Anesth Analg 2002;95:948-951
© 2002 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
The Magnitude of Acute Tolerance to Morphine Analgesia: Concentration-Dependent or Time-Dependent?
Shung-Tai Ho, MD MS*,
Jhi-Joung Wang, MD DMS*
,
Jeng-Chai Huang, PhD,
Mao-Tsun Lin, PhD, and
Wen-Jinn Liaw, MD DMS*
*Department of Anesthesiology, Tri-Service General Hospital, National Defense Medical Center, Taipei; and Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan
Address correspondence and reprint requests to Shung-Tai Ho, MD, MS, Department of Anesthesiology, National Defense Medical Center, Room 8113, No. 161, Sec. 6, Minchuan E Rd., Taipei, Taiwan. Address e-mail to painlab{at}tpts5.seed.net.tw
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Abstract
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We evaluated the relationship of either the infusion time or the plasma morphine concentrations on the magnitude of acute tolerance to morphine analgesia. Male New Zealand White rabbits were randomly allocated to one of four groups. Group 1 received an IV bolus of morphine 40 mg followed by an infusion at 20 mg/h for 8 h. Group 2 received a 20-mg morphine bolus followed by an infusion at 10 mg/h. Group 3 received a 10-mg morphine bolus followed by an infusion at 5 mg/h. Group 4 received a saline bolus and infusion. Analgesia was determined by the paw-pressure test, and the plasma concentrations of morphine were measured by high-performance liquid chromatography. We found that the plasma concentrations of morphine were maintained at a steady-state between 2 and 8 h after the morphine administration. However, from 2 to 8 h after the morphine infusion, the longer the infusion time was, the less the analgesic effect remained. Furthermore, the magnitude of acute tolerance was significantly correlated to the duration of morphine infusion (r = 0.93; P < 0.01) but not the different steady-state plasma morphine concentrations. We conclude that the magnitude of morphine tolerance is significantly correlated to the duration of infusion but not the different steady-state plasma morphine concentrations.
IMPLICATIONS: We evaluated the relationship of either the infusion time or the plasma morphine concentrations on the magnitude of acute tolerance to morphine analgesia in rabbits. We found that the magnitude of morphine tolerance is significantly correlated to the duration of infusion but not to the different steady-state plasma morphine concentrations.
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Introduction
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Morphine and other opioids are widely used in clinical practice as analgesics. However, their use may be associated with the development of acute tolerance (1–6). Previous reports have demonstrated that intraoperative or postoperative use of a relatively large dose (bolus plus infusion) of morphine, fentanyl, or remifentanil resulted in a rapid development of tolerance to their analgesic effect several hours after their use (1–6). In animal studies, acute tolerance to opioid analgesia was also found after a large dose, repeated boluses, or continuous infusion of morphine or other opioids (7–12). Because opioids are widely used clinically, it is important to know which factor may significantly influence the development of acute tolerance to the analgesic effect of these drugs.
A review of the literature suggested two potentially relevant factors that may significantly influence the development of acute opioid tolerance: different plasma opioid concentrations or the duration of drug administration. However, the relative importance of these factors has not been evaluated. Because morphine is one of the most frequently used opioids in acute pain services, we designed a study to evaluate the influence of the steady-state plasma morphine concentration and the infusion duration on the magnitude of acute tolerance to morphine analgesia in rabbits.
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Materials and Methods
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All experiments were performed in accordance with the recommendations and policies of the International Association for the Study of Pain and were approved by our Institutional Animal Investigation Committee. Male New Zealand White rabbits (2.7–3.3 kg) were housed in individual cages with a controlled room temperature (22°C ± 1°C), humidity (50% ± 10%), and a 12-h light-dark cycle (from 6 AM to 6 PM). Food pellets and water were available ad libitum. Experiments were performed only after the rabbits had acclimatized to the above environment for at least 7 days. The experiments were performed between 8 AM and 6 PM in random order.
The experiments took place in a separate, sound-attenuated room in which no other rabbits were present to minimize the variability of the study. Animals were taken into the experimental room individually 30 min before the study to reduce stress. With the animal in a restraining device (13), the central artery of the ear was cannulated by inserting a catheter (22-gauge; Terumo, Tokyo, Japan) to allow blood sampling. The catheter was kept patent by flushing periodically with a solution of 0.9% saline containing heparin 10 U/mL.
Rabbits were randomly allocated into one of four groups (n = 6 for each group). Group 1 received a 40-mg morphine bolus and a 20-mg/h infusion. Group 2 received a 20-mg morphine bolus and a 10-mg/h infusion. Group 3 received a 10-mg morphine bolus and a 5-mg/h infusion. Group 4 received a bolus of saline and then an infusion. All infusions were continued for 8 h.
A pharmacodynamic (PD) with pharmacokinetic study was performed. In the PD part of the study, a hand-held pressure algometer (Somedic Sale AB, Sweden) was used to measure the pressure-pain threshold of the rabbit’s paw (13). The pressure algometer consists of a gun-shaped handle with a pressure-sensitive strain gauge situated at the tip and was connected to a power supply and an amplifier. The tip of the algometer was covered with a circular probe (diameter, 2.3 cm). To lessen the damage to the skin, the probe was covered with a piece of 1-mm thick, soft polypropylene material. A pen recorder (No. 805721, Central Denshikeisoku Co, Japan) continuously monitored the pressure change during testing. The right hind paw of the rabbit was gently put on the ground, and the pressure was exerted by a weight between 0–1999 kPa (1 kPa = 98 g/cm2) with an application rate of 40 kPa/s on the algometer (13). The nociceptive threshold was taken as the point at which the rabbit made a vigorous attempt to remove the paw, and the pressure readings were taken from a pen recorder.
Control values were obtained at 45, 30, and 15 min before the IV administration of drugs. For each rabbit, the first reading was discarded to minimize variability, and the remainder was averaged to obtain a baseline reading. In this way, each rabbit served as its own control. Experimental values were then compared with the predrug baseline values obtained from each rabbit. A predetermined cutoff pressure of 100% more than the baseline values was set for each rabbit. The magnitude of tolerance was calculated by the following formula (11,14):
equation
In the pharmacokinetic part of the study, 5 mL of blood was collected from the auricular artery at zero time for a calibration curve, and 2 mL of blood was collected every 2 h simultaneously with the PD study. Plasma concentrations of morphine were determined by high-performance liquid chromatography using a previously published method (15). The detection limit of the method was 100 pg/mL of morphine.
Results are expressed as mean ± SD. One way analysis of variance with repeated measures followed by Dunnett’s test was used to analyze the plasma concentrations and the analgesic effects of morphine within each group. Linear regression followed by an F test was used to test the correlation between the magnitude of tolerance or the duration of infusion and the different plasma morphine concentrations. A value of P < 0.05 was considered significant.
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Results
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After the IV administration of morphine (Groups 1–3), the plasma concentrations of morphine reached a steady state for the period of 2 to 8 h (Fig. 1). Within each group, the plasma morphine concentrations at 2, 4, 6, and 8 h did not differ significantly (Fig. 1). Rabbits in Groups 1–3 demonstrated a significant analgesic effect, which reached its maximum 1–2 h after the morphine administration and decayed significantly 5 h after the infusion (Fig. 2). From 2 to 8 h after the morphine infusion, the longer the infusion time was, the smaller the analgesic effect. Furthermore, the magnitude of acute morphine tolerance was positively correlated to the duration of morphine infusion (Fig. 3) but not to the different steady-state plasma morphine concentrations (Fig. 4).
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Figure 1. Plasma concentrations of morphine. Values are mean ± SD. Group 1 received an IV bolus of morphine 40 mg plus a 20-mg/h infusion. Group 2 received a 20-mg morphine bolus plus a 10-mg/h infusion. Group 3 received a 10-mg morphine bolus plus a 5-mg/h infusion. The plasma concentrations of morphine were maintained at a steady state between 2 and 8 h in all groups. The differences within the groups were not significant during this period.
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Figure 2. The analgesic effect of morphine (paw-pressure threshold in rabbits). Values are mean ± SD. Group 1 received an IV bolus of morphine 40 mg plus a 20-mg/h infusion. Group 2 received a 20-mg morphine bolus plus a 10-mg/h infusion. Group 3 received a 10-mg morphine bolus plus a 5-mg/h infusion. Group 4 received a saline bolus and infusion. Although the infusion of morphine was continued throughout an 8-h study period, the paw-pressure thresholds decreased significantly 5 h after the infusion. *P < 0.01 when compared with the maximum effect that occurred in each group using the Dunnett’s test.
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Figure 3. The correlation between the magnitude of morphine tolerance and the duration of morphine infusion. Values (mean ± SD) are obtained at the time points of 2 to 8 h after the infusion. A positive correlation is found (r = 0.89; P < 0.01) using the F test.
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Figure 4. The lack of a correlation between the magnitude of morphine tolerance and the steady-state plasma morphine concentration (r = 0.26 and 0.23, respectively; P > 0.05). (A) Normal scale linear model. (B) Log-concentration model. Values (mean ± SD) are obtained at the time points of 2 to 8 h after starting the infusion.
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Discussion
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Our results indicate that acute tolerance to morphine analgesia occurred after an eight-hour constant IV infusion of morphine, and the magnitude of acute tolerance is positively correlated to the duration of morphine infusion but not to the different steady-state plasma morphine concentrations. This is an important finding for those who use morphine or other opioids as an analgesic in acute pain services.
Opioids are often used in anesthesia and pain management. For physicians and patients, the development of tolerance to opioids that may lead to their over-consumption is of concern. McQuay et al. (4) reported that when an IV bolus dose of fentanyl 10 µg/kg was followed by a three-hour infusion of 100 µg/h during surgery, acute tolerance to fentanyl analgesia occurred after surgery. Chia et al. (2) also demonstrated that preoperative administration of 15 µg/kg of fentanyl followed by intraoperative administration of 100 µg/h induces greater consumption of fentanyl and increased pain intensity after surgery than a single preoperative administration of 1 µg/kg of fentanyl. Parker et al. (6) reported that patients who received a continuous morphine infusion for postoperative pain control consumed more opioids than those who received intermittent morphine boluses. After a continuous infusion of a relatively large dose of remifentanil during surgery, Guignard et al. (1) and Vinik and Kissin (5) found an occurrence of acute tolerance to remifentanil analgesia with increased postoperative pain and morphine consumption.
Animal studies have shown the development of acute tolerance to morphine analgesia after a single large dose of subcutaneous morphine in rats and mice (7,9). Others also found that acute tolerance to morphine may develop within two to eight hours after an IV infusion of morphine in rats (8,9,11,12). In our study, we also found that acute morphine tolerance occurred after an eight-hour IV infusion. The analgesic effect of morphine decreased significantly five hours after starting the infusion. At eight hours after the infusion, the analgesic effect of morphine was almost undetectable.
Pain is a complex syndrome that may occur after different stimulus, e.g., thermal, mechanical, electrical, or chemical (11,16). No single stimulus can induce all kinds of pain. Many animal tests, e.g., tail-flick, hot plate, paw-pressure, or writhing test, have been applied to simulate one or more of the characteristics of pain (16). The paw-pressure test, which was used in the current study, presents the mechanically induced pain (16).
In the current study, we did not evaluate the concentration of morphine in the brain. In a previous study, the relationship between the serum and brain concentrations of morphine has been evaluated (9). After a constant-rate infusion of morphine 4 mg · kg-1 · h-1 for eight hours in rats, both the serum and brain concentrations of morphine reached a steady state between two and eight hours after the infusion. The serum concentration of morphine was approximately 10 times larger than that in the brain, and the morphine serum and brain concentrations at eight hours were not significantly different from those at two hours (9).
In the clinical situation, many factors may contribute to the development of acute morphine tolerance, e.g., stress, the use of opioid, the presence of pain, different opioid concentration, and the duration of opioid administration (1–5,9–12). In the current study, we focused on only two of these variables. Therefore, more clinical studies may be required before widely applying the current results to clinical practice.
In summary, we found that acute morphine tolerance developed after an eight-hour IV infusion of morphine and the magnitude of morphine tolerance were significantly correlated to the duration of morphine infusion but not to the different steady-state plasma morphine concentrations.
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Acknowledgments
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Supported, in part, by the National Council of Science, Republic of China, Grant NSC 86–2314-B-016–082.
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Footnotes
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This work was done in the National Defense Medical Center, Taipei, Taiwan
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References
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Accepted for publication May 21, 2002.
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Abstract
Introduction
