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Anesth Analg 2000;90:913-917
© 2000 International Anesthesia Research Society

REGIONAL ANESTHESIA AND PAIN MEDICINE

Magnesium Sulfate Potentiates Morphine Antinociception at the Spinal Level

Jeffrey S. Kroin, PhD, Robert J. McCarthy, PharmD, Natasha Von Roenn, BS, Brady Schwab, BS, Kenneth J. Tuman, MD, and Anthony D. Ivankovich, MD

Department of Anesthesiology, Rush Medical College at Rush-Presbyterian-St. Luke’s Medical Center, Chicago, Illinois

Address correspondence and reprint requests to Jeffrey S. Kroin, PhD, Department of Anesthesiology, Rush-Presbyterian-St. Luke’s Medical Center, 1653 W. Congress Pkwy., 739 Jelke, Chicago, IL 60612.


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Intrathecal magnesium sulfate coinfusion with morphine increases antinociception in normal rats; however, because magnesium also delays the onset of tolerance, it is not clear whether this additional antinociception is a result of potentiated analgesia or tolerance abatement. We examined the antinociceptive interaction of intrathecal (IT) bolus magnesium sulfate and morphine in morphine naive rats and those with mechanical allodynia after a surgical incision. After intrathecal catheter implantation, rats were given preinjections of magnesium or saline, followed by injections of morphine or saline. In morphine naïve rats, IT bolus magnesium sulfate 281 and 375 µg followed by IT morphine 0.25 or 0.5 nmol enhanced peak antinociception and area under the response versus time curve two-to-three-fold in the tail-flick test as compared with morphine alone. Likewise, in rats with incisional pain, IT bolus magnesium sulfate 188 and 375 µg followed by morphine 0.5 nmol reduced mechanical allodynia, whereas morphine 0.5 nmol alone did not. This study suggests that IT magnesium sulfate potentiates morphine at a spinal site of action.

Implications: Magnesium sulfate potentiates morphine analgesia when coadministered intrathecally in normal rats, and in an animal model of mechanical allodynia after a surgical incision. These results suggest that intrathecal administration of magnesium sulfate may be a useful adjunct to spinal morphine analgesia.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Systemic delivery of magnesium sulfate decreases postoperative opioid requirements in patients, suggesting a potentiating effect of magnesium on opioid analgesia (1,2). However, the site of the potentiation seen in these clinical trials is uncertain, because only a small amount of systemic magnesium crosses the blood-brain barrier (3).

Intrathecal bolus injections of N-methyl-D-aspartate (NMDA) antagonists, such as magnesium and dizocilipine maleate (MK-801), block ipsilateral hyperesthesia in rats with unilateral experimental peripheral mononeuropathy without effecting thermal sensitivity on the sham-operated side (4,5). In normal rats, continuous intrathecal infusion of magnesium sulfate alone does not produce analgesia; however, it will produce nearly a 100% effect when coinfused over days with a dose of morphine that produces a 50% increase in antinociceptive response (6). Since magnesium also delays the onset of morphine tolerance, it is unknown whether this additional antinociception results from potentiated analgesia or tolerance abatement (6). To avoid the potential confounding effect of opioid tolerance in the long-term infusion studies, we examined the antinociceptive interaction of acute intrathecal bolus magnesium sulfate and morphine in morphine naïve rats. An additional goal of this study was to test this combination in a model of mechanical allodynia after a surgical incision. This model was chosen because the mechanical allodynia lasting for several days has some similarities to the human postoperative pain state (7).


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
This study was approved by our institutional animal care and use committee. Experiments were performed on male Sprague-Dawley rats (Harlan, Indianapolis, IN) weighing 250–275 g. Animals were anesthetized with 2% halothane and an intrathecal polyethylene catheter (0.28 mm inner diameter, 0.61 mm outer diameter) implanted via the cisterna magna and advanced 8.5 cm caudally so that the tip was at the lumbar enlargement (8). The skin margins were closed, leaving only 2 cm of catheter above the skull exposed for injections. Animals exhibiting neurological impairment after intrathecal catheter placement were not included in the study.

Thermal Antinociceptive Testing
By using a tail-flick apparatus, 5 days after intrathecal catheter implantation, animals (n = 158) were tested for antinociception. Thermal latencies were measured as the time required for the rat to move its tail from a heat source, with the latency to withdrawal determined automatically with a photoelectric sensor (Tail Flick Analgesia Meter; Columbus Instruments, Columbus, OH). Testing was performed in triplicate with 3 min between each trial and an 8-s cutoff time to prevent tissue damage. Animals were also evaluated for motor coordination on a rod rotating at 10 rpm (Economex, Columbus Instruments). Normal rats are able to maintain their balance on this rod for at least 3 min without falling (9).

Animals were randomly assigned to receive an intrathecal bolus injection of magnesium sulfate 375, 281, or 188 µg, or saline. Tail-flick testing was repeated 15 min after the first injection. Immediately after the testing, animals received a subsequent intrathecal injection of morphine sulfate 0.5 or 0.25 nmol, or saline. These combinations resulted in the following 11 groups: saline (S) + morphine (MOR) 0.25 nmol; S + MOR 0.5 nmol; magnesium sulfate (MAG) 188 µg + S; MAG 281 µg + S; MAG 375 µg + S; MAG 188 µg + MOR 0.25 nmol; MAG 281 µg + MOR 0.25 nmol; MAG 375 µg + MOR 0.25 nmol; MAG 188 µg + MOR 0.5 nmol; MAG 281 µg + MOR 0.5 nmol; and MAG 375 µg + MOR 0.5 nmol. All injections were 8 µL and each was followed by 8 µL of saline to clear the catheter dead space.

Antinociceptive testing was repeated after the second intrathecal injection at 15, 30, 45, 60, 90, and 120 min, and motor coordination was evaluated at 25 min. The personnel performing all antinociceptive and motor coordination testing were blinded to the solutions administered. The specific drugs used in this study were morphine sulfate hypodermic tablets for injection (Eli Lilly, Indianapolis, IN), and magnesium sulfate injection (SoloPak Labs, Elk Grove Village, IL). All drug dilutions and saline injections were made with preservative-free 0.9% sodium chloride injection. Data were converted to maximum possible effect (MPE) by using the formula: %MPE = 100 x (latency - baseline)/(cutoff - baseline) (10). Peak antinociceptive effect and area under the %MPE time curve from 0 to 60 min (AUC) after the second injection were compared by using a one-way analysis of variance. Post hoc testing was performed, when appropriate, by using the least significant difference test and P < 0.05 was considered statistically significant.

Mechanical Allodynia Model. In a separate group of 60 animals, 4 days after intrathecal catheter implantation, an incision was made in the plantar surface of the left hind paw under aseptic conditions, according to the method of Brennan et al. (7). Briefly, rats were anesthetized with 2% halothane and a 1 cm longitudinal incision was made through the skin and fascia with a number 11 surgical blade starting 0.5 cm from the edge of the heel and extending toward the toes. The plantaris muscle was elevated and incised longitudinally, with the muscle origin and insertion remaining intact. Hemostasis was achieved with gentle pressure and the skin apposed with 2 mattress sutures of 5–0 nylon.

On the next day, animals were placed over a grid and mechanical allodynia was tested by using Von Frey filaments (20–282 mN) applied to an area of the hind paw adjacent to the incision (7). Testing was performed in triplicate with 5 min between each trial. Then, animals were randomly assigned to receive an intrathecal bolus injection of magnesium sulfate 375, 188, or 94 µg, or saline. A subsequent intrathecal injection of morphine 0.5 nmol or saline was administered 15 min after the first injection. These combinations resulted in the following five groups: S + MOR 0.5 nmol; MAG 375 µg + S; MAG 94 µg + MOR 0.5 nmol; MAG 188 µg + MOR 0.5 nmol; and MAG 375 µg + MOR 0.5 nmol. Mechanical allodynia was again evaluated in triplicate at 25, 30, and 35 min after the second injection. The withdrawal threshold was determined as the minimum force producing a response in the three trials. When there was no withdrawal response to any of the filaments, a cutoff value of 300 mN was recorded. Data were analyzed by using the Kruskal-Wallis H-test and the Mann-Whitney U-test with P < 0.05 considered statistically significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Thermal Antinociceptive Testing. Before intrathecal drug administration, the mean tail-flick latency was 2.86 ± 0.05 s and did not differ between groups. After the first injection, a dose-dependent increase in the %MPE was observed with increasing doses of magnesium sulfate, with the largest dose producing a mean response of 12% (Fig. 1). The time course of the antinociceptive response of three representative groups after the second injection, is illustrated in Figure 2. For all groups that received morphine, peak analgesic responses occurred within 30 min after the second injection.



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  		Figure 1. Effect of increasing doses of intrathecal magnesium sulfate on the thermal antinociceptive response in morphine naive rats. Tail-flick latency converted to percent maximum possible effect (%MPE). Number of animals in each group: saline (n = 40); magnesium sulfate 188 µg (n = 32); magnesium sulfate 281 µg (n = 44); magnesium sulfate 375 µg (n = 42). {dagger} = different from saline, {alpha} = 0.05.

 


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  		Figure 2. Time course of the changes in thermal antinociception after intrathecal drug administration in naive rats. BL = baseline before any intrathecal drug injection. Number of animals in each group: saline then morphine 0.5 nmol (n = 25); magnesium sulfate 375 µg then saline (n = 12); magnesium sulfate 375 µg then morphine 0.5 nmol (n = 15). Data presented as mean ± SEM.

 
The morphine doses we used produced mean peak %MPE responses of <50% when given without magnesium preinjection (Fig. 3). Compared with morphine alone the combination of magnesium sulfate 281 or 375 µg with either morphine 0.25 or 0.5 nmol increased both the peak antinociceptive response and the AUC. All animals were able to stay on the rotating rod for 3 min before and after drug administration.



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  		Figure 3. Effect of increasing doses of intrathecal magnesium sulfate pretreatment on intrathecal morphine peak antinociception. Upper panel, displayed as percent maximum possible effect (%MPE) and lower panel, area under the antinociceptive time curve (AUC) from 0 to 60 min in morphine naïve rats. Each point represents the mean ± SEM of 15–25 animals. * = different from morphine 0.5 nmol alone, {alpha} = 0.05. {dagger} = different from morphine 0.25 nmol alone, {alpha} = 0.05.

 
Mechanical Allodynia Model. There was no difference in the withdrawal threshold between the five groups before drug injection (Fig. 4). Morphine 0.5 nmol alone did not elevate the withdrawal threshold. Likewise, magnesium sulfate 375 µg by itself was without effect. The combination of magnesium sulfate 188 and 375 µg with morphine 0.5 nmol increased the withdrawal threshold (Fig. 4).



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  		Figure 4. Effect of increasing doses of intrathecal magnesium sulfate (MAG) pretreatment on intrathecal morphine (MOR) withdrawal threshold as measured with Von Frey filaments 24 h after plantar hind paw incision. The results are expressed as medians (horizontal line) with first and third quartiles (boxes), and 10 and 90 percentiles (error bars). Number of animals in each group: A (n = 14); B (n = 10); C (n = 12); D (n = 12); E (n = 12). {dagger} = different from saline then morphine 0.5 nmol, P < 0.05.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The important finding of this study is the demonstration that acute bolus dosing of intrathecal magnesium sulfate produces dose-dependent potentiation of the antinociceptive effect of morphine to noxious thermal stimulation in normal rats and mechanical stimulation at an incisional pain site. This confirms the observation of potentiated analgesia during 24–48 hour-intrathecal coinfusion of magnesium sulfate and morphine (6), and extends the findings to a model of acute incisional pain.

At the doses we used, magnesium sulfate produced a small antinociceptive response in the tail-flick test. This finding is consistent with previous intrathecal studies in rats, which have demonstrated either no effect or a small effect of magnesium sulfate alone at doses comparable to those we used (4,6). Larger intrathecal doses of magnesium sulfate (>=500 µg) produce sedation, ataxia, and motor incoordination, which preclude behavioral testing (4). In our study, the 375 µg dose only produced a 12% MPE, making it highly unlikely that an antinociceptive 50% effective concentration could be measured in a behavioral test.

Intrathecal bolus magnesium pretreatment enhanced intrathecal morphine antinociception in morphine naive rats with the peak response and AUC at a given morphine dose increasing as a function of magnesium dose. At a dose of morphine of 0.25 nmol, the pretreatment with magnesium sulfate 375 µg increased both the peak effect and the AUC at least 3 times more than morphine alone. At the larger morphine dose (0.5 nmol), the addition of magnesium sulfate 375 µg increased the peak effect and the AUC approximately twofold. This apparently greater effect at the smaller morphine dose is likely a result of the transformation of the data to %MPE by using the 8-second cutoff time, which truncates the longer latencies that occur at larger doses. This finding contrasts with previous studies in which pretreatment with intrathecal MK-801 did not alter morphine antinociception when evaluated in sham-operated control limbs (5) or by using tail-flick test data from sham-operated control rats (11). The difference in our findings from studies with MK-801 may be a result of the difference in the action of magnesium and MK-801 at the NMDA-receptor channel complex (12), or non-NMDA actions of magnesium at the spinal level (13).

Intrathecal magnesium sulfate alone had no effect on mechanical allodynia in the incisional model of postoperative pain. This finding is similar to the lack of effect of MK-801, a noncompetitive NMDA antagonist, in this model (14). However, mixed {alpha}-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid and kainate excitatory amino acid receptor antagonists have been shown to elevate withdrawal thresholds in this model (15). Magnesium may also have some effect at non-NMDA glutamate receptors and this may relate to the potentiation we observed (16). The lack of inhibition of mechanical allodynia with morphine alone at 0.5 nmol is also consistent with a previous study of intrathecal morphine by using this model (17). In that study, larger morphine doses were effective in reducing mechanical allodynia. Extrapolating from the dose-response effect of morphine from that study, 2 nmol of morphine alone results in an increase in withdrawal thresholds comparable to that of the combination of magnesium 375 µg with morphine 0.5 nmol in our study. Therefore, the addition of magnesium allows a comparable analgesic effect to be achieved with approximately a fourfold reduction in opioid dose. This finding may have potential clinical application to reduce opioid-induced side effects while achieving effective analgesia.

Histological evaluations of the spinal cords were not performed in this study; however, behavior and toxicology after larger (at least 3 times) intrathecal bolus doses of magnesium have been examined. A 1260 µg intrathecal dose of magnesium sulfate alone produced spinal analgesia and sedation in rats; however, this effect wore off after several hours, and by the next day, the animals were active and moving freely (18). After the same dose was given as a series of 15 injections on alternate days for one month, there still were no lasting neurological consequences, and the spinal cords showed identical histologic changes in animals receiving saline injections or those with an intrathecal catheter without any injections (19). In dogs, an intrathecal magnesium sulfate injection of 45–60 mg did not produce spinal cord abnormalities on histopathologic examination (20). In a case in which a patient was inadvertently administered 1000 mg of magnesium sulfate intrathecally, there was a motor block for 5 h, then, a complete recovery (21). Therefore, intrathecal magnesium sulfate appears to have a good safety profile, although more studies in large animals would be desirable before clinical trials.

Magnesium salts given IV without opioids do not block neuropathic pain (22), nor do they reduce postoperative pain in patients (23). Clinical reports of reduced postoperative analgesic requirements with the IV infusion of magnesium salts, support our finding of potentiated opioid analgesia by magnesium (1,2), although this effect has not always been seen clinically (24). The mechanism of potentiation seen in some clinical studies is probably a different mechanism than that seen with intrathecal drug administration in this study, because even at large plasma concentrations, only a small amount of the magnesium ion crosses the blood-brain barrier (3,25). Conversely, plasma concentrations, even after continuous intrathecal infusions, are not increased in rats so that the potentiation we observed was a result of magnesium action at the spinal level (6). Therefore, it is likely that magnesium can potentiate opioid analgesic effects by both central and peripheral mechanisms.

In summary, acute bolus dosing of magnesium sulfate potentiates at the spinal level the effect of morphine on antinociception to noxious thermal stimuli and reduction of mechanical allodynia after a surgical incision in rats. These findings suggest that intrathecal magnesium sulfate merits study as an adjunct to neuraxial opioid analgesia.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication December 16, 1999.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press