A Second Look at a Skeletal Muscle Relaxant: A Double-Blind Study of Metaxalone

Professor Kazem Fathie, M.D., F.A.C.S., F.I.C.S., Ph.D.

The medical literature contains many references to the clinical use of skeletal muscle relaxants in the management of muscle spasm. In spite of the large volume of material that has been published on this subject and the variety of agents available to the practicing physician, there is far from universal agreement on the practical utility of these agents to control skeletal muscle spasm, hypertonicity, rigidity and other symptoms of altered neuromuscular function. Beckman(1), in his chapter on Skeletal Muscle Relaxants, reported that the clinical improvement in patients with muscular disorders is due to an intrinsic relaxant effect on skeletal musculature and pointed out that certain drugs used primarily for their tranquilizing properties are also helpful in the management of certain neurologic disorders with a marked muscular component. In contrast with this attitude is the chapter on Skeletal Muscle Relaxants in which Schlesinger(2) comments that there are no adequate preparations for oral use which can be counted upon to achieve a reliable muscle relaxant effect.

While this controversy continues, the practicing orthopedist, neurologist, and general practitioner are called upon daily to treat patients with neuro-muscular disorders ranging from acute self-limiting, low-back disorders to the more severe conditions with neurological deficit or neurologic disease. One of the most commonly encountered conditions is the low-back syndrome characterized by stiffness, pain and spasm of the paravertebral musculature triggered by ligamentous sprain, poor posture, over-exertion or strain of the paravertebral muscles, or discogenic disorders, such as herniated nucleus putposus. Such disorders have been treated traditionally with heat, analgesics, bedrest, strapping, or taping and, in some cases, with sedatives to allay anxiety and help reduce reflex spasm. If it were possible for patients with such conditions to enjoy complete bedrest for a few days or weeks to put the affected parts to rest, many of the “back problems” would resolve spontaneously. However, patients want to remain active and yet be comfortable while doing so. Hence, the attending physician is expected to shorten the acute stage of the muscle strain or shorten the acute exacerbation of a chronic condition that may have resulted from muscular indiscretions such as over-exertion, improper lifting of large objects, etc. The physician may ask himself, “What is the role of skeletal muscle relaxants in the management of such conditions? How much do they really contribute to the patient’s comfort?”

I have reported previously 3 on a preliminary study of metaxalone(3) in 42 patients with stiffness of the back and muscular rigidity without neurologic findings, postoperative cases of herniated nucleus pulposus, spasmodic paraplegia and spasm associated with arthritis and parkinsonism. In this uncontrolled study, a positive therapeutic response was observed in 71% of the total patients studied. However, when patients with arthritic and neurologic diseases were excluded, a positive therapeutic effect was observed in 80% of the patients with low-back pain and stiffness indicative of muscle spasm of the back, hip, and leg muscles. The drug was not effective in the two cases of parkinsonism or in four out of five cases of arthritis.

The present double-blind studies of 200 patients were designed to further assess the clinical effects of metaxalone in the management of acute low-back syndrome or acute exacerbation of chronic low-back disorders. The purpose of the comparative studies was to evaluate the active agent against an identical-appearing placebo. We would thus be able to quantitate the therapeutic action of the drug, per se. No attempt was made to compare metaxalone with other available skeletal muscle relaxants.

PATIENT SELECTION

A total of 100 patients with low-back pain and discomfort were selected from the regular patient load of the Outpatient Department of Grady Memorial Hospital, Atlanta, Georgia. An attempt was made to exclude patients with obvious neurologic impairment, herniated nucleus pulposus, marked arthritic changes or other structural defects for which a muscle relaxant may not be indicated and to limit the study to patients with reflex spasm or acute soft tissue injury. The selection of patients in this manner enabled us to concentrate our attention on one general category of patients and thereby obtain a large enough sample to make generalizations with a reasonable degree of confidence.

MATERIALS AND ATETHODS

Medication

The skeletal muscle relaxant used in the present studies was metaxalone, a relatively new skeletal muscle relaxant. Chemically, metaxalone is only distantly related to one or two of the other skeletal muscle relaxants, but is similar to mephenoxalone, a mild tranquilizer. Metaxalone is a tasteless, odor- less, white crystalline powder, available in compressed tablets containing 400 mg. of the active agent. The materials used in the present studies were pink 400 mg. metaxalone tablets and matching placebos. The tablets were packaged in identical bottles containing 60 tablets per bottle and labeled with the letter, A, B, C, or D. The bottles were dispensed to consecutive patients according to a randomization schedule. It was known that at least one of the code letters was active medication and the remainder was placebo. In the first study, A and D were active drug and B and C were placebo, but this was not disclosed until the study was completed and the data tabulated. The use of two code letters for the active medication and two for the placebo reduced the possibility of letter preference which may occur with use of only two letters. The entire double-blind study of 100 patients was then repeated to give us a second look and to check the reliability of our findings. A study or test is said to be reliable if the results are consistent (under the same conditions, the test gives the same answers). In the second series of 100 patients, the bottles of active medication and placebo were again identified by code letter. However, the code used was different from that used in the first study in order to eliminate any carry-over of impressions of drug identity from the first study.

Physical Examination

Patients who attended the clinic were selected on the basis of appropriateness for treatment with a skeletal muscle relaxant. All were adults. During the initial visit, each patient was examined physically for range of motion and for palpable muscle spasm. The findings of the initial visit were recorded on the patient’s chart on the basis of a numerical score of 4, very severe; 3, severe; R, moderate; 1, mild; and 0, absent. The medication was then prescribed for a treatment period of seven days. The recommended dose was two tablets after each meal and at bedtime (total daily dose, 39.00 mg. ) . After a week of drug therapy, the examination was repeated in the clinic and range of motion and palpable muscle spasm again assessed according to the numerical score. The patient’s subjective impression, status in comparison with the initial visit, and adverse somatic effects of the drug were elicited at the time of the second visit and recorded on the patient’s chart.

Laboratory Controls

A complete blood count and urinalysis were obtained on most patients at the time of the initial visit and at the end of drug therapy. These included hematocrit, white blood cell count and differential in most cases. When- ever indicated, patients were examined roentgenographically or myelograms were obtained.

RESULTS

The therapeutic response observed in the first study of 100 patients is tabulated in Table 1. Of the 51 patients who received metaxalone, a marked or moderate improvement in symptomatology was observed in 32 patients, the improvement was slight in nine, none in five patients, and five patients did not return. Thus, a medically significant response was observed in 69.6% of the 46 metaxalone-treated patients who completed the course of therapy and returned for re-examination. A measurable therapeutic response (marked, moderate, slight) was observed in 89.1%.

Of the 49 patients who received placebo, in contrast, only eight showed even a moderate improvement in symptornatology, nine were slightly improved, 9.9 were unchanged and three did not return. Thus, only 17.4% of the placebo-treated patients who completed the course of therapy showed a medically significant improvement and 63% were therapeutic failures. The objective evaluation of changes in range of motion and palpable spasm are shown in Table II. The test of significance applied to these observeId differences was the Chi square test.

Observed differences in response were significant at p <0.01 by the Chi Square Test.

All observed differences were statistically significant at the 0.01 level. The therapeutic responses observed in the second 100 patients are summarized in Tables III and IV. In many respects the over-all results of the 2 studies were remarkably comparable. This correlation was greater among patients who received the active medication than among those who received the placebo. The close correlation between the studies indicates that the results observed were reliable measurements of the clinical effects of metaxalone.

Observed differences in response were significant at p <0.01 by the Chi Square Test.

DISCUSSION

The assessment of skeletal muscle relaxants is, at best, inexact. Investigators in the field have devised various pharmocologic studies and numerous kinds of instrumentation to measure the skeletal muscle relaxant effects of drugs with alleged muscle relaxant properties. These include electromyographic studies, motion pictures of patients before and after administration of muscle relaxants, and various other devices, such as Levine’s (4,5) to attempt to measure neuromuscular response to plantar, proprioceptive and electrically- induced stimuli. In the pharmacology laboratory, use is made of electrically-induced stimuli and such convulsant drugs as pentylenetetrazol and strychnine. The ability of the test compound to modify the neuromusculay response to these stimuli is regarded as a measure of its muscle-relaxant properties. However, both the clinical methods and pharmacologic methods are quite artificial when compared with the clinical condition the drug is intended to benefit. Clinicians who have had experience with skeletal muscle relaxants are well aware that the patient’s over-all performance and general well-being depends on many factors. Drugs that sedate or cloud the sensorium may be more readily acceptable to patients in a hospital situation than to outpatients. Although the relaxant properties of such drugs may not be as great as the relaxant properties of other drugs, the patients may be willing to overlook their lesser effect on spasticity because of the enhanced feeling of well-being induced by their sedative-tranquilizing properties. Outpatients who wish to continue their activities of daily living, on the other hand, may prefer the effects of the drug with more potent muscle relaxant properties and less sedative-hypnotic properties. Other considerations such as dosage, speed and duration of action, undesired pharmacologic effects, and route of administration all have a bearing on the attending physician’s choice of a muscle relaxant. In the final analysis, the evaluation of the effectiveness of a given drug depends upon clinical experience and close observation of patients treated with the drug. The present study was designed for this purpose.

The double-blind study of metaxalone and placebo demonstrated quite conclusively that metaxalone is an effective skeletal-muscle relaxant. Of the 91 patients on metaxalone and 89 on placebo who completed the study, a marked or moderate improvement in symptomatology was observed in 69.6% (first series) and 75.6% (second series) of the patients who received metaxalone and in only 17.4% (first series) and 9.7.9% (second series) of those who received placebo. Conversely, there were only 12 therapeutic failures among the patients who received the active medication and 49 failures among those who received placebo.

It is recognized that many of the patients had acute self-limiting dis- orders that would be expected to improve spontaneously in seven days even without treatment. This was reflected in the improved range of motion in 39.1% (first series) and 46.5% (second series) of patients and improvement in palpable muscle spasm in 28.3% (first series) and 46.5% (second series) of the patients who received placebo. In contrast with the spontaneous improvement in this moderate number of patients who received placebo, 86.8% of 91 patients who received metaxalone had improvements in range of mo- tion and severity of palpable spasm. To our way of thinking, these differences in objective assessment of the patients’ status were due to the pharmacologic action of the drug.

A second important consideration when using drug therapy is the side effect potential of the drug. The attending physician must weigh the anticipated benefits of drug therapy against the risk of drug-induced adverse effects. Among the patients who received placebo, one reported heartburn, one nausea, and hypertension was observed in another. Nine patients who received the active medication reported undesirable effects. These included indigestion and nervousness (1 case); nausea and vomiting (3); dizziness (3) and polyuria (1). Another patient reported headache and intensification of muscle cramps. Changes in the complete blood cell counts and urinalyses were, for the most part, within normal limits. White blood cell counts of 4,600 and 3,500 were observed in two patients who received metaxalone, but a much lower white blood cell count of 3,050 was observed in a patient who received placebo. Two patients on placebo had a drop in white blood cells from 4,850 to 3,100 and from 7,900 to 4,600. There was no suggestion of toxicity in any of the laboratory work performed in connection with the study. The study, therefore, indicates that metaxalone may be used to control reflex skeletal muscle spasm in ambulatory patients with low-back pain and restricted range of motion. The drug appears to be reasonably well tolerated and non-toxic. It is of interest that none of the patients reported sedation as a side effect.

SUMMARY

Two double-blind studies of 100 patients each with acute skeletal muscle spasm were conducted to assess the therapeutic effectiveness of metaxalone in comparison with a placebo. Ninety-two patients who received metaxalone and 89 patients who received placebo completed the course of therapy and were available for re-examination. The patients were examined for palpable muscle spasm and range of motion before and after seven days of treatment with the test medication, two tablets four times a day. Among the 91 patients who received the active medication, 86.8% had a positive improvement in both palpable spasm and range of motion compared to only 37.0% and 42.7%, respectively, among patients who received placebo. Over-all, the patients who received the active medication had a markedly better response than those who received the placebo.

CONCLUSION

Under the conditions of the study metaxalone (Skelaxin@) was a safe and effective skeletal muscle relaxant for the management of patients with acute reflex skeletal muscle spasm.

References

1. Beckman, H.: Drugs that depress skeletal muscles. Pharmacology, The Nature, Action and Use of Drugs. end Edition. 19, p. 115, 1961.
2. Schlesinger, E. B.: Drugs for skeletal muscle disturbances. Drugs of Choice. p. 301, 1964-65.
3. Fathie, K.: AHR-438. Metaxalone (Skelaxin) and clinical effects on muscular rigidity and spasm. Electroenceph. and Clin. Neurophysiol. 14:953-956, 1962.
4. Levine, I. M., et al.: The evaluation of neurospasmolytic agents in man by objective means. Ann. N. Y. Acad. Sci. 86:908-915, (March) 1960.
5. Levine, I. M.: Muscle relaxants in neurospastic diseases. Med. ClinicR North Amer. 45:1017-109,6, (July) 1961.