hysterectomy to assess its efficacy to provide postoperative pain relief and its role as a pre-emptive analgesic agent. Intrathecal adenosine was administered prior to surgery or at the end of surgery. There was no significant difference in VAS scores, 24-h morphine consumption and time to first rescue analgesia among the three groups. Even the combined data of the two adenosine groups did not show any significant difference compared with control. Thus, this study did not reveal any analgesic effect of intrathecal adenosine in a dose of 1000 μg for postoperative pain relief.
Pre-emptive analgesia is thought to prevent establishment of altered processing of afferent inputs, which amplify postoperative pain . There are primarily two approaches that have been used to study pre-emptive analgesia: comparing a preoperative treatment with no treatment, and comparing a preoperative treatment with the same treatment at the end of surgery . In the present study, both models were studied, and in both, adenosine was not found to be effective as a pre-emptive analgesic.
Adenosine has been reported to have antinociceptive properties when given i.v. and intrathecally [2,3]. Belfrage and colleagues studied efficacy and safety of intrathecal adenosine in patients having chronic neuropathic pain . The analgesic effect started after 20–30 min and analgesia lasted from 10 h to 6 days, suggesting that adenosine receptor activation in the central nervous system exerts its effects on more persistent pain modulator control system .
A phase-I clinical safety study in healthy human beings concluded that intrathecal adenosine in doses up to 1000 μg lacked adverse effects . Rane and colleagues conducted a placebo-controlled, randomized, double-blind study to evaluate the analgesic effect of intrathecal adenosine for postoperative visceral pain . Forty patients undergoing elective abdominal hysterectomy received an intrathecal injection of either adenosine 500 μg or saline before induction of anaesthesia. Intrathecal adenosine did not influence the requirement of anaesthetic drugs or of postoperative analgesics. The authors postulated that 500 μg may not have been adequate for postoperative pain relief. They further suggested that while i.v. adenosine may act by peripheral anti-inflammatory mechanism or via the vasculature reaching supraspinal structures, the same sites may not be accessible through the intrathecal route. In another randomized double-blind study, addition of 500 μg of adenosine to 10 μg of intrathecal sufentanil did not prolong pain relief during labour .
As intrathecal adenosine was found to be safe up to a dose of 1000 μg in healthy volunteers , and a dose of 500 μg was reported to be ineffective in relieving postoperative pain , we decided to study the effect of 1000 μg. However, we were unable to find any analgesic efficacy with that dose. Intraoperative administration of repeated doses of morphine may blunt immediate findings of decreased postoperative analgesic consumption. However, in the present study, none of the patients required a repeated dose of morphine.
There are limitations of this study. First, average morphine consumption and pain scores were low. Some patients did not require any analgesics during the first 24 h. It may be argued that these patients did not have enough pain to test the analgesic efficacy of adenosine. It may be worthwhile to study the potential analgesic efficacy of intrathecal adenosine in patients undergoing major surgery. Second, besides having an opioid-sparing effects in the immediate postoperative period, pre-emptive analgesia should also reduce the incidence of chronic and neuropathic pain . The present study could not demonstrate any benefits of adenosine, whether administered before or after surgery, on immediate postoperative pain relief. However, there was no follow-up of the patients for long-term residual pain or chronic pain syndromes, as the primary aim of the study was to evaluate acute postoperative pain relief. Third, double blinding using a double-dummy design is known to give unbiased results. In the present study, observers were unaware of treatment allocation. Keeping in mind the potential complications that are associated with dural puncture and subarachnoid injections, it was considered unethical to use an intrathecal placebo. Thus, proper blinding of the patients was not possible.
While the literature supports the role of intrathecal adenosine to relieve experimental and neuropathic pain, the efficacy of this drug to relieve postoperative pain remains unproven. The results of the present study failed to show any effect of intrathecal adenosine administered in dose of 1000 μg, pre-emptively or after surgery in patients undergoing abdominal hysterectomy. Mechanisms of action of adenosine for pain relief need to be further explored.
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Keywords:© 2006 European Society of Anaesthesiology
DRUG ADMINISTRATION, intrathecal; DRUGS, adenosine; PAIN, postoperative; ANALGESIA, pre-emptive