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ANALGESIA

The Characteristics of Intravenous Adenosine-Induced Antinociception in a Rabbit Model of Acute Nociceptive Pain: A Comparative Study with Remifentanil

Masakazu Hayashida, MD, PhD^*, Atsuo Fukunaga, MD, PhD, Ken-ichi Fukuda, DDS, Satoru Sakurai, DDS, Hideki Mamiya, DDS, Tatsuya Ichinohe, DDS, PhD, Yuzuru Kaneko, DDS, PhD, and Kazuo Hanaoka, MD, PhD

From the *Surgical Center, Research Hospital, Institute of Medical Institute, The University of Tokyo, Tokyo, Japan; Department of Anesthesiology, University of California, Los Angeles, California; Department of Anesthesiology, Tokyo Dental College; and Department of Anesthesiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Address correspondence to Masakazu Hayashida, Surgical Center Research Hospital, Institute of Medical Institute, The University of Tokyo, 4-6-1 Shiroganedai, Minato-ku, Tokyo 108-8639, Japan. Address e-mail to hayashida-todai{at}umin.ac.jp.

Abstract

BACKGROUND: Adenosine and remifentanil are potent IV analgesics with ultrashort half-lives. The antinociceptive effect of IV adenosine has not been clearly characterized. We compared the antinociceptive effects of adenosine and remifentanil in rabbits.

METHODS: Sixteen rabbits, placed on a sling allowing reasonably free movement, received IV adenosine (400 µg · kg^–1 · min^–1) or remifentanil (0.4 µg · kg^–1 · min^–1) over 240 min.

RESULTS: Both drugs produced profound antinociception, as assessed by the number of animals unresponsive to clamping the forepaw and the electrical stimulation threshold of escape movement. With remifentanil, the antinociceptive effect increased rapidly, reaching its peak at 60 min, and then began to decline despite continued infusion. After stopping the infusion, it decreased rapidly and disappeared within 30 min. The vasodilating effect of IV adenosine was immediate in onset and ultrashort in duration. The antinociceptive effect of adenosine increased slowly but progressively during the infusion, reaching its peak only when the infusion ended. Then it decreased slowly over the following 360 min after terminating the infusion.

CONCLUSION: Remifentanil had a rapid onset and short duration of action, and probably showed signs of tolerance development, whereas the antinocieptive effect of adenosine was slow in onset and long-lasting, despite its ultrashort plasma half-life and the immediate on–off profiles of its vasodilating effect.

Adenosine and remifentanil are potent IV analgesics that have been used to provide the analgesic component of balanced anesthesia (1,2). Adenosine has also been used to alleviate neuropathic pain (3,4). When used as IV analgesics, both drugs are infused continuously because of their ultrashort half-lives (1–5). Remifentanil is a µ-opioid receptor agonist that is rapidly metabolized by blood and tissue nonspecific esterases. Its effective half-life is very short, approximately 5–10 min (5). The antinociceptive property of IV remifentanil has been clearly characterized in animals (6,7) and humans (5,8). It has a rapid onset, short latency to peak effect, and very short duration of action.

Adenosine exerts multiple influences on pain transmission at peripheral and central sites (9). Intrathecal administration of long-acting adenosine analogs, acting primarily on A₁ receptors, produces analgesia in acute nociceptive, inflammatory, and neuropathic pain tests in animals (9–11). IV adenosine has an ultrashort plasma half-life (0.6–10 s) because of cellular uptake and enzymatic metabolism (12). However, several studies in humans have shown that adenosine-induced analgesia lasts many hours after an infusion (1–4,13,14). It has not been determined whether such prolonged analgesia is due to the antinociceptive property of adenosine. The ability of IV administered adenosine to act as an anesthetic adjunct, replacing opioids and reducing anesthetic requirements, suggests profound antinociceptive properties (1,2,13). However, it is difficult to estimate the antinociceptive effect per se during general anesthesia (1). Further, because IV or intrathecal adenosine failed to affect nociception while consistently attenuating allodynia/hyperalgesia in human inflammation/sensitization models and in patients with neuropathic pain (3,14–16), adenosine-induced analgesia reported in such subjects may not have resulted from its antinociceptive effect, but rather from its neuromodulatory effect on neuronal changes involved in central sensitization (17). In addition, because intrathecal adenosine failed to attenuate nociceptive pain in humans (17–19), postoperative analgesia achieved after intraoperative IV infusion of adenosine (1,2,13) may have been primarily due to its peripheral A₂ or A₃ receptor-mediated antiinflammatory effects, rather than its spinal A₁ receptor-mediated antinociceptive effect (17,18). No animal or human studies have clearly demonstrated or characterized the antinociceptive property of IV adenosine. Because accumulating clinical evidence indicates prolonged analgesia induced by IV adenosine (1–4,13), the analgesic action of IV adenosine deserves further evaluation.

The aims of the current study, conducted in a rabbit nociceptive pain model for evaluation of surgical anesthesia and analgesia (6), were to determine whether IV adenosine produces significant antinociception, and to compare adenosine-induced antinociception with remifentanil- induced antinociception (1,2).

METHODS

The study protocol was reviewed and approved by the Institutional Animal Care and Use Committee. Sixteen male New Zealand White rabbits weighing approximately 3 kg were studied. Preparation of experimental animals has been described in detail elsewhere (6). Briefly, animals were tracheotomized under 3% isoflurane anesthesia, so that isoflurane and oxygen at precise concentrations could be administrated. A marginal ear vein was cannulated with a 24-gauge catheter for drug administration and maintenance of fluid infusion. A central ear artery was cannulated with a 22-gauge catheter for blood arterial pressure monitoring and blood sampling. Rectal temperature was maintained between 38 and 39°C with a heating lamp.

The rabbits were then placed in the normal physiological position on a rubber sling that allowed them to move their heads and extremities freely. The animals spontaneously breathed isoflurane in oxygen-enriched air (Fio₂ = 0.4) delivered from an anesthesia apparatus incorporating a 500-mL reservoir bag, a carbon dioxide (CO₂) absorber, and a calibrated isoflurane vaporizer. A pair of hooked platinum needle electrodes was placed in the plantar aspect of a forepaw 10 mm apart and 5 mm deep into the skin, tightly secured with tape, and connected to Grass S48 electrical stimulator (Grass Medical Instruments, Quincy, MA).

Invasive arterial blood pressure and heart rate were continuously monitored. Respiratory rate and CO₂ tension of arterial blood (Paco₂) were measured intermittently. A forepaw clamp test was performed to assess the anesthetic/antinociceptive effects of isoflurane, remifentanil, and adenosine. Briefly, a neoprene-covered 16-cm hemostat was applied across a forepaw and moved back and forth as a simulated surgical stimulus until the animal showed an escape movement (running or jumping) or 10 s (cutoff time) passed. At each measurement time, the number of animals that did not show the escape movement (the number of nonresponders) was determined as an indicator of surgical antinociception. Subcutaneous electrical stimulation was applied to another forepaw. Voltage of the electric current (square wave, 1 ms duration, 5 Hz frequency) was increased linearly, from 0 to 150 V (cutoff voltage), at a rate of 5 V/s, and the threshold voltages required to evoke the head lift response (head lift threshold) and the escape movement response (escape movement threshold) were determined as sedative/hypnotic and analgesic/antinociceptive indices, respectively (6).

After completion of all preparations, isoflurane concentration was reduced stepwise from 3% to 1.5%, and then to 0%. Thirty minutes after awakening from isoflurane anesthesia, animals received IV infusion of adenosine (400 µg · kg^–1 · min^–1) or remifentanil (0.4 µg · kg^–1 · min^–1) over 240 min (n = 8 for each group). The doses used were based on the results of clinical studies suggesting that adenosine at 166 ± 17 µg · kg^–1 · min^–1 and remifentanil at 0.2 ± 0.03 µg · kg^–1 · min^–1 (1), and adenosine at 50–500 µg · kg^–1 · min^–1 and remifentanil at 0.05–0.5 µg · kg^–1 · min^–1 (2), respectively, were equipotent as anesthetic adjuncts, and also based on results of our preliminary dose– response studies on these drugs in rabbits (6,20).

Arterial blood pressure, heart rate, respiratory rate, Paco₂, the number of nonresponders, the head lift threshold, and the escape movement threshold were measured repeatedly at the steady-state isoflurane concentrations of 3%, 1.5%, and 0% (i.e., baseline at 0 min). Subsequently, these variables were measured at 15 and 30 min of the adenosine or remifentanil infusion, and then every 30 min until 360 min after starting the infusion. Only in animals in the adenosine group, measurements were repeated further every 60 min until both head lift and escape movement thresholds returned to ±20% of the baseline values or 720 min passed after starting the adenosine infusion. If both thresholds returned to baseline levels before 720 min in an animal, the experiment for the subject ended, and the last values measured were substituted for values for the following measurements.

Data are reported as mean ± sem. Changes in variables over time were analyzed with repeated measures analysis of variance (ANOVA) followed by Fisher's protected least significant difference test. Intergroup comparisons of the head lift threshold or the escape movement threshold and intragroup comparisons between head lift and escape movement thresholds were respectively made with ANOVA. The number of nonresponders at each time was compared with the baseline value at 0 min using Fisher's exact probability test. P < 0.05 was considered statistically significant.

RESULTS

Arterial blood pressure decreased immediately after starting the adenosine infusion and remained at a decreased level throughout the infusion period. After stopping the infusion at 240 min, arterial blood pressure increased immediately and returned to the baseline level by 270 min (Fig. 1A). With remifentanil, arterial blood pressure remained unchanged throughout the infusion period (Fig. 1B). Arterial blood pressure decreased dose-dependently with isoflurane in both adenosine and remifentanil groups (Figs. 1A and B).

View larger version (20K): [in this window] [in a new window]   Figure 1. Changes in systolic, diastolic, and mean arterial blood pressure in the adenosine (A) and remifentanil groups (B), and changes in heart rate in the adenosine (C) and remifentanil groups (D), during and after infusion of adenosine or remifentanil, and during isoflurane inhalation. *P < 0.05 versus the baseline values (BL).

Heart rate increased only transiently with adenosine (Fig. 1C) and decreased rapidly with remifentanil. After reaching its minimum at 60 min, heart rate began to increase and returned to the baseline level at 150 min, despite the continuing remifentanil infusion (Fig. 1D). Heart rate remained unchanged with isoflurane in both groups (Figs. 1C and D).

Respiratory rate increased transiently with adenosine (Fig. 2A) and decreased rapidly with remifentanil. After reaching its minimum at 120 min, respiratory rate began to increase toward the baseline level, despite the continuing remifentanil infusion. After stopping the infusion at 240 min, respiratory rate increased rapidly and returned to the baseline level at 270 min (Fig. 2B). Respiratory rate decreased dose-dependently with isoflurane in both groups (Figs. 2A and B).

View larger version (18K): [in this window] [in a new window]   Figure 2. Changes in respiratory rate in the adenosine (A) and remifentanil groups (B), and changes in carbon dioxide tension of arterial blood (Paco2) in the adenosine (C) and remifentanil groups (D) during and after infusion of adenosine or remifentanil, and during isoflurane inhalation. *P < 0.05 versus the baseline values (BL).

Paco₂ did not change with adenosine (Fig. 2C) but increased rapidly with remifentanil. After reaching its maximum at 90 min, Paco₂ began to decrease toward the baseline level, despite the continuing remifentanil infusion. After stopping the infusion at 240 min, Paco₂ decreased rapidly and returned to the baseline level at 270 min (Fig. 2D). Paco₂ and increased dose-dependently with isoflurane in both groups (Figs. 2C and D).

No pain behavior was observed in response to the adenosine or remifentanil infusion itself. After starting the adenosine infusion, the number of nonresponders increased slowly but progressively throughout the infusion period, and reached its maximum (6/8) at 210 min. After stopping the adenosine infusion at 240 min, the number of nonresponders decreased slowly and returned to the baseline (0/8) at 600 min (Fig. 3A). After starting the remifentanil infusion, the number of nonresponders increased rapidly. After reaching its maximum (7/8) at 60 min, it began to decrease despite the continuing remifentanil infusion. After stopping the infusion at 240 min, it decreased rapidly and returned to the baseline (0/8) at 270 min (Fig. 3B). With isoflurane, the number of nonresponders increased dose-dependently; with 0%, 1.5%, and 3% isoflurane, none (0/16), nearly half (7/16), and all (16/16) of animals, respectively, qualified as nonresponders to clamping the forepaw (Figs. 3A and B).

View larger version (22K): [in this window] [in a new window]   Figure 3. Changes in the number of nonresponders to clamping the forepaw in the adenosine (A) and remifentanil groups (B), and changes in the head lift threshold (HLT) and escape movement threshold (EMT) in the adenosine (C) and remifentanil groups (D) during and after infusion of adenosine or remifentanil, and during isoflurane inhalation. *P < 0.05 versus the baseline values (BL); #significantly higher (P < 0.05) than the escape movement threshold during 1.5% isoflurane inhalation head lift threshold (HLT) = electrical stimulation threshold required to evoke the head lift response (sedative/hypnotic index), escape movement threshold (EMT) = electrical stimulation threshold required to evoke the escape movement response (analgesic/antinociceptive index).

After starting the adenosine infusion, the head lift threshold and the escape movement threshold increased slowly but progressively throughout the infusion period, reaching their maxima at 270 min. After stopping the infusion at 240 min, the head lift threshold and the escape movement threshold decreased slowly and returned to baseline levels at 330 min and 600 min, respectively (Fig. 3C). With remifentanil, the head lift and escape movement thresholds increased rapidly. After reaching their maximum at 60 min, these thresholds began to decrease toward the baseline levels, despite the continuing remifentanil infusion. After stopping the infusion at 240 min, these thresholds decreased rapidly and returned to the baseline levels at 270 min (Fig. 3D). The head lift and escape movement thresholds increased dose-dependently with isoflurane in both groups (Figs. 3C and D).

With isoflurane, the head lift threshold (sedative/hypnotic index) and the escape movement threshold (analgesic/antinociceptive index) increased in a parallel manner, and these two thresholds were not statistically different. With adenosine and remifentanil, the escape movement threshold increased predominantly, and the head lift threshold remained significantly less than the escape movement threshold throughout the drug infusion period (Figs. 3C and D). The maximum escape movement threshold achieved by adenosine or remifentanil was more than the escape movement threshold achieved by 1.5% isoflurane, but less than that achieved by 3% isoflurane (Figs. 3C and D). The escape movement threshold was more with remifentanil than with adenosine during the first 90 min of the drug infusion, whereas it was more with adenosine at and after the end of the drug infusion. The maximum escape movement threshold achieved by adenosine at 270 min was not statistically different from that achieved by remifentanil at 60 min. A similar tendency was observed with the number of nonresponders.

DISCUSSION

In the present study, we found that both adenosine and remifentanil, IV infused at relatively large doses, could produce significant antinociception in rabbits, as assessed by the escape movement threshold to subcutaneous electrical stimulation and the number of nonresponders to clamping the forepaw. The maximal antinociceptive effects of adenosine and remifentanil were comparable, and were more than the antinociceptive effect of 1.5% isoflurane, although they were less than that of 3% isoflurane. With 1.5% isoflurane, nearly half of the animals did not show the escape movement in response to clamping the forepaw, a simulated surgical stimulus, implying that 1.5% isoflurane was nearly one minimal alveolar concentration in anesthetic potency. Therefore, these results indicated that IV adenosine and remifentanil could produce profound antinociception of comparable magnitude. However, on–off profiles of the antinociceptive effects were quite different between the two drugs. In agreement with previous studies (5–8), remifentanil had a rapid onset, short latency to peak effect, and very short duration of action, whereas adenosine-induced antinociception was slow in onset and long in duration.

During IV infusion of remifentanil at a constant rate, its plasma concentration should increase rapidly to reach a steady-state level (5). Reflecting such pharmacokinetic property, all of its hemodynamic, respiratory, sedative/ hypnotic, and analgesic/antinociceptive effects increased rapidly to reach their maxima once the infusion began. Subsequently, however, these effects began to decline toward baseline levels at varying rates, despite the continuing remifentanil infusion. Studies in animals and humans have demonstrated rapidly developing acute tolerance to analgesic (7,8) and nonanalgesic (7) effects of remifentanil. Therefore, declines in these effects observed during the infusion presumably reflected the development of acute tolerance. In addition, it has been suggested that remifentanil is associated with withdrawal hyperalgesia, which may enhance, rather than inhibit, postoperative pain, and increase the opioid requirements for postoperative analgesia (21). Such difficulties of large-dose remifentanil may diminish its clinical utility to some extent.

Because of its extremely short plasma half-life (0.6–10 s) (12), the plasma concentration of adenosine should increase immediately to reach a steady state once the infusion begins, and then decrease immediately once the infusion ends. Consistent with these predictions, and in agreement with a previous study (22), arterial blood pressure decreased immediately to reach a plateau once the infusion began, and increased back to baseline immediately after the infusion ended. In contrast to its hemodynamic effect, IV adenosine produced an antinociceptive effect that was slow in onset and lasted for several hours after the infusion. Therefore, the analgesic response does not follow the pharmacokinetic behavior. Permeability of adenosine across the blood–brain barrier unlikely accounts for the slow on–off profiles of the adenosine-induced antinociception. The transport of adenosine across the blood–brain barrier is rapid, using multiple transporter systems (23). The spinal cord, rather than the brain, is considered the primary site of adenosine analgesia (9,19). Further, the analgesic effects of long-acting A₁ receptor agonists seem slow in onset, even with their direct spinal application (10,11,24). The vasodilating activity of adenosine is mediated by A₂ receptors that are coupled to Gs protein activating adenylate cyclase, whereas adenosine analgesia is mediated by A₁ receptors that are coupled to Gi protein inhibiting adenylate cyclase (25). It is thus conceivable that the difference in the receptor and second messenger systems involved in signal transduction might contribute to the observed difference between on–off profiles of hemodynamic and antinociceptive effects.

In the present study, we clearly demonstrated that IV adenosine, at 400 µg · kg^–1 · min^–1, could produce pronounced and sustained antinociception to simulated surgical stimuli. This indicates that the long-lasting postoperative pain relief after intraoperative adenosine infusion reported in clinical studies (1,2,13) may have been at least partly due to the long-lasting antinociceptive effect of adenosine, and not necessarily or exclusively due to the ability of adenosine to suppress inflammation or sensitization (17), especially when adenosine was given at relatively large doses [e.g., up to 1600 or 500 µg · kg^–1 · min^–1 (1, 2)].

Our study also demonstrated that large-dose remifentanil may be associated with the development of acute antinociceptive tolerance and withdrawal hyperalgesia (7,8,21), and therefore, it may be reasonable to consider some alternatives to its use for perioperative analgesia. The progressive manifestation and gradual withdrawal of adenosine-induced antinociception during and after the infusion suggested that IV adenosine was not associated with acute tolerance or withdrawal hyperalgesia. In this regard, adenosine may be advantageous over remifentanil, especially in providing improved postoperative analgesia, in accordance with previous clinical studies (1,2). The intraoperative use of IV infusion of adenosine may be rationalized by its several pharmacokinetic and pharmacodynamic profiles.

1. Adenosine-induced antinociception can last long after the infusion.
   
2. Excellent intraoperative hemodynamic stability can be achieved with IV adenosine, especially when titrated using a variable-rate infusion (1,2), as adenosine can effectively inhibit acute cardiovascular responses to noxious surgical stimuli through its vasodilating, sympatholytic, and antinociceptive activities (17,25).
   
3. Adenosine may also contribute to improved postoperative analgesia by suppressing inflammation and/or central sensitization (17,25).
   
4. Patients under general anesthesia are least likely to feel adenosine-induced pain. Adenosine at 70 µg · kg^–1 · min^–1 or more can cause pain from various parts of the body, most commonly chest pain, via direct activation of peripheral nociceptive afferents via A₂ receptors (3,9,17), although adenosine-induced pain behaviors were not observed in our awake rabbits.
   
5. IV infusion of adenosine is not likely to cause severe bradycardia, unlike the profound effects of an IV bolus injection of adenosine on heart rate (1).
   
6. Adenosine's side effects, if any, rapidly disappear after discontinuation of the infusion (17), reflecting its extremely rapid elimination from plasma (12).
   
7. Adenosine is an analgesic, rather than a sedative/hypnotic drug, as was suggested by our findings that the adenosine-induced increase in the head lift threshold (sedative/hypnotic index) was less and more transient compared with that in the escape movement threshold (analgesic/antinociceptive index).
   

Intraoperative adenosine infusion thus may provide excellent intraoperative hemodynamic stability, as well as pronounced and sustained postoperative analgesia, without retarding recovery from anesthesia or producing adenosine-related postoperative side effects (1,2,13).

In conclusion, we demonstrated distinctive antinociceptive properties of IV adenosine and remifentanil in rabbits. Both drugs produced profound antinociception. The antinociceptive effect of remifentanil was rapid in onset and short-lived, whereas that of adenosine was slow in onset and long-lasting, despite its ultrashort plasma half-life and immediate on–off vasodilating effect. Further, our data support the development of acute tolerance to the antinociceptive effect of large-dose remifentanil, but we did not see similar evidence of tolerance to the antinociceptive effects of adenosine. The pharmacokinetic and pharmacodynamic properties of IV adenosine make it uniquely suited to produce pronounced and sustained perioperative analgesia while maintaining intraoperative hemodynamic stability.

Footnotes

Accepted for publication June 12, 2006.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Hayashida, M. Articles by Hanaoka, K. Search for Related Content PubMed PubMed Citation Articles by Hayashida, M. Articles by Hanaoka, K. Related Collections Mechanisms Pain Pharmacology