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

Metaxalone was administered to 50 patients with skeletal muscle dis- orders, of whom 42 were available for followup. A beneficial therapeutic effect was observed in 80 per cent of those with low back pain and stiffness indicative of muscle spasm of the back, hip and leg muscles. Ten patients had mild side effects.-A This report is based on a clinical evaluation of a skeletal muscle relaxant with a chemical structure unrelated to that of other skeletal muscle relaxants. This compound, metaxalone,t is 5- (3,5-dirnethylphenoxymethyl) – 2-oxazolidinone(1). It is a tasteless, odorless, white crystalline powder that melts without decomposition at 121.5 to 123 C. Extensive pharmaeodynamic studies(2) showed metaxalone to have a specific antagonism to strychnine-induced convulsions. It completely blocked the polysynaptic linguomandiibular and flexor reflexes at closes that did not alter the normal posture and gait of unanesthetizecl animals. It had neither sedative nor tranquilizer properties, but was analgetic. No apparent effects on blood pressure, heart rate, body temperature, electrocardiogram or electromyogram were noted. Thus, any muscle relaxant effect from this drug observed clinical- ly is probably due to an interruption of noxious impulses at the internuncial neurons of the cord.

Materials and Methods

The present study included 50 patients treated on an outpatient basis at the Medical College of Virginia. The conditions inclucled low back pain and stiffness, acute lumbosacral pain, cervical stiffness or torticohis, arthritic pain and parkinsonism. The type of discomfort and degree approximated those usually observed in a general medical clinic.

A complete interview and medical examination was performed on each patient and laboratory studies were ordered. These included a complete blood count, urinalysis, and blood urea nitrogen. The degree of muscle stiffness and skeletal muscle spasm was assessed by interview, inspection, palpation and estimation of the range of motion. Muscle spasm was identified as sudden, violent, involuntary contractions of a muscle or muscle group attended by pain and interference with proper function. Patients ranged in age from 20 to 80 years with the largest number in the sixth decade. The duration of symptoms ranged from one day to 30 years with a median duration of approximately two years. Dosage ranged from 2400 to 4000 mg. daily (average 3200 mg.) and duration of treatment from one to 21 days with an average of 14 days.

Results

Of the 50 patients originally included in the study, completed records are available on 42 and eight did not return for re- evaluation. Of the 42, results were considered excellent in 16, good in seven, fair in six and poor in 13. These results are shown by diagnosis in Table 1.

Table 1
Results of Metaxalone Therapy in 42 Patients
Diagnosis No. of Patients
Therapeutic Effects*
 
1
2
3
4
A. Low back pain and stiffness
19
9
(47%)
2
(11%)
5
(26%)
3
(16%)
B. Low back pain, stiffness of back and hips
8
3
(37%)
4
(50%)
5
(26%)
3
(16%)
C. Low back and leg pain
8
4
(50%)
____
1
(13%)
3
(37%)
 
______________________________________________
SUBTOTAL
35
(46%)
(17%)
(17%)
(20%)
D. Arthritis
5
___
1
___
4
E. Parkinsonism
2
___
___
___
2
 
______________________________________________
TOTAL
42
16
7
6
13
* 1= Excellent; 2 = good; 3 = fair;
4 = poor

The greatest therapeutic effect was obtained in patients with painful spasm or stiffness of the back and leg muscles. When groups A, B, and C in Table 1 are taken as a whole, 80% had a positive therapeutic response to medication. Only one of the five arthritic patients had a favorable re- sponse and there was no improvement in the symptomatology of parkinsonism in two patients. It was interesting to observe complete control of hemiballismus in one of the latter patients. The other com- plained of an increase in rigidity after one day’s medication and because of this and his emotional status the medication was discontinued. Two of the patients (C) with low back and leg pain failed to respond to medication in the clinic and were subsequently treated surgically for herniated disc by the neurosurgical service. The third was a 200-pound patient with tendencies toward malingering.

Case Histories

Case I

A woman of 35, weight 153 pounds, was admitted with symptoms of low back pain and stiffness present intermittently for approximately six months. Physical examination revealed no neurological deficit or changes in reflexes. There was no evidence of disc pathology. Her blood pressure was 120/80, pulse 88. The history was non-contributory. Metaxalone was prescribed, 800 mg. three times daily. On re-examination five days later, the patient reported that pain was gone and stiffness diminished. The patient was well satisfied with the results of therapy. Medication was continued for an additional four days. When re-examined eight days after initial admission, all muscle stiffness and pain were resolved, and results were confirmed by re-examination two weeks later. Hemoglobin, white blood count and differential, urinalysis, and blood urea nitrogen were within normal limits. There were no side effects.

Case II

A man of 59, weight 155 pounds, had for several years a history of muscle tightness in the cervical area. Approximately one week prior to admission the patient noticed pain and stiffness of the right hip and lumbosacral area. Blood pressure on admission was 160/100, pulse 90. The neurological examination was negative. Metaxalone was prescribed, 800 mg. three times daily for four days. On re-examination, neck and back muscles were more relaxed and spasticity was completely absent. Patient reported moderate residual pain. Dosage was increased to 800 mg. four times daily. Within two days, only mild pain and stiffness remained and within two weeks after the original visit, all symptoms had disappeared. This patient mentioned polyuria on the first night after initiation of drug therapy, but no other untoward symptoms thereafter. Hemoglobin, white blood count, differential, urinalysis and blood urea nitrogen remained un- changed.

CASE III

The patient was admitted with symptoms of acute back and leg pain and acute rigidity of lumbar muscles of three to four days’ duration. On admission blood pressure was 110/80, pulse 90. History revealed symptoms of arthritis for two to three years. Neurological examination was negative except for diminished deep tendon reflexes and some radiation of pain to both hips. Metaxalone was prescribed, 800 mg. four times daily for 14 days. On re-examination after seven days, pain was completely re-solved and only minor muscle spasm was detectable on palpation. Fourteen days after admission patient felt much improved, pain and stiffness gone.

Side Effects

Of the 42 patients, 32 were without side effects that could be attributed to the medication. Six patients mentioned a feeling of nausea during the period of drug therapy. Of these, two had slight nausea and loss of appe- tite on the first day or two of treatment. The nausea then disappeared and medication was continued for 10 to 14 days. Two patients had nausea on days 13 and 14 and one patient had to discontinue medication during the second week of treatment because of persistent nausea. The sixth patient with gastrointestinal symptoms developed fever and pain (possible arach- noiditis from myelograph dye) after taking only 10 tablets and was transferred to another service. In contrast, two other patients noticed an increase in appetite during drug therapy. One of these patients, a 106-pound woman with chronic painful rigidity of the lower back had pre- viously complained of poor appetite and was very pleased with the unexplained improvement. Two patients, one of whom had an excellent therapeutic effect, complained of slight headache. One patient mentioned polyuria on the first day of drug treatment and another mentioned frequent micturition. One patient reported a loss of taste while taking metaxalone.

Comments

This study was conducted during the early clinical trials of metaxalone when the indications were not definitely pinpointed. It was recognized at that time that the drug had marked skeletal muscle relaxant properties in animals, but the clinical efficacy and indications had not been determined. Hence, no effort was made to limit the study population to patients with a specific syndrome or condition with common etiology. In some patients, the muscle manifestations were more prominent and, in others, muscle involvement appearecl to be secondary to joint pain. In all, there was stiffness, limited range of motion and guarding. Neurologic examination in most cases was negative. The onset of drug action ap- peare to be quite rapid. Painful symptoms began to subside after the second or third dose and, in those cases in which the patient was to respond favorably, a definite therapeutic response was observed in three clays. Medication was continued in most cases for 10 to 14 days unless the patient was uncooperative or side effects intervened.

The problems inherent in evaluating a new therapeutic agent in a clinic population markedly reduce the amount of valid data on which to base conclusions of efficacy and patient acceptability. Many of the patients were repeaters whose attendance at the clinic was sporadic and who did not return for followup examination. Although it may be presumed that symptoms were sufficiently alleviated to permit reasonable comfort or a return to normal activity, this has not been confirmed. Sufficient experience was gained with the drug, however, to arrive at certain impressions of its therapeutic usefulness and primary indications. Metaxalone was well accepted and except for mild nausea in six cases, was apparently well tolerated. Nausea might have been less prominent if the medication had been taken with food. Other untoward symptoms that occurred during the period of drug therapy could not be un- equivocally attributed to drug action. Metaxalone was most useful in those patients in whom acute spasm and muscle stiffness were most prominent. In cases of arthritic pain or neurological involvement such as parkinsonism, no beneficial effect could be discernecl. A dose of 800 mg. four times a day appeared to be optimum. A moderate therapeutic effect was observed in some patients who were started on 2400 mg. daily and as much as 4000 mg. was tolerated. For general use, 3200 mg. a day appears appropriate.

Summary and Conclusions

1. A skeletal muscle relaxant, metaxalone, was dispensed to 50 patients with skeletal muscle disorders, treated on an outpatient basis at the Medical College of Virginia. Sufficient followup data were available on 42 of these patients to permit evaluation of drug effect.
2. A beneficial 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 patients with parkinsonism or in four out of five patients with arthritis. One arthritic patient noticed a reduction in muscle spasm but no effect on pain.
3. Side effects included nausea and possibly slight headache and urinary frequency.