The Effects of Methylprednisolone and Naloxone on Spinal Cord Injuries: A Review
Jason Fuller, Megan Lynch, Laurie Olnes, and Dinh Trinh
Writer’s comment: The main goal of this assignment was to teach us to work with one another to make a collaborative review of current research in a chosen health-related field. We were complete strangers at the time of our group’s formation, but not so after the hours of researching and editing required to complete this review. Laurie first came up with the topic of researching new ways to help spinal cord injury victims because of a class she was taking; the rest of us were also interested in her suggested topic, so we decided to form our group.
We first began our group paper individually by each reviewing and summarizing a research article. Then as a group, we decided which parts of the summaries were appropriate for the collaborative paper. The hard part was left at this point: editing. The four of us crammed in front of a single computer for hours to change words, restructure sentences, and alter tenses. Basically, we had to make the paper coherent.
After we finished, we were all satisfied with the result and we realized that group writing was not so difficult.
—Jason Fuller, Megan Lynch, Laurie Olnes, and Dinh Trinh
Instructor’s comment: Jason, Megan, Laurie, and Dinh wrote this paper for a section of English 102 designed for students in the health sciences. It is a scientific review article, which they researched, proposed, wrote, and revised as a team (and for which they all received the same grade). This is a very “real world” assignment in that most medical research is collaborative. But real reviews are generally exhaustive, covering many more articles; I arbitrarily asked the students to review no more than seven and to write for their fellow students. The assignment challenges the students to find a topic suitable for such a narrow review, to work together productively, to read the original research critically, and to synthesize this research in a carefully structured article giving a clear picture of the current state of knowledge about the topic. These writers were very smart about finding a topic: they followed their interests and they talked with a professor. But their real accomplishment—aside from very successful group work—is the argument structure of their paper. This review is a very reader-oriented assessment of treatment alternatives for spinal cord injuries.
—Susan Palo, Campus Writing Center
INTRODUCTION
A primary goal of health care is to reverse any damage done to the human body; however, because neither the spinal cord nor the spinal nerves can regenerate once damaged, reversing serious spinal cord injury, at this time, seems impossible. Over the last twenty years, the longevity of spinal cord patients has increased due to advances in nursing and rehabilitational care; nevertheless, there have not been significant advances in aiding neurological recovery (1).
Although at the cellular level acute spinal cord injury appears to be irreversible, there have been recent advances in the prevention of secondary effects. Spinal cord injuries produce a breakdown of cell membranes leading to stimulation of the pituitary gland, which then releases vasoactive and edematous agents, causing fluid build-up in the spinal cord (1,2). This progressive, secondary damage leads to further neurological impairment which can potentially be prevented with effective pharmacological therapy using methylprednisolone or naloxone (1,2,3,4,5).
Methylprednisolone (MP) and naloxone act primarily by increasing local blood flow (2,3,4). MP has been found to cross the cell membrane more quickly than other therapuetic agents and to increase cellular metabolism; therefore, it aids in cell repair (3). The mechanism of naloxone is unclear, but it is thought to act by blocking opiate receptors within the spinal cord (2).
In many studies over the last twelve years, spinal cord injuries in both humans and animals have been treated with varying dosages of naloxone and MP. Because of the variations in tested dosages, time lapse between injury and treatment, and animal models, these studies have yielded unclear results concerning the effectiveness of both drugs. Therefore, we feel that a review of literature is necessary to clarify the state of knowledge regarding the abilities of both drugs to limit the extent of spinal cord injuries.
ANIMAL STUDIES
In the earliest animal study reviewed, Faden, Jacobs, and Holaday (1980) tested the effects of naloxone on blood pressure and neurologic recovery in adult cats afflicted with low cervical spinal injury. The cats received either a 2-mg bolus of naloxone or saline 45 minutes after injury, followed by a maintenance treatment of 2-mg per kilogram per hour over 4 hours. Blood pressure was monitored over the length of the treatment period. After the cats recovered, their neurologic recovery was evaluated by their motor function improvement; evaluation took place at 24 hours, 1, 2, and 3 weeks after injury (2).
The results showed that blood pressure in the saline-treated cats declined over the first hour while the pressure in the naloxone-treated cats increased to a maximum between 5 and 15 minutes after treatment. The differences between the two groups declined until the mean arterial blood pressure in each group was identical (at the end of 4 hours). Neurologic recovery also significantly improved in the naloxone-treated cats. After 1 week, the saline-treated cats could support themselves with only the forelimbs while the naloxone-treated cats could walk well with spasticity only in the hind limbs (2).
Faden, Jacobs, and Holaday concluded that naloxone was effective in increasing blood pressure, thereby increasing local blood flow to the site of injury. In addition, they speculated that neurologic recovery was due not only to increased blood flow but also to the blockage of opiate receptors in the spinal cord (2).
Arias (1987) studied the effects of naloxone on the neurologic recovery of rats inflicted with acute spinal cord injury by the application of a clip to their spinal cords. At 45 min and 120 min after the injury, the animals were treated with naloxone or saline in two 0.8-mg bolus injections. Arias assessed the motor function of the animals on a weekly basis by an inclined plane method; the evaluation was based on the highest angle the animal could remain on the board for five seconds. After a ten-week assessment period, the spinal cords of the animals were removed and examined to determine the degree of cellular damage (5).
Arias found that the performance of the naloxone group improved significantly throughout the assessment period, whereas the control group showed no improvement after the first week. No major differences were found between the naloxone and control groups in the degree of cellular damage (5). Accordingly, Arias concluded that naloxone is beneficial for the treatment of experimentally induced spinal cord injury. His conclusion is in accordance with the 1980 study (2), but he adds that naloxone’s opiate inhibition resulted in increased post-traumatic pain. Thus, the effectiveness of other drugs which do not affect the analgesic system should be seriously considered (5).
In another study using rats as subjects, Zileli, Ovul, and Dalbasti (1988) compared the abilities of naloxone and methylprednisolone to prevent irreversible secondary spinal cord damage. Injury was induced by dropping a 2-g weight from 40 cm onto an impounder situated above the exposed dura mater of the spinal cord; this method of injury applied 80 g/cm of pressure to the midthoracic region of the rats. In order to simulate a somewhat realistic injury situation, the researchers waited 45 minutes to close the wounds and administer the intraperitoneal bolus of drugs to the subjects. Nine animals received a naloxone megadose of 10 mg/kg, 10 animals received 15 mg/kg of MP, and 10 control animals received saline injections (4).
The researchers investigated the effects of injury on the electrophysiological functioning of the corticospinal and spino-thalamic tracts by recording the somatosensorial-evoked potentials (SEPs) resulting from sciatic nerve stimulation. SEPs were made before injury, 12 hours, and 14 days after wounding. In addition, the daily evaluation of lower extremity motor function was made (4).
The naloxone-treated group exhibited quick and effective electrophysiologic recovery. The group treated with MP showed no relative electrophysiologic improvement when compared to the control animals. With respect to motor function recovery, both MP- and naloxone-treated groups showed improvement over the control group; however, neither MP nor naloxone had a significant effect on preventing total paralysis (4).
Zileli, Ovul, and Dalbasti discovered that both drugs were rather ineffective in halting the irreversible secondary motor function damage due to spinal cord injury. However, they do suggest that the dosages may in fact be the reason for the apparent ineffectiveness. The researchers noted that previous studies by Hall et al. (6) and Young and Flamm (7) had shown 30 mg/kg of MP to be the most beneficial, but only 15 mg/kg was administered in Zileli, Ovul, and Dalbasti’s study. Like the 1980 (2) and 1987 (5) experiments, they showed naloxone to be effective for electrophysiological improvement. However, Zileli, Ovul, and Dalbasti proposed that higher dosages would permit increased positive mechanical results (4).
HUMAN STUDIES
Because MP and naloxone have shown promise for treatment of spinal cord injury in animals (2,4,5), the Second National Acute Spinal Cord Injury Study (NASCIS 2) has undertaken a trial to test the safety and efficacy of the two drugs in humans. In a randomized, double-blind study conducted at ten different medical centers across the country, patients with acute spinal cord injuries were given MP, naloxone, or placebos within 14 hours of injury. MP was given initially as a bolus of 30 mg/kg of body weight and then by infusion at 5.4 mg/kg per hour for 23 hours. Naloxone was given as a bolus of 5.4 mg/kg, followed by infusion at 4.0 mg/kg per hour for 23 hours. Neurological function was assessed upon admission to the center, also at six-week and six-month follow-ups (1).
NASCIS 2 found that the scores for pinprick sensation, touch, and motor function of the group treated with MP within 8 hours of injury improved significantly in comparison to the placebo group. Those patients treated with MP more than 8 hours after injury did not show significant improvement over the placebo group; neither did those treated with naloxone. However, the few patients with only partial sensory loss showed greater improvement after treatment with naloxone than with either MP or placebo. There were no significant differences in mortality between the three groups (1).
The researchers of NASCIS 2 concluded that MP improves recovery of neurological function after both complete and incomplete spinal cord injuries; consequently, they recommend its use in the immediate treatment of acute spinal cord injury. Because they did not find consistent evidence in support of naloxone as an effective treatment for the secondary effects of spinal cord injury, the researchers could not recommend its use (1).
In a one-year follow-up study, NASCIS 2 found that MP-treated patients still had significant neurologic recovery, where the naloxone-treated patients did not. The authors suggested that the failure of naloxone to improve neurological outcomes may be due to the dose of naloxone being below its therapeutic threshold (3).
CONCLUSION
In these studies, both drugs seem to be relatively effective in treating secondary effects of spinal cord injury (decreased blood flow, edema, and ischemia). Recovery depends primarily on the expediency and dosage of the drug treatment. Subjects receiving less than 10 mg/kg responded less favorably to naloxone treament than those at higher dosages; likewise, treatments of less than 30 mg/kg of MP proved to be less effective than higher dosages. In humans, treatment with MP within 8 hours of injury, according to the most recent research, is most beneficial in preventing secondary, irreversible spinal cord injury. Concerning naloxone, positive results in animal species were not seen in human patients; these results could be explained by variations in species-dependent drug metabolism.
Based on our review of current research, it appears that MP is the more promising drug for treatment of secondary spinal cord injuries. MP provides increased sensory perception and increased mobility in human patients. Naloxone has also shown some beneficial effects, but because of its anti-opiate characteristics, it seems to be less promising than MP for clinical treatment. Further research with MP to determine the most effective dosage would be valuable.
VOCABULARY
Bolus—single dose.
Corticospinal and spinothalamic tracts—pathways between the brain and the periphery.
Dura mater—the outer covering of the central nervous system.
Edematous—causing swelling.
Intraperitoneal—within the body cavity.
Ischemia—lack of oxygen.
Opiate—natural pain-killer.
Sciatic nerve—main nerve in the leg.
Somatosensorial-evoked potentials—electrical nerve impulses resulting from outside stimulation.
Vasoactive—having the ability to increase blood flow.
REFERENCES
1. Bracken MB, Shepard MJ, Collins WF, et al. A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal cord injury. Results of the second National Acute Spinal Cord Injury Study. NEJM 1990; 322:1405-11.
2. Faden AI, Jacobs TP, Holaday JW. Opiate antagonist improves neurologic recovery after spinal injury. Sci 1981; 211:493-4.
3. Bracken MB, Shepard MJ, Collins WF, et al. Naloxone or methylyprednisolone treatment after acute spinal cord injury: 1-year follow-up data. Results of the second National Acute Spinal Cord Injury Study. NEJM 1992; 76:23-31.
4. Zileli M, Ovul I, Dalbasti T. Effects of methylprednisolone, dimethyl sulphoxide and naloxone in experimental spinal cord injuries in rats. Neurological Research 1988; 10:233-4.
5. Arias MJ. Treatment of experimental spinal cord injury with TRH, naloxone, and dexamethasone. Surg Neurol 1987; 28:335-8.
6. Hall ED, Wolf DL, Braughler JM. Effects of single large dose of methyl prednisolone sodium succinate on experimental spinal cord ischemia—dose-response and time-action analysis. J Neurosurg 1984; 61:124-130.
7. Young W, Flamm ES. Effect of high dose corticosteroid therapy on blood flow, evoked potentials, and extracellular calcium in experimental spinal injury. J Neurosurg 1982; 57:667-673.