THE ROLE OF CARISOPRODOL I N PHYSICAL MEDICINE

Arthur C . Jones University of Oregon Medical School, Portland, Oreg.

The objectives of physical medicine are to relieve pain, to improve tissue metabolism, and to enhance the ability of the patient to perform significant movements. The achievement of these objectives depends on many factors in addition to the actual physical effects of energy applied or physiological responses elicited by physical procedures. Any means by which clinical im- provement may be enhanced is a proper objective of study in medicine. In a search for such means, carisoprodol (N-isopropyl-2-methyl-2-propyl-l,3- propanediol dicarbamate) was chosen for a clinical study in relation to physical medicine by reason of properties that, on the basis of preliminary studies, seemed to offer possible improvement in the results of physical treatment. Physical therapy is related specifically to the stretching of muscles, tendons, and ligaments, to the mobilization of joints and, particularly, to exercise.

Muscle strains result from sudden application of a stretching force, the degree of strain varying with the force applied. The resultant pathological state in muscle will exhibit a variable amount of edema, and, often hemorrhage, induration, and muscle spasm. Circulatory disturbance, relative hypoxia, and pain occur, followed by fibrosis. Sprains of ligaments exhibit similar changes expressed as fixation of the parts, muscle spasm, pain, and induration. Inflammatory conditions in muscle, fascia, or joints tend to cause spasm along with all the adverse effects of trauma, as well as infiltration, degeneration, ischemia, or even necrosis. Physiological responses that are necessary initially for protection against further damage often prolong the period of immobiliza- tion and ischemia of soft tissues. The resultant fibrosis is notoriously apt to lead to permanent impairment, adaptive shortening, and disability.

The usual sequence of essential measures prescribed to counteract the adverse histologic and metabolic changes of trauma and inflammation includes heat in some effective form, mobilization, and stretching of contractile and elastic elements of the affected part, all leading to movement and active exercise. Movement is essential to the restoration of function of the movable parts of the body and to restoration of the integrity of tissues. It is our strong convic- tion that significant movement is a major goal of the healing arts.

Repetitive heating has been shown by numerous investigators' to increase the vascularity of the tissues. This is demonstrated by an increase in the number of patent blood vessels and in the volume of blood flow. This results in increased local metabolism of the part and in an increased number of histio- cytes in the tissues, as I have shown in unpublished studies. Stretching of elastic and contractile tissues tends to restore normal muscle length2 and hence to improve performance and strength and to restore normal length of ligaments. Increases in mobility and metabolism are accompanied by reduction of pain. I t cannot be overemphasized that physical therapy results in microscopic and gross anatomical changes in tissue, especially muscle, fascia, and blood vessels.

226

Jones : Carisoprodol in Physical Medicine Procedure

227

A group of 84 cases was selected in which muscle spasm, vasospasm or ischemia, and adaptive shortening were characteristic. This group included cases of sprains, strains, contusions, bursitis, tenosynovitis, nerve-root com- pression or radiculitis, and myositis, fibrositis, and both degenerative and rheumatoid arthritis. Where practicable, the mobility of related parts was measured by protractor at appropriate intervals. Muscle strength was tested by the deLorme3 or other techniques of muscle grading, and every effort was made to quantify indices of improvement under the clinical conditions of this study. The presence of pain and local tenderness was noted, but these factors were given only accessory weight in determining grades of improvement. The age range was from 24 to 57 years, the median age being 42.2 years.

The patients were treated by the usual physical methods under standard clinical conditions by registered physical therapists, using standard equipment and following the prescription of the physiatrist. Pertinent measurements were taken in the initial examination and repeated a t regular intervals during the course of observation. Initially, standard physical therapy was used exclusive of drugs for the first two or three weeks. The medication under investigation was then added, and the single-blind placebo method was used as control. Carisoprodol* was prescribed in a dosage of 350 mg. 4 times daily. The placebo tablets were exactly the same size, shape, and color as the drug tablets. Patients were asked simply to take the tablets as part of their regular medical management. All these patients were refractory cases from a referral practice or a community rehabilitation center.

An attempt was made to determine whether the medication elicited any measurable increment of improvement over that obtained in the initial period of physical treatment. Statements of patients regarding sleep and ability to perform certain routine tasks and to return to employment were correlated with the objective measurements taken. The ratings of the therapists, the medical observers, and the patients were tabulated and weighed against the objective measurements recorded during physical therapy plus drug or placebo. Efforts to assign percentile values to the observed changes will not be reported at this time.

Results

Of the 84 patients, 56 (14 men, 42 women) were studied in sufficient detail to permit a qualitative report of results. Measurable parameters were so varied as to preclude valid statistical evaluation in this preliminary analysis.

Without exception, the 26 patients under treatment for sprains, muscle strains and contusions showed increments of gain upon addition of carisoprodol, as compared with their responses to previous regular physical therapy. The majority of this group, 24 in number, described pain relief, and all showed increased ranges of motion and muscle strength and release of muscle spasm. These changes became apparent in a rather short time-two to three weeks,

* Supplied by the Wallace Laboratories, New Brunswick, N. J.

228 Annals New York Academy of Sciences on the average, after the beginning of the combined therapy-in contrast to the prolonged periods of impairment prior to institution of the combined treat- ment.

The 7 patients with chronic bursitis, tendinitis, and capsulitis showed similar responses, but increments of gain were less rapid and dramatic, varying from slight to marked, as indicated by increases in range of motion, muscle strength, and ability to do gainful work. These patients returned to work within an average of 4.2 weeks after the start of combined therapy.

The reactions of the 5 patients with rheumatoid arthritis and spondylitis varied according to the degree of activity and the stage of the disease a t the time therapy was begun. Four patients showed further reduction of palpable muscle spasm and slight to marked increases in ranges of motion of affected joints. One patient exhibited no changes and experienced no pain relief; it was later discovered that he had been on placebo tablets during the entire course of his treatments. Of the 5 cases of myositis and fibrositis, 2 were markedly better on combined therapy, 1 was moderately improved, and 2 showed no measurable improvement.

Cervical nerve root compression or radiculitis, of which 5 cases are reported, is often associated with trauma or degenerative arthritis and commonly with both. Etiological factors are usually complex. Physical treatment includes depth heating, massage of neck and back muscles, and traction. The effective- ness of such therapy depends to a large degree on the amount of muscle relaxa- tion and mechanical stretching of neck structures that can be achieved, the degree of distraction of skeletal elements, and decompression of nerve roots. Repetition of effective treatments of this type results in tissue readjustments that may be permanent. Increments of gain in neck motion range, reduction or erasure of muscle spasm, and subjective relief of pain were marked in 4 of these patients, and moderate in 1.

In one case of cerebral palsy, a 40-year-old man who had sustained multiple sprains of cervical and lumbar spinal ligaments and severe back muscle strains in an automobile accident, a marked reduction of hyperactive stretch reflexes and ablation of a life-long bilateral ankle clonus was observed as a result of prolonged physical treatment plus carisoprodol. The clonus and exaggerated tendon reflexes reappeared 3 days after drug administration was stopped, but disappeared when it was resumed. Slow improvement in neck and back muscles continued.

Degenerative arthritis associated with painful muscle spasms and tension was? the indication studied in 8 cases. The addition of carisoprodol to routine physical therapy resulted in measurable increases in the ranges of motion of involved parts and also provided relief of pain in 4 cases and partial improve- ment in 2; in 1 case, no improvement occurred.

Adverse side effects were of a minor nature, and in no case in this series were they of such a severe nature as to require discontinuance of the drug. Six of the 56 patients noted a sleepiness sufficient to render a reduction in dosage advisable; with all 6 , omission of the midday dose was sufficient to correct for this factor. One patient reported epigastric distress after taking the drug for 6 days; omission of the medication for 3 days relieved the symptoms. Two patients developed hives within 2 days after starting the drug. These disap-

Jones : Carisoprodol in Physical Medicine 229 peared promptly after withdrawal of the medication. The relative lack of side reactions was commented on by the staff members concerned with the series. The influence of the placebo was negligible in the entire series, being indis- tinguishable from the progression of changes due to physical therapy alone.

Discussion A significant number of the patients studied showed increments of gain in

ranges of motion, elasticity of fasciae and muscle strength, and reduction of palpable muscle spasm and pain after carisoprodol was added to physical therapy. This conclusion is based on clinical judgment, without a formal attempt to apply statistical methods. The results tend to verify the observa- tions of Berger and his co-workers4 on the relief of pain, produced by injection of silver nitrate into the joints of rats, through administration of carisoprodol in nontoxic doses. The authors interpreted this relief not as an anti-idam- matory effect, but rather as evidence of depression of pain responses in the mid-brain reticular formation or the nucleus lateralis of the diffuse thalamic system.

Muscles that are in constant tension or spasm have been shown by Dickel and his associates6 to require the extra energy supplied by adenosine triphos- phate in order to relax. Both heat and carisoprodol have been shown to enhance muscle relaxation.lS4 One may postulate some restoration of the energy store of muscle by the additive effects of these two factors, as evidenced by observed improvements in passive stretch, muscle strength, and pain relief in spastic muscles. The increases in ranges of joint motion may be corollary to this cumulative effect of physical and pharmaceutical factors, through restoration of a more nearly normal muscle metabolism. The restoration of increased blood volume flow and oxygen exchange incident to this improvement in metabolic gradient in muscle is accompanied by a parallel improvement in that of all associated tissues. Hence the observed tendency toward resolution of exudates, reduction of infiltrates, and fibrosis.

Much physical medicine is directed toward alteration of the physiological state of neuromuscular receptors, expecially those of the muscle spindles. Fischer and Solomon" state that the stationary frequency of the muscle spindle discharges evoked by a given tension varies slightly with the absolute tempera- ture of the spindles, and that a quick warming of the spindles causes a tem- porary but complete inhibition of the firing of the spindles, whereas sudden cooling elicits a short burst of excitations. The demonstrated effects of a variety of meprobamate derivatives and other muscle-relaxant drugs would tend, in theory, to potentiate the known effects of heat, stretching, massage, and exercise on the neuromuscular spindles, with their small fiber feedback system which modulates muscle action. A reduction of proprioceptive (muscle) stimuli, plus an inhibition of pain responses in the diencephalon, would cer- tainly tend to break the vicious circle of tense muscles, tied-up energy, pain, ischemia, and anxiety such as we commonly see in many patients who have suffered pain in some segment of the body for any length of time.

We may conclude that carisoprodol does exhibit measurable potentiating effects on certain responses to physical procedures in the treatment of a variety of traumatic and inflammatory neuromuscular conditions.

230 Annals New York Academy of Sciences References

1. KRUSEN, F. H. 1941. Physical Medicine. : 59-69. Saunders. Philadelphia, Pa. 2. DARLING, R. C. 1958. Physiology of exercise and fatigue. In Therapeutic Exercise. :

30-31. S. Licht, Ed. Licht. New Haven, Conn. 3. DELORME, T. L. & A. WATKINS. 1951. Progressive Resistance Exercise. Appleton-

Century-Crofts. New York, N.Y. 4. BERGER, F. M., M. KLETZKIN, B. J. LUDWIG, S. MARGOLIN & L. S. POWELL. 1959.

Unusual muscle relaxant and analgesic properties of N-isopropyl-2-methyl-2-propyl-1,3- propanediol dicarbamate (carisoprodol). J. Pharmacol. Exptl. Therap. 127: 66.

5. DICKEL, H. A., J. A. WOOD & H. H. DIXON. 1957. Electromyogra hic studies on meprobamate and the working, anxious patient. Ann. N. Y. Acad. Sci. i7(10): 780-788.

6. FISCRER, E. & S. SOLOMON. 1958. Physiological responses to heat and cold. I n Thera- peutic Heat. : 16147. S. Licht, Ed. Licht. New Haven, Conn.