A Phase I trial of naloxone treatment in acute spinal cord injury

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1 J Neurosurg 3: , 1985 A Phase I trial of naloxone treatment in acute spinal cord injury EUGENE S. FLAMM, M.D., WISE YOUNG, PH.D., M.D., WILLIAM F. COLLINS, M.D., JOSEPH PIEPMEIER, M.D., Gu~ L. CLIFTON, M.D., AND BOGUSLAV FISCHER~ M.D. Departments of Neurosurgery and Neurology, New York University Medical Center, New York, New York; Section of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut; and Department of Neurosurgery, Baylor College of Medicine, Houston, Texas Results of a Phase I trial of the opiate antagonist naloxone for treatment of patients with acute spinal cord injury are reported. Naloxone was administered in doses ranging from 5 to 200 mg/sq m (0.14 to 5.4 mg/kg) for up to 48 hours. The patients ranged in age from 1 to 79 years (mean 37 years). Twenty patients received naloxone as a loading dose of 5 to 50 mg/sq m (0.14 to 1.43 mg/kg), followed by a maintenance dose of 20% of the loading dose given as a continuous infusion hourly for 47 hours (Group 1). Nine patients received a loading dose of 100 to 200 mg/sq m (2.7 to 5.4 mg/kg) and a maintenance dose of 75% of the initial dose hourly for 23 hours (Group 2). These higher doses (2.7 to 5.4 mg/kg) have been found to be effective in experimental spinal cord injury. Neurological examinations were performed and somatosensory evoked potentials (SEP's) were obtained as soon after admission as possible and again 1, 2, 3, and 7 days, 3 weeks, and weeks to months after admission. The 20 Group 1 patients who received 1.43 mg/kg or less of naloxone showed no improvement in neurological status or SEP's. All but three (l 5%) of these patients had a neurological deficit at the time of admission. Treatment was begun an average of 12.9 hours after injury. Among the nine Group 2 patients treated with 2.7 mg/kg or more, there were five patients (5%) with in deficits. This group received naloxone an average of. hours after admission. Two of the five Group 2 patients with in lesions showed improvement in their neurological condition and/or SEP's within 3 hours of receiving the drug. One of the four Group 2 patients with a lesion at the time of admission was able to localize pressure sensation in his legs 3 hours after completion of the drug infusion. Four Group 2 patients (two with and two with in lesions) have shown improvement in their SEP's, suggesting recovery of SEP's in a dose-related fashion. Four patients experienced increased pain after administration of the loading dose and during the maintenance infusion; in only one patient was this severe enough to require discontinuation of the drug. Of the 29 patients treated with naloxone, four died within weeks of admission, for a mortality rate of 13.8%. This study demonstrates that, in spinal cord-injured patients, naloxone given as an intravenous loading dose of 200 mg/sq m, followed by a continuous infusion of up to 150 mg/sq m/hr for 23 hours, has minimal side effects. The observed improvement in the clinical examination and SEP's at the higher doses, while not statistically verified in this Phase I trial, is encouraging. KEY WORDS - spinal cord injury 9 naloxone 9 Phase I trial A MAJOR impetus in acute spinal cord injury research has been the hypothesis that mechanical trauma initiates secondary and progressive injury processes in the spinal cord. This has created the hope that the injured spinal cord is amenable to treatment administered shortly after trauma. To test this hypothesis, experimental models of spinal cord injury have been used to assess treatments aimed at reducing the secondary damage. From those experiments, two drugs have recently been identified as useful: methylprednisolone 1'4-8'19-2j'2,31 and naloxone) 3-~5A8'25,32 Both drugs, given in high doses shortly after trauma, have been found by several laboratories significantly to improve functional recovery, blood flow, metabolic function, and biochemical measures of membrane damage in injured spinal cords. Naloxone, an opiate receptor blocker, is one of the most promising pharmacological therapies to be stud- 390 J. Neurosurg. / Volume 3/September, 1985

2 Naloxone trial for spinal cord injury therapy ied recently in experimental models of spinal cord injury '18'25'32 Two independent laboratories have reported that naloxone, given in large doses (2 to 10 mg/ kg), improves functional recovery and spinal blood flow in cats. ~3-~5'~s'3~ The dose required is much greater than that necessary to reverse opiate actions in humans. Naloxone is an attractive candidate for clinical trial because of its low toxicity. Relatively high doses (4 mg/ kg) have been given to normal adults with no demonstrable side effects that would contraindicate its use in patients with acute spinal cord injury. 9'1~ Because of the encouraging results observed following naloxone treatment of experimental spinal cord injury, a Phase I trial of naloxone in patients with acute spinal cord injury was undertaken at New York, Yale, and Baylor Universities. Twenty-nine patients with acute spinal cord injury were treated with naloxone in doses ranging from 5 to 200 mg/sq m (0.14 to 5.4 mg/kg), followed by a continuous infusion for up to 48 hours. These patients underwent repeated neurological examinations and measurement of somatosensory evoked potentials (SEP's). This trial is preparatory to a randomized clinical trial, a continuation of the National Acute Spinal Cord Injury Study (NASCIS), 4 which will compare naloxone, methylprednisolone, and a placebo. Summary of Cases Clinical Material and Methods The 29 patients in this study ranged in age from 1 to 79 years (mean age 37 years). There were four females and 25 males. The majority of the patients had suffered severe spinal cord injuries and had no neurological function, either sensory or motor, below the level of the lesion at the time of admission. Five of the patients had sustained gunshot injuries. The other patients had been injured in falls or athletic or motor-vehicle accidents. One patient had a dislocated hip; the others had no significant injuries to any organ system other than the spinal cord. The naloxone trial was divided into two stages. In the first stage, 20 patients received doses ranging from approximately 5 to 50 mg/sq m of body surface, roughly equivalent to 0.14 to 1.43 mg/kg (Group 1). This is below the level found to be effective in experimental spinal cord injury. All patients in the first stage were studied at the New York University-Bellevue Spinal Cord Injury Center. In the second stage of the study, nine patients received naloxone in doses ranging from 100 to 200 mg/sq m of body surface, or about 2.7 to 5.4 mg/kg (Group 2). These patients were studied at New York, Baylor, and Yale Universities. All patients gave informed consent for these studies. Naloxone Protocol Naloxone was obtained as naloxone hydrochloride in ampules containing 10 mg/ml without any paraben preservatives. Altogether, 29 patients were treated in the two stages, the first to ascertain the effects of esca- TABLE 1 Summary of treatment in patients receiving O. 14 to 1.43 mg/kg naloxone (Group 1) Infusion Case Injury Extent Loading Dose Time No. Level of Injury* (mg/kg) Postinjury (hrs) 1 C C T C- C z~ C- C-7 in C C C I z~ 12 C-5 C C- C t T t T ~ C t 19 T- 12 C-7 in z~ C-5 in * Complete deficit: no motor or sensory function below lesion level; in deficit: some motor and/or sensory function below lesion level. t Deficit due to a gunshot wound. z~ Patient died within weeks of admission. lating doses of naloxone and the second to assess the effects of higher doses that were within the range found to be effective in animal studies. In the first stage, naloxone was given to 20 patients (Group 1) in an escalating dosage protocol in which loading doses ranging from 5 to 50 mg/sq m (0.14 to 1.43 mg/kg) were administered (Table 1). A continuous maintenance infusion at a dose of 20% of the loading dose/hr was then given for 47 hours according to the schedule outlined in Table 2. The loading dose was administered over a 10- to 15-minute period while the electrocardiographic records and blood pressure were monitored. TABLE 2 Dosage schedule in patients receiving 0.14 to 1.43 mg/kg naloxone (Group 1) Loading Dose Mainte- Total nance Dose No. of Dose Cases mg/sq m mg/kg mg/70 kg (mg/sq m)* (mg/70 kg) * The maintenance dose in the 20 patients in Group 1 was 20% of the loading dose/hr infused continuously for 47 hours. J. Neurosurg. / Volume 3/September,

3 E. S. Flamm, et al. TABLE 3 Summary of treatmenl in patients receiving 2.7 to 5.4 mg/kg naloxone (Group 2) TABLE 4 Dosage schedule in patients receiving 2.7 to 5.4 mg/kg naloxone (Group 2) Loading Infusion Mainte- Case Injury Extent Dose Time Loading Dose nance Total Dose No. of No. Level of Injury* (mg/kg) Postinjury (hrs) mg/sq m mg/kg mg/70 kg (mg/sq Dose m)* (mg/70 kg) Cases 21 t 22 T- T- 12 in in C t T T- 12 in C- C- in T- 11 C-5 in * Complete deficit: no motor or sensory function below lesion level; in deficit: some motor and/or sensory function below lesion level. t Deficit due to a gunshot wound. In the second stage of the study, the dose of naloxone was raised in nine patients (Group 2) to the range found to be effective in experimental spinal cord injury ~3-~5''8'32 (Table 3). The protocol is summarized in Table 4. In this stage, the loading and maintenance doses were increased while the treatment period was shortened to 24 hours. The loading dose ranged from 100 to 200 mg/sq m (2.7 to 5.4 mg/kg), and the maintenance dose was increased to 75% of the initial dose/hr for continuous infusion over 23 hours. Four patients were studied at New York, three at Baylor, and two at Yale Universities. Somatosensory Evoked Potential Measurement In the patients studied at New York University, SEP's were obtained on the day of admission and 1, 2, 3, and 7 days, 3 weeks, and weeks to months after admission (see Table 5). Three SEP averages were obtained from stimulation of a nerve in each limb: fight median, left median, right posterior tibialis, left posterior tibialis, and simultaneous bilateral posterior tibialis. The nerves were stimulated with bipolar constant-current pulses delivered with abraded metal disc electrodes securely fastened to skin sites overlying appropriate nerves. The stimulus parameters were 0.1-msec duration and 10- to 15-mA constant current adjusted to twice motor threshold, delivered at 2.3 Hz. All patients were studied in the supine position and instructed to relax as much as possible. Platinum electroencephalographic scalp electrodes were used to record differential potentials from the contralateral scalp overlying Fz (frontal midline) and Cz (vertex) for posterior tibialis evoked potentials and Fz versus C-3 for median nerve evoked potentials. The SEP's were averaged on a Tracor 3000 clinical evoked potential system* and a two-channel averager * Tracor 3000 clinical evoked potential system manufactured by Tracor Northern, Madison, Wisconsin * The maintenance dose in the nine patients in Group 2 was 75% of the loading dose/hr infused continuously for 23 hours. with a single-channel constant-current stimulator. Data were stored on floppy disks. Amplifier filters were set to 10 to 25 Hz (-3 db rolloff). These filter settings were carefully determined through a systematic comparison of SEP traces over the entire frequency range in 20 spinal cord-injured patients, using reproducibility and size of the cortical responses as the primary criteria for choice of filter settings. Sweep windows of 100 to 200 msec were used, 100 msec for median nerve and 200 msec for posterior tibialis SEWs. Amplifier sensitivity was set at 50 #V full-scale (with potentials greater than 80% of this value being rejected from the averaging). Sampling rate was 512 points per sweep with 200 repetitions per average. Triplicate averages were obtained from each limb, alongside a "no-stimulus" average. Peak-to-peak amplitudes of the first 50 or 100 msec of each trace were measured for the median and posterior tibialis SEP's, respectively. Latencies of the first negative and first positive waves, for both the median and posterior tibialis nerves, were noted. In addition, the SEP's were subjectively scored on a 0- to 5-point scale in which 0 is no response, 1 represents a questionable response (that is, a response appears to be present but the peak-to-peak amplitude is just above the noise level of the control no-stimulus traces), 2 is a definite but small response, 3 indicates a response that is abnormal in waveform or latency, and 4 is a normal response. A score of 5 was assigned when an SEP was larger than normal. This occurred only occasionally, in response to median nerve stimulation in patients with thoracic injuries. These scores were assigned by impartial observers unaware of the clinical findings in the patients. It has been shown previously that a similar scoring system predicted neurological function with a high degree of correlation. 3~ The scores from the three sets of lower-limb SEP's (that is, right, left, and bilateral posterior tibialis SEP's) were added to give a maximum of 12. The change in score was obtained by subtracting the scores on admission from those at follow-up examination. Neurological Examination Detailed neurological examinations were carried out on admission. At New York University, an independent 392 J. Neurosurg. / Volume 3 / September. 1985

4 Naloxone trial for spinal cord injury therapy TABLE 5 SEP scores in 20 Group 1 and 2 patients studied at New York University Somatosensory Evoked Potential (SEP) Score~ Leg Case Injury Extent of Naloxone Wks- Score No. Level Injury* (hrs)t Day 0 1 Day 2 Days 3 Days 1 Wk 3 Wks Mos Changew Group l: 0.14 mg/kg 2 C T mg/kg 5 C mg/kg 7 C C C C died mean score(~ 0.14 to ~ 0.42mg/kg): mg/kg I l C died 0 12 C C C T mean score (0.71 mg/kg): mg/kg 1 T C died 0 18 T C-7 in mean score (1.43 mg/kg): +1.5 Group 2: 2.7 mg/kg 23 C mg/kg 25 T- 12 in mg/kg 28 T- 1 l in C t l I +2 mean score (_> 2.7 to -< 5.4 mg/kg): +4.5 * Complete: no motor or sensory function below lesion level; in: some motor and/or sensory function below lesion level. t Indicates time after injury that treatment began. SEP scores are listed from left to fight in each column for the fight median, left median, right posterior tibialis, left posterior tibialis, and bilateral posterior tibialis nerves. Scoring was according to the following system: 0 = no response; 1 = a questionable response (that is, a response appears to be present but the peak-to-peak amplitude is just above the noise level of the control no-stimulus traces); 2 = a definite but small response; 3 = a response abnormal in waveform or latency; 4 = a normal response; and 5 = a larger than normal SEP. Scores in the legs were added for a maximum total of 12. w Change in score was obtained by subtracting the admission score from the follow-up score. examination was carried out by one of us (B.F.), according to a protocol developed for NASCIS. 4 Fourteen muscles on each side were graded from 0 (no voluntary movement) to 5 (normal strength). Muscles on each side were scored independently. A normal examination received a score of 70 for both upper extremities, 70 for both lower extremities, and 20 for abdominal muscles, for a total of 10. Touch and pinprick response, position sense, and deep muscle perception, together with sphincter function and reflexes, were also noted. Other Tests In addition to sequential neurological examinations, measurement of SEP's, and delivery of routine care, the patients' vital signs were recorded every 15 minutes for the 1st hour after drug administration and hourly thereafter. The vital signs included blood pressure and heart and respiratory rates. It was considered particularly important to monitor these signs in light of the reports by Cohen, eta/., 9"~~ that blood pressure and respiratory rates changed in normal volunteers who were given 4 mg/kg of naloxone. Electrocardiograms were obtained several times during the treatment period. A battery of blood tests, including liver chemistries, electrolytes, blood urea nitrogen, creatinine, prothrombin time, partial prothrombin time, and blood cell counts, was obtained daily for the first 3 days after treatment and at weekly intervals thereafter. Results The 20 Group 1 patients who received 50 mg/sq m (1.43 mg/kg) or less of naloxone showed no improvement in neurological status or SEP's (Table 5). All but J. Neurosurg. / Volume 3 / September,

5 E. S. Flamm, et al. TABLE Changes in vital signs in patients receiving naloxone* Vital Before After Naloxone Sign Naloxone 1 Hr Hrs 24 Hrs blood pressure systolic diastolic heart rate _ _ _ respiration rate 20 _ _ * Values are means + standard deviations for 29 patients. three (15 %) of these patients had a neurological deficit at the time of admission. Treatment was begun an average of 12.9 hours after injury (range 2 to 48 hours). Since these doses were below those found to be effective in experimental spinal cord injury, an improvement in neurological recovery or in SEP's was neither expected nor observed Among the nine Group 2 patients treated with 100 to 200 mg/sq m (2.7 to 5.4 mg/kg), five patients (5%) had in deficits at the time of admission. This group of patients received naloxone an average of. hours after admission (range 2 to 1 hours). Two of the five Group 2 patients with in lesions showed improvement in either neurological status and/or SEP's within 3 hours after receiving the drug. One patient (Case 22) showed some improvement in motor strength from 4/5 to 5/5 in the right leg and from 2/5 to 3/5 in the left leg after completion of naloxone infusion; sensation was normal before and after naloxone administration. Another patient (Case 23), who had a C- lesion at the time of admission, was able to localize pressure sensation in his legs 3 hours after completion of the naloxone infusion. His motor score on admission was 18 out of a possible 10, with a score of 0 in the lower extremities. Six months after admission he was able to stand and had a score of 50/70 in the upper extremities, 3/70 in the lower extremities, and 10/20 in the abdominal muscles, for a total of 9/10. The most recent examination performed 10 months after injury and treatment revealed scores of 47/70 and 48/ 70 in the upper and lower extremities, respectively, and 10/20 in the abdominal muscles, for a total score of 105/10. He is currently able to stand and walk with the support of a walker. In one patient with an in injury at T-12 (Case 25), strength improved in both legs by 3 weeks after naloxone infusion. Eight months after injury and treatment, his lower-extremity motor score had improved from 19/70 to 34/70, and he was able to ambulate with a walker. Another patient (Case 28), admitted with a T-11 injury, had no motor function in the lower extremities but some sensation remained in the sacral area. By 19 weeks after injury and treatment she was able to stand and walk with assistance, and sensation in the lower extremities had returned. Examination at that time revealed a motor score of 32/70 in the lower extremities. These three FIG. 1. Scatter plot of the changes in posterior tibialis somatosensory evoked potential (SEP) scores between admission and the -week follow-up examination as a function of the naloxone loading dose. The SEP's were scored on a scale of 0 to 5 for the right, left, and bilateral posterior tibialis SEP's (see text). Scores in the legs were added together for a maximum total of 12. Change in score was obtained by subtracting the admission score from the follow-up score. Mean scores for each dosage category are given within the angular brackets. The black circles indicate patients admitted with lesions; open circles represent patients admitted with in lesions. patients (Cases 23, 25, and 28) showed improved SEP's to 8 weeks after admission. The changes in the SEP scores from admission to the -week follow-up examination for the 20 patients studied are plotted in Fig. 1. Of the eight patients who received 1.43 mg/kg or more of naloxone, five had and three had in lesions at the time of admission. Although the numbers in each group are small, and not all patients had lesions, there is a suggestion of improved recovery of SEP's in a doserelated fashion; however, the difference was not statistically significant. Four patients experienced increased pain after administration of the loading dose and during the maintenance infusion. In Case 21 this was controlled with diazepam. In Case 25, pain was tolerated during the 24 hours that he received naloxone. One patient (Case 2) had a dislocated hip and could not endure the maintenance naloxone infusion. His pain increased after the loading dose, and only 1 hour of the maintenance dose could be given. Concurrent with his pain, an increase in blood pressure from 120 to 180 systolic was observed. In Case 27, the patient reported pain, but he was able to tolerate it during the course of treatment. Significant changes in vital signs were not observed in any of the other patients who received naloxone. This is in agreement with other reports in the literature. 9'1~ Changes in vital signs are summarized in Table. There were no changes in blood glucose that were 394 J. Neurosurg. / Volume 3/September, 1985

6 Naloxone trial for spinal cord injury therapy not commensurate with the intravenous glucose that the patients were receiving. Electrolytes, prothrombin time, partial prothrombin time, and creatinine levels showed no change. Three patients had an elevated serum glutamic-oxaloacetic transaminase (SGOT) level 1 day after admission, which returned to normal within 1 week. Another patient with a history of cirrhosis had an elevated amylase level 1 month after receiving naloxone. Samples of blood have been drawn in this patient for determination of blood levels of naloxone, and are being analyzed. Of the 29 patients treated with naloxone, four (Cases 7, 11, 17, and 20) died within weeks of admission, for a mortality rate of 13.8%. One (Case 7) died of a pulmonary embolus 22 days following treatment, after having been transferred to a rehabilitation institution; another (Case 1 l) died of respiratory complications 1 month after treatment; the other two patients (Cases 17 and 20) also died of pulmonary complications that were present before naloxone was administered. Discussion The purpose of this study was to determine the safety and feasibility of giving very high doses of naloxone to patients with acute spinal cord injury. In particular, we hoped to resolve several issues with this study. First, it was our objective to rule out major adverse effects of naloxone which might result in increased mortality or deterioration in neurological function. Second, we were concerned about the results of Cohen, et al., 9"~~ who reported increases in blood pressure and respiratory rate in normal volunteers given naloxone in doses up to 4 mg/kg. Although these increases were on the order of 10% and therefore not of clinical significance, we were worried that the unstable respiratory and blood pressure status of some acutely injured patients, particularly those with cervical spinal cord lesions, might be adversely affected by high doses of naloxone. Third, since naloxone blocks the opiate receptors and might enhance existing pain, it was important to ascertain whether naloxone aggravated or even produced pain in patients with acute spinal cord injury. The mortality rate of 13.8% observed in this small series is comparable to that in other series of patients with acute spinal cord injury. 4 In a case-by-case assessment of the causes of death in our patients, we found no complications attributable to naloxone. For example, one patient (Case 7) had been doing well enough to be transferred to the rehabilitation medicine service where she died from a pulmonary embolus 3 weeks after receiving naloxone. The other three patients (Cases 11, 17, and 20) all had relatively high cervical injuries with some evidence of respiratory compromise before treatment was initiated. There were no deaths among patients receiving higher doses of naloxone (100 to 200 mg/sq m, or 2.7 to 4.7 mg/kg). There were no noteworthy changes in blood studies which could not be attributed to other causes. For example, although elevated SGOT levels were observed in three patients, an increased level in patients sustaining significant trauma to muscles is not surprising. These elevations subsided within 1 week. Such rises in these enzymes were nonspecific and were not distributed in a dose-related manner. One patient had an elevated amylase level 1 month after treatment. He had a history of cirrhosis, and the increase in the amylase level was considered too delayed to be due to acute naloxone effects. No significant changes in vital signs were observed during the treatment period in any of the patients with the exception of one (Case 2), in whom the blood pressure rose, presumably due to pain and stress. Thus, the blood pressure and respiratory response of patients with spinal cord injury were similar to those of normal volunteers. 9"l~ There are several reports in the literature of adverse effects in patients treated with small amounts of naloxone. These include hypertension, 3 pulmonary edema, ~7"29 ventricular arrhythmias, 2v and cardiac arrest. 2 These events all occurred in the setting of general anesthesia and following administration of 0.2 to 0.8 mg of naloxone. In each case, other factors in addition to naloxone could have contributed to the complications. Cohen, et al., 9"~~ noted temporary decreases in memory performance and changes in mood following the administration of a single 4-mg/kg dose of naloxone to normal volunteers? These tests were not carried out in our patients; however, no behavioral changes were observed that were not attributable to their general condition in the acute phase of spinal cord injury. With the exception of the increased awareness of pain in four patients (Cases 21, 25, 2, and 27), we did not encounter any difficulties in the patients' ability to tolerate large doses of naloxone. Three of the four patients who reported pain during the time they received naloxone had in lesions of the spinal cord. In only one (Case 2) was the pain severe enough to require discontinuation of treatment. This patient had an in spinal cord injury and a dislocated hip. His pain increased after the loading dose, and only 1 hour of maintenance infusion could be given. Concurrent with his pain, an increase in systolic blood pressure was observed, from 120 to 180 mm Hg. In the other three patients, pain was adequately controlled with mild tranquilizers, such as diazepam, and with non-narcotic analgesics. Although pain was not a major problem in this trial, it will have to be carefully monitored. Our data may suggest that we are approaching the upper limit of tolerance for naloxone, particularly in patients with partial lesions. The incidence of pain may not be so much a result of the naloxone treatment as due to the restriction of narcotic analgesics. The small number of patients who suffered pain in this trial is in accord with our general experience that only a very small minority of patients with acute spinal cord injury require narcotic analgesics. Analysis of SEP's obtained from the patients treated J. Neurosurg. / Volume 3/September,

7 E. S. Flamm, et al. with the higher doses of naloxone suggests a trend toward greater recovery of evoked potentials over a period of weeks to months after injury (Table 5). Figure 1 correlates the mean improvement in SEP scores with the naloxone dose. It should be noted, however, that the groups are not comparable and that there were more in lesions among patients receiving more than 1.43 mg/kg (Group 2) than in the lower-dose group. Despite this, we believe that naloxone treatment is not detrimental to neurological recovery in these patients. The doses of naloxone used in animal studies (2 to 10 mg/kg) are several orders of magnitude greater than the dose required to block morphine action. Less than 2 mg/kg was consistently ineffective in experimental spinal cord injury. All the laboratory data suggest an optimum dose exceeding the amount of naloxone needed to saturate the mu receptorsfl 8 Faden, et al.,~ 1,12.14 have hypothesized that the beneficial effect of naloxone in spinal cord injury is related to its blockade of kappa receptors, a class of opiate receptors that naloxone does not antagonize as powerfully as it does mu receptorsfl 3'33 This may explain why such high doses of naloxone are needed in spinal cord injury. Direct evidence supporting the hypothesis of Faden, et al, is lacking, however. The separate function of kappa receptors, defined by pharmacological binding of ketocyclazocine, 24 is still debated. 1'22'33 Specific antagonists of kappa receptors are not yet available for clinical use. Meanwhile, naloxone has been shown to be effective in animals; it is one of the most specific opiate receptor antagonists known, and it has a short half-life, allowing it to be withdrawn rapidly should complications arise. The suggested improvement in clinical examination and SEP's in our current study is encouraging, but these results do not necessarily imply a direct effect of naloxone on the injured cord. They do, nevertheless, emphasize the need for a randomized clinical trial of this drug. In the present series, administration of high doses of naloxone to patients with acute spinal cord injury did not cause any deterioration of their neurological status, nor were any significant adverse reactions or deaths attributable to the medication. Since no major complications have occurred, we have proposed the highest dose of naloxone (5.4 mg/kg, or 200 mg/sq m) for use in one arm of a randomized clinical trial, a logical extension of this Phase I study; in the proposed trial, this drug will be coupled with methylprednisolone (30 mg/kg, or 1100 mg/sq m) and a placebo. Such a study will test two of the most promising agents to have emerged from recent experimental research. Acknowledgments The authors wish to thank Donna Whittam, R.N., for her assistance as Clinical Coordinator of the Spinal Cord Injury Center at New York University. Naloxone was generously supplied by E. I. Du Pont de Nemours & Co., Wilmington, Delaware. References 1. Anderson DK, Means ED, Waters TR, et al: Microvascular perfusion and metabolism in injured spinal cord after methylprednisolone treatment. J Neurosurg 5: , Andree RA: Sudden death following naloxone administration. Anesth Analg (Cleve) 59: , Azar I, Turndorf H: Severe hypertension and multiple atrial premature contractions following naloxone administration. Anesth Analg (Cleve) 58: , Bracken MB, Collins WF, Freeman DF, et al: Efficacy of methylprednisolone in acute spinal cord injury. JAMA 251:45-52, Braughler JM, Hall ED: Acute enhancement of spinal cord synaptosomal (Na + + K+)-ATPase activity in cats following intravenous methylprednisolone. Brain Res 219:44-49, Braughler JM, Hall ED: Correlation of methylprednisolone levels in cat spinal cord with its effects of (Na + K lipid peroxidation, and alpha motor neuron function. J Neurosurg 5: , Braughler JM, Hall ED: Lactate and pyruvate metabolism in injured cat spinal cord before and after a single large intravenous dose of methylprednisolone. J Neurosurg 59: 25-21, Braughler JM, Hall ED: Uptake and elimination ofmethylprednisolone from contused cat spinal cord following intravenous injection of the sodium succinate ester. 3 Neorosurg 58: , Cohen MR, Cohen RM, Pickar D, et al: High-dose naloxone infusions in normals. Dose-dependent behavioral, hormonal, and physiological responses. Arch Gen Psychiatry 40:13-19, Cohen MR, Cohen RM, Pickar D, et al: Physiological effects of high dose naloxone administration in normal adults. Life Sci 30: , Faden AI: Opiate antagonists and thyrotropin-releasing hormone. I. Potential role in the treatment of shock. JAMA 252: , Faden AI: Opiate antagonists and thyrotropin-releasing hormone. II. Potential role in the treatment of central nervous system injury. JAMA 252: , Faden AI, Jacobs TP, Holaday JW: Opiate antagonist improves neurologic recovery after spinal injury. Science 211: , Faden AI, Jacobs TP, Mougey E, et al: Endorphins in experimental spinal injury: therapeutic effect of naloxone. Ann Neorol 10:32-332, Faden AI, Jacobs TP, Smith MT, et al: Comparison of thyrotropin-releasing hormone (TRH), naloxone, and dexamethasone treatments in experimental spinal injury. Neurology 33:73-78, Fishman J, Hahn EF, Norton BI: Comparative in vivo distribution of opiate agonists and antagonists by means of double isotope techniques. Life Sei 17: , Flacke JW, Flacke WE, Williams GD: Acute pulmonary edema following naloxone reversal of high-dose morphine anesthesia. Anesthesiology 47:37-378, Flamm ES, Young W, Demopoulos HB, et al: Experimental spinal cord injury: treatment with naloxone. 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8 Naloxone trial for spinal cord injury therapy (Na + K+)-ATPase activity. Dose-response analysis during I st hour after contusion in the cat. J Neurosurg 57: , Hall ED, Braughler JM: Glucocorticoid mechanisms in acute spinal cord injury: a review and therapeutic rationale. Surg Neurol 18: , Hiller JM, Simon EJ: Specific, high affinity [3H]ethylketocyclazocine binding in rat central nervous system: lack of evidence for r receptors. J Pharraacol Exp Ther 214:51-519, Kosterlitz HW, Leslie FM: Comparison of the receptor binding characteristics of opiate antagonists interacting with ~t- or ~-receptors. Br J Pharmaeo14:07-14, Martin WR, Eades CG, Thompson JA, et al: The effects of morphine- and nalorphine-like drugs in the nondependent and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther 197: , McNicholas LF, Martin WR: New and experimental therapeutic roles for naloxone and related opioid antagonists. Drugs 27:81-93, Means ED, Anderson DK, Waters TR, et al: Effect of methylprednisolone in compression trauma to the feline spinal cord. J Neurosurg 55: , Michaelis LL, Hickey PR, Clark TA, et al: Ventricular irritability associated with the use of naloxone hydrochloride. Two case reports and laboratory assessment of the effect of the drug on cardiac excitability. Ann Thorac Surg 18:08-14, Snyder SH: Opiate receptors and internal opiates. Sci Am 23(3):44-5, Taft RH: Pulmonary edema following naloxone administration in a patient without heart disease. Anesthesiology 59:57-577, Young W: Correlation of somatosensory evoked potentials and neurological findings in spinal cord, in Tator CH (ed): Early Management of Acute Spinal Cord Injury. New York: Raven Press, 1982, pp Young W, Flamm ES: Effect of high-dose corticosteroid therapy on blood flow, evoked potentials, and extracellular calcium in experimental spinal injury. J Neurosurg 57:7-73, Young W, Flamm ES, Demopoulos HB, et al: Effect of naloxone on posttraumatic ischemia in experimental spinal contusion. J Neurosurg 55: , Zukin RS, Zukin SR: The case for multiple opiate receptors. Trends Neurosci 7:10-14, 1984 Manuscript received February 19, This study was supported in part by Grants NS 1014 and NS from the National Institute of Neurological and Communicative Disorders and Stroke. Address reprint requests to: Eugene S. Flamm, M.D., Department of Neurosurgery, New York University Medical Center, 550 First Avenue, New York, New York J. Neurosurg. / Volume 3/September,