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Anesth Analg 2002;95:661-666
© 2002 International Anesthesia Research Society

PAIN MEDICINE

Intrathecal Magnesium Prolongs Fentanyl Analgesia: A Prospective, Randomized, Controlled Trial

Asokumar Buvanendran, MD, Robert J. McCarthy, PharmD, Jeffrey S. Kroin, PhD, Warren Leong, MD, Patricia Perry, MD, and Kenneth J. Tuman, MD

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

Address correspondence and reprint requests to Asokumar Buvanendran, MD, Department of Anesthesiology, Rush-Presbyterian-St Luke’s Medical Center, 1653 W Congress Parkway, Chicago, IL 60612. Address e-mail to Asokumar{at}Aol.com


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Magnesium is a noncompetitive, N-methyl-D-aspartate receptor antagonist that does not effectively cross the blood-brain barrier when given IV. Intrathecal magnesium potentiates opioid antinociception in rats, and the safety of intrathecal magnesium has been demonstrated in animals. This is the first prospective human study evaluating whether intrathecal magnesium could prolong spinal opioid analgesia. Fifty-two patients requesting analgesia for labor were randomized to receive either intrathecal fentanyl 25 µg plus saline or fentanyl 25 µg plus magnesium sulfate 50 mg as part of a combined spinal-epidural technique. The duration of analgesia of the intrathecal drug combination was defined by the time of patient request for additional analgesia. There was significant prolongation in the median duration of analgesia (75 min) in the magnesium plus fentanyl group compared with the fentanyl alone group (60 min). There was no associated increase in adverse events in the group that received intrathecal magnesium. Larger doses of intrathecal magnesium were not studied in this group of patients because of the limitations on cephalad spread when hyperbaric solutions are injected in the sitting position. Our data indicate that intrathecal magnesium prolongs spinal opioid analgesia in humans and suggest that the availability of an intrathecal N-methyl-D-aspartate antagonist could be of clinical importance for pain management.

IMPLICATIONS: Magnesium occurs naturally in the spinal cord and blocks the NMDA glutamate channel. In animal studies, intrathecal magnesium sulfate improves spinal morphine analgesia. For patients receiving spinal analgesia for labor, the addition of magnesium sulfate to the opioid fentanyl prolonged analgesia with no increase of side effects.


   Introduction
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 Abstract
 Introduction
Methods
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 Discussion
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The advantages offered by the combined spinal-epidural (CSE) technique make it a popular modality of providing anesthesia and analgesia for patients undergoing surgery below the umbilical level and in laboring parturients (1). However, one of the limitations of the CSE technique is the relatively short duration of analgesia provided by intrathecal (IT) opioids. Combination or single drug therapy that prolongs analgesia would therefore be advantageous in laboring parturients. The most common IT drug used in this setting is fentanyl because it produces rapid, profound analgesia during labor at an optimal dose of approximately 25 µg (2). Diverse classes of drugs, such as local anesthetics (3), epinephrine (4), clonidine (5), and neostigmine (6), have been added to IT opioids in attempts to prolong analgesia and reduce the incidence of adverse events (3) observed when opioids are used alone.

No clinical studies have examined the effect of a N-methyl-D-aspartate (NMDA) receptor antagonist administered intrathecally with opioids. Magnesium blocks NMDA channels in a voltage-dependent fashion, and such NMDA antagonism can prevent the induction of central sensitization from peripheral nociceptive stimulation (7). Administration of IV magnesium sulfate (MAG) during surgery reduces intra- and postoperative opioid requirements (8) in association with improved comfort and better quality of sleep but without increased adverse effects (9). However, IV MAG, even at doses often used for the treatment of preeclampsia, is associated with limited passage across the blood-brain barrier (10). We have previously shown that IT MAG potentiates opioid antinociception in an acute incisional model in rats (11). The suppression of nociceptive responses by IT MAG has also been demonstrated in a rat model of neuropathic pain (12) and its safety profile evaluated, including histopathological analysis (13,14). We therefore conducted a prospective, randomized, controlled clinical trial to determine if IT MAG potentiated spinal opioid analgesia in laboring parturients.


   Methods
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 Abstract
 Introduction
 Methods
Results
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 References
 
After approval of our IRB, 52 ASA physical status I or II patients requesting labor analgesia were randomized into two groups. Allocation of subjects to study groups was made by computer generated random number assignment before the start of the study and sealed in envelopes that were opened just before entry in the study. Parturients with significant coexisting diseases (preeclampsia and hepatorenal diseases), allergy to opioids, and patients who had received any partial opioid agonist or agonist/antagonist in the preceding 6 h or any IV opioid for labor analgesia within 60 min before enrollment were excluded, as were patients who received IV magnesium during obstetrical management. After obtaining written consent, 52 patients were randomized into one of two study groups: 25 µg of fentanyl citrate (0.5 mL) + 3.0 mL of preservative-free 0.9% sodium chloride injection (Group F) or 25 µg of fentanyl citrate (0.5 mL) + 50 mg of MAG (3.0 mL) (Group F + MAG). The 50 mg of MAG was prepared after randomization by withdrawing 3.0 mL from a mixture of 0.35 mL of preservative-free 50% MAG injection (500 mg/mL) with 10 mL of preservative-free sterile water.

Patients received 500–1000 mL of lactated Ringer’s solution IV and were then placed in the sitting position for initiation of the CSE procedure. A 17-gauge Tuohy needle was introduced into the epidural space at the L2-3 or L3-4 vertebral level via a midline approach using the loss of resistance technique. A 27-gauge, 119-mm Whitacre tip spinal needle was placed through the Tuohy needle into the subarachnoid space. After return of clear cerebrospinal fluid (CSF), IT fentanyl was injected followed immediately by either saline or MAG. If clear CSF was not obtained after placement of the spinal needle, the patient was removed from the study, and her group assignment was re-randomized. After the IT injection, the spinal needle was withdrawn, and a 19-gauge, single-orifice, epidural catheter was inserted 3–5 cm into the epidural space and secured. Patients were then repositioned supine with left uterine displacement and slight elevation (15–20 degrees) of the head for the comfort of the parturient. No additional medications were administered until the patient requested further analgesia. At that time, study data collection ended, and catheter position was evaluated with aspiration followed by injection of 3 mL of 1.5% lidocaine containing 1:200,000 epinephrine. An epidural infusion of fentanyl 2 µg/mL, bupivacaine 0.67 mg/mL, and epinephrine 1.3 µg/mL was then initiated and titrated to achieve analgesia.

The following demographic data were recorded for all patients: gestational age, maternal age, height, weight, gravida status, and cervical dilation at the time of initiation of CSE analgesia. An observer blinded to the treatment group performed all postinjection assessments. Visual analog pain scale (VAS) scores (0–10 scale) were recorded 5 min before the IT injection, 5, 10, and 15 min after the injection, and subsequently every 15 min until the patient requested additional analgesia, at which time the VAS score was assessed for the final time.

Pruritus was assessed before the IT injection and 5, 10, 15, 30, and 45 min thereafter. Pruritus was graded as 1 = no pruritus; 2 = pruritus without scratching, and treatment is not required; 3 = pruritus with scratching, and treatment is desirable; 4 = severe pruritus and scratching, and treatment is required; and 5 = intractable pruritus and scratching (15). The upper level of loss of sensation to cold was assessed in the midclavicular line 5, 10, 15, 30, and 45 min after the injection using an alcohol swab bilaterally. The intensity of motor block and somnolence were simultaneously assessed. Motor block was graded as 0 (none) = full flexion of knees and feet; 1 (partial) = just able to move knees; 2 (almost complete) = able to move feet only; and 3 (complete) = unable to move feet or knees. Somnolence was categorized as 1 = fully awake; 2 = somnolent and responds to call; 3 = somnolent and no response to verbal stimulation; and 4 = asleep and responds to only painful stimulation.

Systolic and diastolic blood pressures, together with maternal and fetal heart rates, were recorded from the prenatal chart and 5 min before and 5 and 15 min after the IT drug injection. Systolic blood pressure 20% below baseline (prenatal) or <90 mm Hg was treated with an IV fluid bolus of 500 mL of lactated Ringer’s solution followed by IV ephedrine 5 mg if required. The use of oxytocin for the induction or augmentation of labor was recorded.

The duration of analgesia was recorded as the time from IT injection until the patient’s request for additional analgesia. If the patient complained of persistent pain (VAS score >=7) 10 min after the IT injection, the patient was excluded from the study, epidural analgesia was administered via the catheter, and the patient assignment was re-randomized. The occurrences of unintentional dural puncture and the need for epidural blood patch were recorded. Patients were assessed for the presence of motor or sensory complications on the day after delivery by a blinded observer performing a routine clinical postanesthesia evaluation.

Sample size analysis determined that n = 25 per group was required to detect a 15 min difference in the median duration of analgesia between groups using a Mann-Whitney U-test, with a power of 0.9 and an {alpha} of 0.05. Assumptions for the sample calculation were that the control group (Group F) would have a median duration of 62.5 min (3) with a SD of 25% of the median, the variance would be equal, and there would be uniform distribution in the samples (PASS version 6.0, NCSS, Kaysville, UT). Demographic variables were compared using the Mann-Whitney U-test. VAS scores, motor scores, sedation scores, pruritus scores, and sensory level were evaluated within groups using the Friedman test and the Wilcoxon’s signed rank test and between groups using the Mann-Whitney U-test. Between and within group comparisons were corrected for multiple comparisons using the Bonferroni method. Hemodynamic data were analyzed between groups across time using repeated-measures analysis of variance with post hoc testing performed using Bonferroni-corrected paired t-tests. The log-rank statistic was applied to Kaplan-Meier survival curves for the patients with continued analgesia to compare the duration of analgesia between groups. Data are presented as median (range) unless otherwise specified, and statistical significance required P < 0.05.


   Results
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 Abstract
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 Methods
 Results
Discussion
 References
 
Fifty-two patients were enrolled and 50 patients completed the study protocol (Group F, n = 25; Group F + MAG, n = 25). Two patients were excluded from the study because they delivered before requesting additional analgesia, which confounded the end-points for IT analgesia. No patients were excluded for complaints of persistent pain (VAS score >=7) 10 min after the IT injection. There were no differences in the demographic characteristics between the two groups (Table 1). At the time of the IT drug administration, there was a 32% incidence of oxytocin use in both groups for obstetrical reasons. The incidence of vaginal delivery was 72% and 76%, respectively, for Group F and Group F + MAG. There were no differences in the Apgar scores at delivery between groups.


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  		Table 1. Table 1. Demographic Characteristics
 
The median duration of analgesia after the IT drug administration was significantly longer for Group F + MAG, 75 min (range, 30–140 min), compared with Group F, 60 min (range, 25–133 min). Figure 1 shows the percentage of parturients in each group with continuing pain relief as a function of time. A log-rank test between pairs of curves was significant for Group F + MAG versus Group F ({chi}2 = 4.78; P = 0.0289). There was no difference in the VAS score between the groups 5 min before the initiation of neuroaxial analgesia or at 5 min after receiving the IT medication. The intensity of motor block, sensory levels, sedation scores, and severity of pruritus were similar between groups (Table 2). The incidence of pruritus in Group F + MAG and Group F was 65% and 77%, respectively (P = 0.358).



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  		Figure 1. Kaplan-Meier analysis showing the percentage of patients in each group with continuing pain relief as a function of time. A log-rank test indicated a significant difference between curves (P = 0.029).

 

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  		Table 2. Table 2. Characteristics of Spinal Analgesia
 
The systolic and diastolic blood pressures were significantly higher 5 min before the IT drug administration compared with prenatal values in both groups. Both systolic and diastolic pressures decreased 5 min after the IT drug administration compared with before the IT administration, but there was no difference between the groups. Although there was a decrease in the blood pressure after the IT drug administration in both groups, this was not different from prenatal blood pressure, and no patient required administration of ephedrine or additional fluids. A similar pattern to the blood pressures was observed for the maternal heart rate (Table 3). There was no difference between groups or across time for the fetal heart rates. No patient in either group had any sensory or motor complications identified during routine postanesthesia evaluation on the day after delivery.


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  		Table 3. Table 3. Maternal and Fetal Hemodynamic Data
 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This is the first randomized human study of spinal MAG as an antinociceptive modulator. We have demonstrated that the addition of IT MAG, a noncompetitive NMDA antagonist, to fentanyl prolongs spinal analgesia. The median duration of analgesia when 50 mg of IT MAG was added to 25 µg of fentanyl was prolonged to 75 minutes compared with 60 minutes when 25 µg of fentanyl was used with saline. This longer duration of analgesia was not accompanied by increased adverse events. We reported a median duration of analgesia during labor of 62.5 minutes in a previous study (3) when IT fentanyl plus saline was used under similar clinical conditions. Although the difference of 15 minutes between the study and control group in the current study may have limited clinical impact, we evaluated only a single dose of MAG. The dose of MAG was based on data from a rat model of postoperative pain in which 188 µg of IT MAG potentiated morphine antinociception (11). Based on the relative difference between human and rat CSF volume and body weight, the 188 µg dose was conservatively extrapolated to 50 mg because this is the first randomized study using IT MAG in humans.

Noxious stimulation leads to the release of glutamate and aspartate neurotransmitters, which bind to various subclasses of excitatory amino acid receptors, including the NMDA receptor. Activation of NMDA receptors leads to calcium and sodium influx into the cell with an efflux of potassium and initiation of central sensitization and wind-up (7,16). NMDA receptor signaling may be important in determining the duration and intensity of postoperative pain (7). Selective NMDA receptor antagonists are not available for clinical pain management. However, several compounds approved for use in humans for other indications, such as ketamine and MAG, have significant NMDA receptor-blocking properties (17). Magnesium blocks NMDA channels in a voltage-dependent way (depolarization removes magnesium blockade), and the addition of magnesium produces a dramatic reduction of NMDA-induced currents (18). A limitation to the parenteral application of MAG for modulation of antinociception via NMDA channel antagonism is insufficient blood-brain barrier penetration to achieve effective CSF concentrations. Even when IV MAG is given in large doses (6 g followed by infusion of 2 g/h), no significant amount crosses the blood-brain barrier (10). Although no decrease in postoperative analgesic consumption was observed in a randomized clinical trial using IV MAG (bolus and infusion), the authors did demonstrate an inverse relationship between CSF magnesium concentration and analgesic consumption in the study group (19). This is consistent with animal data that show modulation of spinal analgesia by IT MAG (11–13). Consideration of these factors led us to postulate that IT MAG administration could potentiate opioid spinal analgesia and avoid the potential side effects of the larger doses of IV MAG that may be required to observe antinociceptive modulation in humans.

The safety of IT MAG administration has been evaluated in animal studies. In rats, a 1.26 mg IT bolus of MAG given on alternate days over a 30 day period produced transient motor and sensory block similar to lidocaine with no adverse clinical consequences. In addition, histological examination of the spinal cord showed identical findings to those of animals receiving saline, lidocaine, or no injections via implanted IT catheters (13). In a randomized, controlled canine study, IT MAG at a dose of 3 mg/kg was administered before aortic cross-clamping. The dogs were assessed after surgery for neurological deficits followed by histopathological examination of the spinal cord. None of the dogs (n = 8) that received IT MAG (45–60 mg) had neurological deficits (assessed by Tarlov’s scale) or changes in cord histopathology compared with seven of eight control dogs that exhibited adverse neurological outcome and an ischemic-injury pattern on histopathological examination (14). If the 45–60 mg IT MAG dose that is protective of the spinal cord in dogs were extrapolated by comparing the relative CSF volumes (approximately 12 mL versus 120 mL), this would represent a 450–650 mg dose in humans. Comparatively, the 50 mg IT MAG dose used in this study represents 10% of a dose shown to be nontoxic in dogs.

Clinical experience with IT MAG administration is sparse. In 1906, Haubold and Meltzer (20) showed that 1000–2000 mg of IT MAG produced spinal anesthesia that included profound motor and sensory block associated with transient sedation but without any permanent untoward effects. More recently, Lejuste (21) described an inadvertent IT injection of 1000 mg of MAG that produced a dense motor block followed by a complete resolution within 90 minutes and no neurological deficit at long-term follow-up.

This study is limited by the absence of a dose-response evaluation of IT MAG. The ability to evaluate such a dose-response was constrained by our practice of performing the CSE procedure in the sitting position and the known baricity dependence of IT drug spread in this position (22). Measured by refractometry, both solutions in Group F + MAG (50 mg in 3 mL sterile water) and Group F (in saline) have similar density and are slightly hypobaric compared with CSF (although F + MAG has lower osmolality than the F). However, our previous experience indicates that F + MAG (100 mg) is hyperbaric compared with CSF and would limit cephalad spread and diminish the usefulness of IT MAG when injected in the sitting position for labor analgesia (23). Further investigation will be required to determine if larger (and more hyperbaric) doses of IT MAG produce greater potentiation of spinal analgesia when administered in the lateral position or when applied in other clinical scenarios. In addition, future study will be required to determine whether similar analgesic efficacy can be achieved with smaller doses of spinal opioid.

In conclusion, we have demonstrated that the noncompetitive NMDA antagonist MAG, intrathecally administered, prolongs the duration of spinal opioid analgesia in humans. Further studies are required to determine if larger doses of IT MAG can produce greater potentiation of analgesia or reduce opioid requirements.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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  13. Chanimov M, Cohen ML, Grinspun Y, et al. Neurotoxicity after spinal anaesthesia induced by serial intrathecal injections of magnesium sulphate: an experimental study in a rat model. Anaesthesia 1997; 52: 223–8.[ISI][Medline]
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Accepted for publication May 13, 2002.




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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