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H. F. Fraser, M.D., C. F. Essig, M.D., & A. B. Wolbach. Jr., M.D. National Institute of Mental Health. Addirtion Researeh Center P.ILS. Hosyitai, Lexington. Kentueky

Evaluation:of carisoprodol and phenyramidol for addictiveness

B-399

Dr. Iscell

Reprinted from Bullerin on Narcoties (Vol. XII, No.·4, Pp. 1-5, 1961).

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Evaluation of carisoprodol and phenyramidol for addictiveness

By H. F. Fraser, M.D., C. F. Essig, M.D., & A. B. Wolhaeh, Jr., M.D. National Iastitute of Mental Health. Addietion Researel Center, P.II.S. Hospital, Lexiogtou, Kentueky

Carisoprodol (N-isopropyl-2-methyl-2-propyl-1,3-propanediol dicarbamate) is closely related to meprobamate in chemical structure (1). It is a centrally acting skeleal " muscle relaxant ", and is said to be particularly effęctive in releasing decerebrate rigidity (1). In experimental animals it produces high voltage, low frequency brainwave paters and blocks electroencephalographic activarion (1). It is unique in that it is ineffective as an analgesic by nociceptive or withdrawal refex tests, but it is effective in counteracring pain produced by injection of silver nitrate into the joints of tats. That it may affect che centtal perception of certain forms of pain is suggested by behaviour of a dog subjected to painful stimulation of an exaremity. The animal woudd withdraw the limb promptly in response to painful srimulus, but would not show dilatation of pupil usually noticed in response to pain (1). Evidence has also been provided that carisoprodol may elevate the pain threshold in man using (a) high frequency electronic stimulation to the tooth (Margolin, 2) and (b) an ultrasonic stimulus to induce deep, aching pain to the hand (Holliday & Dille, 2).

Phenyraridol (2-{Beta-hydroxyphenethyiamino] pyridine) is also a CNS acting muscle relaxant, but in contradistinction to carisoprodol, it is effective as an analgesic by orthodox withdrawal reflex tess, and its potency in animals is comparable to that of codeine (12).

Both compounds ure being marketed as muscle relaxants, effective in the relief of pain due to muscle spasms (11, 2). Since both compounds represent new structural departures for analgesics, experinents were carried out at the Addicrion Research Center to ascertain if either possessed morphine-like addictive qualities in man.

General methods

The subjects' used in these studies were healthy adult negro or white males serving sentences for violation of state or federal narcotic laws, who volunteered for the experiments. All were forner opiate addicts. Since both drugs are being marketed for clinical use by the oral coute, and since addicts would have difficulty extracting these drugs for injection from the inert ingtedients with which they are mixed, they were evaluated orally only. The tests employed to ascertain addictiveness were:

1. Administration of' single doses to non-tolerant subjecs for the detection of morphine-like effeets, This was evaluated by means of the single dose opiate questionnaires [patients' and observers' ratings (7)].

2. Twenty-four-hour substitution of these drugs for morphine in patients addicred to morphine. to ascertain their effectiveness in preventing symptoms of abstinence from morphine (6).

3. “ Direct addiction ", which invoives admninistration of these drugs in progressively increasing doses as tolerated for 18 days (5) and/or stabilization on the maxinum dosage artained for an additional 36 to 43 days, and abrupt withdrawal of the drugs to ascertain whether physical dependence develops after either 18 or S4 days of chronic administration.

Other tests and specific details will be described under each experiment 1.1

Part I.  Carisoprodal

1. Effect of Single Oral Doses in Non-addicted Patients

Methods. — Single doses of carisoprodol were administered oraily in capsules to fasring, zon-tolerant addicrs at 8.30 a.m., and observarions were carried out at hourly intervals for six hours, using the single-dose opiate questionnaires (pariencs and observers' ratings).

Results. —Preliminary experiments indicated hat doses below 1,000 mg induced no significant subjective effecs, but with higher doses certain effects were dernonstrated, as shown in table 1. It was not, however, until a dose of 2,000 mg

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was given that effects were consistently observed. With 2,500 mg of carisoprodol, evaluated in 15 tests, oniy one of 15 patients idencified it as being “ dope ". (opiate), and this patient identified it as such on only two of six observations. The predominate effects subjectively and objectively were similar to those of a barbiturate or alcohol, and not similar to those of an opiate. In contrast to patients intoxicated with barbiturates and alcohoł, none of the patients who teceived large doses of carisoprodol were obstreperóus, belligerent, silly or difficult to manage. One or two hours after 2,500 mg of carisoprodol, most of the subjects became quite sieepy, some profoundly so, and were difficult to arouse. They węre somewhat confused when awakened, but did not show as much dysarthria as one might anticipare from an equiváleat hypnotic dose of barbiturates. All patients thus affećted, however, were moderately ataxic. These effects disappeared almost completely in six hours. Carisopsodol, even in the highest doses. did got induce pupillaró constriction

2 Twenty-four-hour Substitution of Carisoprodol for Morphine Methods. — 3,600 to 4,900 mg of carisoprodol (divided inco three equal oral deses) was substituted for morphine in 6 and

3 patients respectiveiy. All pacients receiving morpiine,were stabilized on 240 mg of subeutaneous morphine sulfate daily. The study was controlled in other tests, negitively, by substitution of a placebo for morphine, and positively, by continuing the customary dose of morphine in the same subjects. Observations for intensity of abstitence were made hourly fror the 11th though the 2+th hour.of abscinence (6. 8). Since carisoprodol seemed to be barbiturite-like in many respects, the study was also controlled by substituting intramuscular pentobarbital in an average dose of 1.11 grammes divided among Sve doses, in anoter experiment using 11 other subjects. As in the preceding experiment, negative (placebo) and positive (morphine) control tests were mide at weekly intervals in the same subjects.

The comparative efiecriveness of the various agents in suppressing absinence was evaluated by the paired t-test (3), using TAS values (total area scores) under the time-action curve for the 11 observadons.

Results, — Carisoprodol partiaily but significantly $( \pmb { \mathscr { P } } < 0 . 0 5 )$ suppressed symptoms of abstinence (figure 1), as tabulated by the hourly point scote of Himmelsbach (8). Abstinence was

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also suppressed partially by pentobarbital (figure 1), but not to a sratistically siguificant degree (P <.1 and >.05). The 3 patients receiving the 4,S00-ing subsritution dose of carisoprodal were quite sedated and somewhat ditficult to arouse, but showed only a slighe degree of dysarthria and ataxiz. All patients who reccived peatobarbital were sedated and showed a slight to moderate degree of ataxia and dysarthria; certain subjects were confused.

3. Direat Addiction to Carisoprodol

Methods.  Five non-tolerant subjects were used in a " single-blind" test —i.e., patients but not observers were unaware of the nature and schedule of medication. Starch placebos and carisoprodol powder were prepared in identically appearing capsules, and all medication was divided equally among four doses daily. All patients initially received placebo capsules for 12 days, + reccived carisoprodol for 18 days and one for 54 days. Carisoprodol was withdrawn abrupdy and replaced by idenrically appearing capsules. The initial daily dose of carisoprodol was 1,200 mg; this was increased at a rate of 200 mg daily for 16 days to 2 daily dose of 4,200 mg, and then by 300 mg on the 17th and 18th days, attaining a daily dose of 4,800 mg. The patient receiving carisoprodol for 54 days received 4,800 mg daily from the 18th to the 54th day.

Observations were made chree times daily throughout the experiment, and the degres of abstinence was calculated by the daiy point scores of Kolb &: Himmelsbach (10). In one patient, evidence of physical depeadence was also evaluated (5) by administering 2 mg of nalorphine subeucaneóusly on the 44th day, and 5 mg on the 4Sth day of carisoprodol administration. Throughout the, test, parients and aides independently completed a chronic dosage opiate questionnaire (7) at 7 p.. daily. Clinical toxicity was evaluated by observations and by laboratory teses made prior to drug administrarion.and repeated at bi-weekly intervals, when carisoprodol was administered, as follows: routine analyses of urine, red and white blood cell counts, hemoglobin content, hematocrit and liver fumction tests (thymol turbidity cephalin foccularion and evidence of bilirubin in the urine). An electrocardiogram was made on eack patient while receiving placebos, and again after a high dosage of carisoprodol had been reached —ie., 4,200 or 4,800 mg daily.

EEGs were obcained using an cight-channel resistance capacitance coupled Grass apparatus. Using ncedle electrodes, one bi-polar and three moro-polar tracings (linked and grounded) were obrained from frontal, temporal, parictal and occipical areas (4) prior to adninistering drugs to the 5 patients used in this direcr addiction test. In 3 of these, the subsequent eifecs of a single 300-nug dose of carisoprodol was ascercained about one hour after carisoprodol was administered orally. In a similar manner, the effeets of a single dose of 1,000 ng were determined in oue parient, and those of 2,000 mg in another paticnt. During dhe ditect addiction test, EEGs: were taken on all 5 patients oie hour after the 10 a,m. medication, when a daily dosige of 4,200 ot 4,800 mg had been attained. The patient receiving cacisoprodol for S4 days had an additional EEG after 45 days on the drug. During withdrawal, each of the 5 patients that had taken carisoptodol for 18 days had in EEG 18 and 36 houts after the last dose, and the patient that had carisoprodol for 54 days lad one EEG 13 hours and another at 24 hours after the last dose.

Results. — During chronic administration of carisoprodol, except for changes in the EEG pattern, the outstanding feature. was a complete absence of any significant subjective cffects even when the dosage was increased to 4,500 mng"daily. In other words, it was not possible to differentiate carisoprodol from a'placebo (figure 1).

Following abrupt withdrawal of carisoprodol, the 4 pacients that received it for 18 days showed no autonoauic signs of abstinence, and did not tealize that dheir medication had been changed. TAS scores (total scores under the time-action curve during the 10 days of withdrawal) averaged 77.3 during withdrawal as compared with an average TAS score of 41.0 observed during their lase 10 days on carisoprodol. This increase in the abstirience scores during withdrawal is insignificane, particularly in view of the fact that the maximun daily score was only 10.3 points during, withdrawal, The patient who received carisoprodol for 54 days showed no signs of absrinence when the drug was discontinued abrupdy; the TAS score was 38 points, and the maximum daily score was only 7 points. This patient likewise stated that at no time did he feel the medication, and he was completely unaware of the fict that carisoprodol had been discontinued.

The EEG pattern after single doses of 300 mg showed questionable barbiturare-like effects as compared with the pre-drug EEG, but after single doses of 1,000 and 2,000 mg, and during chronic intoxication (4,200-4,800 mng daily), barbiturate-like effects were obtained. These changes consisced of rhythmic and non-rhythnic low- and mediumn-voltage fast activity (18-32 cps) seen more prominenty in the frontal leads, In the 4 men who received carisoprodol for 18 days, the EEG pacterns 17 and 36 hours after the last dose of the drug were normal. In the case ot the patient who took cariso prodol for 54 days, the first EEG, taken 14 hours after the last dose of carisoprodol, showed a barbiturate-like effeer, but the one taken 36 hours after the last dose was normal. None of these patients showed focal or generalized abnormalities of the paroxysmal type during withdrawal, such as those seen following withdrawal of barbiturates (9, 13, 4).

None ef the clinical observations or laberatory tests showed significant ceviations fron pre-drug observations.

Chronic administration of carisoprodol on a progressive dosage schedule did not induce a characteristic barbiturare inuoxication patenn (nystagmus, dysarthria, ataxia in gait and station, confusion, poor judgennent and loss of enotional control), and whea carisoprodol was abruptly withdrawn, no signs of barbiturate-like abstinence (anxiccy, fine tremor, weakness. convulsions and deliriunt) were observed (9). However, it remains to be seen whetiier admninistering carisoprodol continuousiy in larger doses would inciuce a chronic state of intoxication and whether abrupt wichdrawal under such circuanstances would provoke a barbiturate or meprobamate rype of abstinence. Such a possibility is suggested

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by the faet that carisoprodol is a congener of meprobanate and exhibits many barbiturate-like pharmacological effeets.

Part l. — Phenyramuidol

1. Effeats of Single Doses

Àfethods,—These were the same as those described for carisoprodol.

Resules. —Seventeen tests in a dose range of 100-750 mg were conducted using non-toleraut subjects; 6 patients received the maximum dose of 750 mg. No effects were repotted atter any of these doses by any patient or observer, except sleepiness, which was noticed by one patient after a 750-mg dose. The pupils were not constricted. Neither the pacients nor observers identified phenyramidol as an opiate; in fact, the most impressive finding was an absence of detectable objective or subjective pharmacological etfects in these tests.

2. 24-lour Substitntiont of Phenyrauidol for Morphiue

Afethods. -These were the same as those outlined for carisoprodoi.

Resukts,  Phenyramidol in a total dosage of 1,500 ng (divided into shrce cqual doses) was subsriruted for 240. nig of morphine sulfate in 9 patients, and was compared with morphine (continued in the customary dosage) and with a placebo substituted in other tests using the same patients. As compared widt a placebo, phenyramnidol slighdly depressed symptoas of absrinence from morphine, bur the degtee of suppression was statistically insignificant (figure 2)..

Figure 2 Ratings of puticns dbring sdireat sddistiou tests. À cosnparisoa of the average pecceutage responses to the single dose questionnuite (patents' ratngs) toe codeine, carisuprodol, phenyramidol and a piacebo for the paraaeters " fel drug ". " idetrtslicarion as" dnpe", " wuuld like wo take Laily ", and " feel bad ". The comparisua derweeu codeine sad a placrbo was made wita dire same subjects in the sante experiment, but other conpurisons between drugs were niade in anaiogons but didcrent experinteats using diderenst subjeers.

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3. Diredt Addiction to Phenyramidol

Methtods. — Four non-colerant subjects were used in a doubleblind test—i.e,, neider patients nor observers were aware of the nature and schedule of medication. Starch placebo and phenyranidol powder were prepared in identically appeating capsules, and all medication was divided into four equal doses daily, Initially all patients reccived placebo capsules for 7 to 10 days, then all were given phenyramidol for 18 day. after which the drug was zbruptly withdrawn for two days. Medication was then resumned for an additional 42 days. The initial daily dose of phenytanidol was 600 mg, which was progressively increased unril a daily dose of 4,500 mg was atmined by the 18th day, and an attempe was made to stabilize patients on this dosage for the remainder of the experiment. After a total of 61 days of chronic drug administration, phenyramnidol was withdrawn on a doue-blind basis by replacing it with idenrically appearing placebo capsules.

Observarions were che same as chose made for evaluating carisoprodol, except EEGs and EKGs were not obtainéd.

Rendts. — One patient took phenyranidol for 16 days. The experiment was terminated on the 17th day, when a dosage of 4,200 mg had been attained, because he had diffuse urticaria. Prior to this, the oaly syuiptom noted by this patient was " sleepiness ". No symptoms or signs of abstinence developed after phenyramidol was discontinued, and the urticaria gradually subsided.

The other 3 parients attained a daily dose of 4,500 mg by the 18th day, and when medication was withdrawn abrupdy for two days they showed ao evidence of abstinence. Medication was resumed on the 21st day, but it was necessary to reduce the dosage of two parients to 3.300 mg daily because of such complaints as indigestion, sleepiness, dizziness and numbness of the skin (figure 2). One parient continued on 4,500 mg of phenyramidol daily, but he had a multiplicity of complaints; fot example. he stated ". . . It made my face feeł numb, I got a buzzing in both ears, and ( lad eróuble hearing." He also deseribed a sensatiou at times resenubling effeets of benzedrine of cocaine, which woukd last for only a few nuinutes. On the other land, he had a relaxed feeling when he laid quictly in bed. Since these effeets appearedl contradietory to hin, he inquired as to whether his medication had been changed from tiae to time. None of the patients liked the effects of phenyramidol, and the higl incidence of "feel bad " reports as compared to the zero incidence of such repors during chronic intoxication with codcine is noteworthy (figure 2).

After 61 days of chronic intoxication, none of these parients realized that placebo capsules had been substituted. Absdinence scores were insignificans; in fact, hey wete sinaller than comparably computed scores obtained while recriving phenyramidol.

Diseussion

In the tests employed, neither carisoprodol nor phenyramidol showed any addictive properties of an opiate type. Although carisoprodol is pharmzeologically similar in certain respecs to barbiturates, it is not as rapidly acting as certain barbiturates. When the dosage of carisoprodol was rapidly increased from 1,200 to 4,800 mg daily within 2 period of 18 days, no evidence of intoxication was noted — suggesting chat some tolerance developed to the sedative and hypnoric effects.

Summnary sud eonelusions

The addictiveness of orally administered carisoprodol and phenyramidol has been studied in former opiate addicts. The procedures included effects of single doses, substitution tests to supptess abstinence from morphine, and direct addiccion tests.

It is concluded thar neither carisoprodol not phenyramidol possesses addictive quatities of an opiate type.

REFERENCES