Metaxalone, a new skeletal muscle relaxant

LLOYD W. MOREY, A.S., B.S., D.O.,* Milwaukee, identification of the poisoned arrows in the Orinoco Wisconsin, and ALLAN R. CROSBY, B.A., D.O., River basin and the work of Claude Bernard in Wauwatosa, Wisconsin 1857. 1 Those curarelike substances acted by pre- venting muscle motor end-plate depolarization from acetylcholine. In 1935, King isolated the alkaloid d-tubocurarine from curare. It was not until 1942 The compound 5- ( 3,5-dimethylphenoxy-methyl ) 2 that it was first used for general anesthesia by oxazolidinone ( AHR-438, metaxalone, or Skelaxin ) Griffith and Johnson. These curariform compounds is a new skeletal muscle relaxant of central action. are characterized as being quaternary ammonium There are many compounds in this field. They are compounds and by their peripheral action. They related to, or are derivatives of, curare, curarelike are: chondodendron tomentosum (Intocostrin ), tu- substances, or tranquilizers. None of the previous bocurarine chloride, dimenthyl tubocurarine iodide substances used by us have seemed very successful ( Metubine), succinylcholine chloride ( Anectine in achieving symptomatic relief from the pain and and others ), and gallamine triethiodide (Flaxedil). tension of muscular spasm. Of course each physician Beckman considers these drugs as potentially has his own "favorite," but no single compound very dangerous. They have to be given by intra- seems to be outstandingly effective for everyday venous drip under constant expert supervision. He clinical use. cites a study of almost 600,000 surgical anesthestic Before the introduction of the skeletal muscle cases by Beecher and Todd in 1954, in which it relaxants, the allopathic physician could offer his was found that death associated with the use of patient nothing more than addicting analgesics, striated muscle relaxants was six times as high as mud plasters, and prolonged bed rest. The adjunc- without them! These agents will antagonize hypo- tive use of skeletal muscle relaxants with osteo- calcemia and hypokalemia, the effect of a fever pathic manipulation should enhance the patients blocking the myoneural conduction, and reduced chances of responding more quickly to treatment for blood flow to respiratory muscles. They are metabo- skeletal muscular problems. lized in muscles, liver, and kidneys. Ether has a curarelike action. General considerations Another group of muscular relaxants are related to cinchona derivative, quinine. Quinine has been Historical notes • The class of drugs known as most useful to prevent leg cramping, and in myo- muscular relaxants has come a long way since tonia congenita. Its antimalarial activity has been °Address, 7729 W. Burleigh St. well documented.

JOURNAL A.O.A., VOL. 62, FEB. 1963 517/61 The third group of muscle-relaxing agents consists of tremors or small muscle spasm. It fails to alter of those having a central action. They are usually blood pressure, heart rate, temperature, the electro- taken by the oral route. These compounds appear cardiogram, or electromyographic studies. It does to be less toxic in general, and they may be given not alter gait, posture, or alertness. orally and without such close supervision. However, a great variety of side effects are noted. Renal and Previous clinical studies • A previous report on hepatic function may be impaired. the clinical use of metaxalone in 952 patients re- Included in this group are: mephenesin (Tolserol lated that there were some side effects in 82 (8.5 and others ), carisoprodol ( Soma, Rela), zoxazola- per cent) . However, it must be remembered that mine ( Flexin), methocarbamol (Robaxin), styra- when patients know they are taking a new drug, mate ( Sinaxar), and various tranquilizers. they become overly concerned about their bodily functions and feelings. This is easily demonstrated Ideal characteristics of a muscle relaxant • The by noting that of those patients in the study who selection of a medication to use with an acute or were receiving up to 2,000 mg. per day, 11 per cent chronic muscular spasm should meet the following noted side effects. Among those patients taking basic requirements: 2,400 to 9,200 mg. per day, only 7 per cent reported 1. Safety. There must be no interference with any side effects. In this instance the number of side vital process. Addiction potential should be absent. effects were inversely proportional to an increase Patient mismanagement should not result in severe in dosage. morbidity. The side effects noted during a treatment period 2. Side effects. These should be minimal or ab- of from 1 to 345 days were: nausea, 23 cases; sent. Those that occur should not be embarrassing drowsiness, 10 cases; gastrointestinal upset, 8 cases; to the patient or interrupt any activity which he vertigo, 6 cases; elevated blood urea nitrogen, 6 was able to do previously. cases; and headache, 6 cases. Also reported were 3. Action. It should be immediate but not neces- diarrhea, nervousness, rash, vomiting, pruritus, ede- sarily prolonged over 12 hours. ma, blood pressure elevation, constipation, border- 4. Dosage. Availability for use by oral, rectal, line leukopenia, anorexia, excessive perspiration, intramuscular, and intravenous routes is desirable. and insomnia. Probably of significance (2 per cent 5. Performance. An ideal muscle relaxant would of all patients) was the increased frequency of relieve muscular spasm promptly, allowing a mini- drowsiness, headache, and elevated blood urea ni- mal loss of time from work, without incurring side trogen in the higher dosage range (over 2,400 mg. effects or a high financial burden. per day).

Background information on metaxalone Present clinical study Methods and materials • The purpose of this Pharmacology • Metaxalone is a bitter, ordorless, clinical study was to compare metaxalonet with a white crystalline powder which melts at about 122° placebo in a double-blind study. Neither patient C.3 It is practically insoluble in water. nor physician knew which patient was receiving This medication acts as an interneuronal depres- the medication and which the placebo. The cap- sant. The oral LD-50 in rats is one half that of sules used were identical in size, color, and weight. mephenesin. Acute toxicity results in sedation pro- A total of 61 patients participated in this study, gressing through hypnosis and then death from all of whom had a diagnosis involving striated mus- respiratory failure. Prolonged dosage at eight times cular spasm. They were all considered "tough" cases the maximum recommended dose in animals re- —those not expected to improve rapidly. All were sults in a moderate reduction in hemoglobin and given two tablets four times daily, after meals and packed-cell volume. This compound is unique at bedtime; the amount of the metaxalone per cap- among muscle relaxants in that it markedly pro- tects experimental animals against convulsive sei- sule was 400 mg., for those who received it. zures from strychnine, probably by acting on the For all patients, the following tests were per- caudal reticular formation. In contradistinction, formed before the medication was begun: complete carisoprodol results in electroencephalographic hy- blood count, urinalysis, blood urea nitrogen, and persynchronous spiking. serum glutamic oxalopyruvic transaminase. These same tests were checked 3 or more weeks later to Metaxalone appears to have very little tranquiliz- see if there had been any changes. A sufficient ing effect, anti-inflammatory activity, or analgesic property. It does not alter the sciatic inhibition of number of laboratory tests to allow evaluation were the patellar reflex. It will completely block the performed on 51 of the 61 patients. crossed extension reflex, whereas phenyramidol Forty-nine of the 61 patients displaying one (Analexin) will only partially block this reflex. It form of muscular spasm or another also received does not appear to have any value in the treatment t Supplied for this study as Skelaxin, by the A. H. Robins Company, Inc., who also furnished the placebo. 518/62 osteopathic manipulative therapy where indicated. tionalized. Another patient complained of nausea; this patient is considered to have a moderate anxi- Results • Of the 61 patients, 36 were considered ety neurosis. Another patient complained of vertigo, to have good to excellent results. Twenty-five had and there was a question as to whether or not he fair to poor results. Of the 36 who had good to had had a concomitant episode of influenza. excellent results, 19 were on the placebo and 17 Of the 5 patients on the placebo, one complained were on metaxalone. of swelling in the anterior cervicoclavicular area, Of the 49 patients who also received osteopathic another of syncope, one of diarrhea, another of manipulative therapy, 24 were on metaxalone and pruritus and "burning" of the eyes, and the fifth 25 on the placebo. Thirteen of those on metaxalone of malaise. did well, and 17 of those on the placebo did well, with the adjunctive use of osteopathic manipula- Laboratory studies • Table I shows the laboratory tion. Of the 12 patients who did not receive osteo- results on the 51 patients on whom adequate pathic manipulative therapy, 4 of the 6 who were studies were done. Laboratory analyses of the al- on metaxalone had good to excellent results, where- bumin and sugar content of the urine, as well as as only 1 of the 6 patients on the placebo did well. microscopic examination, were carried out, but the All patients were given a questionnaire to fill out results showed so little variation as to be totally 1 week after they had started the medication. This insignificant. consisted of four main questions : (1) Has this drug In the 16 males on metaxalone, a small average helped you? (2) When did you first notice improve- increase was noted in hemoglobin fraction, lympho- ment? (3) In what ways did this drug help you? cyte count, and urinary specific gravity, while small (4) Was this drug of more help than others? average decreases were found in the segmented In evaluating the first question, it was found that neutrophil count, serum glutamic oxalopyruvic 17 of the 30 patients who were on metaxalone stated transaminase, and blood urea nitrogen. The 10 fe- that they felt that the medication did help them. Of males who received the medication had small the 31 patients on the placebo, 21 thought that the average increases in the serum glutamic oxalopyru- medication helped them. The average length of vic transaminase and blood urea nitrogen. How- time before most patients on metaxalone noted ever, the over-all results for all the patients on improvement was 2% days, whereas it was 3% days metaxalone were within normal limits of individual for those on the placebo. variability and laboratory error. It is interesting that 4 patients on metaxalone The changes in results on patients taking the reported less nervousness, and 6 patients on the placebo are not too different from those on the placebo found the same thing. Fourteen patients medication. The changes were not as great, but on metaxalone and 10 patients on the placebo re- it is our opinion that there is no significance in ported relief from pain. None of the patients re- the average changes in either group. The average ported an increase in appetite. Four of the patients figures for all the patients further illustrate this on metaxalone and 10 on the placebo noted that point. One would expect the same variations to they were able to sleep better. Eleven of the occur in a similar group over the same period patients on metaxalone and 16 on the placebo re- without any medication being given. ported less joint stiffness. Five of the patients on The figures showing the greatest differences metaxalone reported that they were able to do found in individual patients indicate that the heavier work, but none of the patients on the place- changes were much greater than the average in a bo reported this. few individuals. But it is the patients who were on the placebo, for the most part, in whom the greatest Fourteen of the patients on metaxalone felt that variability was noted. Therefore one would be the drug was more effective than others they had forced to conclude that the changes reflected by taken previously for this condition, but 17 patients laboratory analysis of patients receiving metaxalone on the placebo reported the same thing. are of little statistical consequence. However, be- One patient in the study was pregnant. She cause of the way that this medication is metabolized received treatment during the third month of preg- in the human body, we would suggest that it be nancy for a severe whiplash injury. However, she used with caution in patients who have hepatic or was later found to be on the placebo, and she de- renal problems. livered a healthy normal female baby.

Side effects • There were nine systemic com- Discussion plaints noted by the 61 patients in the study. This included 4 patients who were receiving metaxalone. The most interesting part of this study to us was One complained of a rash on the legs and another the use of the placebo in a double-blind study. It of heartburn; both of these had hypochrondiac ten- is our opinion that no medication, despite great dencies, and one has in fact recently been institu- promise from chemical structure or from its use in

JOURNAL A.O.A., VOL. 62, FEB. 1963 519/63 TABLE I-CHANGES IN RESULTS OF LABORATORY STUDIES ON BLOOD AND URINE IN 51 PATIENTS, BEFORE AND AFTER RECEIVING METAXALONE OR A PLACEBO z a O 0 0 h 9 a -0 4C4 O 0 4 e ..o O E a a 0 0 o I as cn

Average change, 31 males +0.42 +425 -3.5 -1.0 - +4.5 - +1.0 -0.8 - -0.005

Average change, 20 females +0.23 +255 -1.0 - - +3.0 - +3.0 -0.6 - -0.007

Average change, all 51 patients +0.35 +340 -2.25 -0.5 - +3.75 - +2.0 -0.7 - -0.006

Average change, 18 males on metaxalone +0.45 +234 +1 -3.5 -1.5 - +5.5 -0.5 -2.0 -1.0 - +0.009

Average change, 10 females on metaxalone +0.02 +35 -1 +0.5 - -0.5 +4.5 +2.5 - +0.007

Average change, all 26 patients on metaxalone +0.24 +135 -1.5 -1.0 - +3.0 -0.5 +1.0 +1.0 - +0.008

Greatest increase, patients on metaxalone +3.60 +2,500 +9 +17 +4 +2 +37 +5 +32 +16 +1.0 +0.020

Greatest decrease, patients on metaxalone -2.60 -3,300 -5 -35 -4 -1 -17 -6 -28 -6 -1.0 -0.016

Average change, 15 males on placebo +0.39 +616 +0.5 -3.5 -0.5 - +3.5 +1.0 +4.0 -0.5 - -0.005

Average change, 10 females on placebo +0.53 +475 +0.3 -2.5 - - +6.0 - +1.0 -1.0 - -0.020 Average change, all 25 patients on placebo +0.46 +546 - -3.0 - - +4.5 +0.5 +2.5 -0.75 - -0.013 Greatest increase, patients on placebo +3.40 +6,200 +8 +18 +3 +1 +24 +7 +81 +5 +1.5 +0.012 Greatest decrease, patients on placebo -2.40 -3,350 -6 -26 -5 -1 -19 -6 -44 -9 -2.0 -0.010

any series of patients, has been adequately evalu- Any person doing clinical research must be very ated until a double-blind study with placebo has careful that he does not affect the truthfulness of been done. his results by subconscious suggestion to the pa- In a recent issue of The Medical Letter, the tient ( caused by enthusiasm for a particular medi- problem of muscle relaxants in relation to placebos cation), because bodily mechanisms certainly can was specifically discussed.5 The editors found that be responsive to cortical impulses. The patient may most of the experts considered the evidence of be trying very hard to please his physician, or he effectiveness of muscle relaxants unconvincing. may want very much to get well, and thus may They cited a report by Denhoff and Holden which subconsciously induce himself to feel better. Of stated that the mean response to muscle relaxants course, he may also induce himself to feel worse, was 33 per cent, whereas the mean response to the depending on the psychologic situation. placebo was 39 per cent; so these authors con- The patient can report any one of a number of cluded that the placebo was actually more effective psychological manifestations while taking placebos, than the muscle relaxants under study. including nausea, diarrhea, palpitations, headache, Wolfs states that a good definition of the placebo insomnia, and even rashes or other manifestations effect would be "any effect attributable to a pill, of anxiety. However, definite objective findings may potion or procedure but not to its pharmacodynamic also be found in these patients, such as increased or to its specific properties." He states that there systolic and diastolic blood pressure readings, sinus are definite measurable changes in bodily mech- tachycardia, eosinophilia, and sinus arrhythmia. One anisms which occur with placebo administration. must take into account these various problems when

520/64 evaluating clinical research using a placebo. there was an elevated blood urea nitrogen, in the This brings up the problem of the "placebo per- dosage range of 2,400 mg. per day. sonality." We could use this term to describe a In the present study, 61 patients were included; neurotic person who goes from physician to physi- 30 of these were given metaxalone and 31 received cian, seeking a cure for an imaginary illness, but a placebo. Adequate laboratory studies before and this would be false. Many patients with the "placebo from 1 to 3 weeks after beginning the medication personality" have no outward symptoms of the were obtained for 51 patients. By coincidence, al- problem. Rather, they may be patients who try most an identical number of males and females hard to get better just to please their physicians, or received metaxalone or the placebo. on the other hand may refuse to get better because Clinical improvement was noted in 36 patients; they "hate doctors." 25 either did not improve or showed little significant Therefore, it is absolutely necessary that a pa- change. Almost the same number of patients im- tient who is a subject in clinical research never be proved on the placebo as on metaxalone. It is there- given an opportunity to find out that he or she is fore our impression that metaxalone may be of some on a placebo medication or even in a research value in certain instances of patients with problems project. It is also imperative that the investigator requiring the use of skeletal muscle relaxants. How- does not know who is receiving the real medica- ever, it does not fulfill all the requirements for an tion or the placebo; otherwise he cannot give an ideal skeletal muscle relaxant. It is hoped that fur- unbiased opinion as to whether the patient is re- ther investigation will provide a medication that ceiving help or not. will perform more rapidly and with greater objec- It is our feeling that the "placebo personality" tive clinical effect, as proved by a good double- can be detected if one searches for those patients blind study. who are highly suggestible, or who display hope- Metaxalone does have two of the ideal character- lessness in their feelings toward the possibility of istics—those of safety and lack of side effects. How- being helped. This is very important, because the ever, its action is slow enough that it takes an aver- optimistic "placebo personality" could make a age of Di days for its effect to be noticed. Its only worthless medication look good in many instances, route of administration at present is oral. We feel whereas the pessimistic "placebo personality" would that an ideal muscle relaxant should promptly re- cause many justifiably good medications to assume lieve muscle spasm without side effects, and allow a label of inadequacy or total worthlessness. the patient to return quickly to his normal daily duties. It is our belief that metaxalone is at least as Summary good as any oral product on the market, and perhaps better if double-blind studies were to be done on Clinical evaluation of metaxalone, compared with all of them. a placebo in a double-blind study, has been re- ported in this paper. Although some skeletal muscle Sincere thanks are expressed to Fletcher B. Owen, relaxants can be quite toxic in inexperienced hands M.D., Ph.D., of the A. H. Robins Company, Inc., and some must be given intravenously to be of any for his many suggestions and great helpfulness to clinical value, metaxalone is considered safe for us in performing this study. oral usage. 1. Wilson, A., and Schild, H. 0.: Clarks Applied pharmacology. The five prime considerations in choice of a Ed. 8. Blakiston Co., New York, 1952. 2. Beckman, H.: Pharmacology; nature, action and use of drugs. skeletal muscle relaxant are safety, side effects, ac- Ed. 2. W. B. Saunders Co., Philadelphia, 1961. 3. Carroll, M. N., Jr., Luten, W. R., and Southward, R. W.: Phar- tion, dosage methods, and performance. On previous macology of new oxazolidinone with anticonvulsant, analgetic and clinical studies it was noted that patients receiving muscle relaxant properties. Arch. internat. pharrnacodyn. 130:280- 298, March 1, 1981. a higher dosage of metaxalone reported less side 4. A. H. Robins Co., Richmond, Va.: Personal communication. effects than those on a lower dosage range. It was 5. The Medical Letter on drugs and therapeutics. Drug and Thera- peutic Information, New York, Nov. 10, 1981. found that 2 per cent of all patients noticed an in- 8. Wolf, S.: Pharmacology of placebos. Pharmacol. Rev. 11:089- creased frequency of drowsiness or headache, or 704, Dec. 1959.

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