C) cri m u 0 r t4 C4 cis tn CIS Evaluation of car* oprodol is and phenyrarni(lol for addictive-ness By 11. F. Fraser@ II.D., C. F. Essig, 31.D." & A. B. Woll)acli, Jr., II.D. P.1l.S. Ilarpital, Lemingtoti, Reiitueliy N2ational Institute of'.%Ieiiial Ilenith. A(141!ctlon ]Rcsetreh Cinter, Carisoprodol (N-isopropyl-2-Methyl-2-pro'pyl-1,3-propane- 2. Twenty-four-hour substitution of these drugs for nior- cliol dicarb=ntc) is closely related to meprobainate in che- phin2e iii patients addicted to morphine, to ascertain their mical structure (1). It is a ccn=llv acting skelcral " muscle effectiveness in preventing symptoms of abstincncc from relaxant ", and is said to be pu-dcularly c&ctive in releasing morphine (6). decerebrate rigidity (1). In 2experimental aairaals it produces 3. ' Direct addiction which involves administration of high voltage, low frequency brain-,vive patterns and blocks these@.drugs in progressively inc-msin-, doses as tolerated for clectroencephalograp2hic -activation (1). It is uniqxic in that it 18 days (5) and/or stabilization on die ina.@dnium dosage is inettecdve as = analgesic by nociceptive-or withdrawal attained for an additional 36 to 43 da@-s, and -,tbrupt .vithdrawal reflex tests, but it is citective in counter2acting paiii produced of the drugs to ascertain whether physical dependence develops by injection of silver nitrate into the l'o@its of rats. That it after either 13 or 54- days of chronic 2cLminiscradorL may attect the central perception of certain form@ of pain other tests and specific det2i2ls'wiU be described under each is suggested by behaviour of a. dog subjected to painful stimu- experiment. 12rion of an extremity. The animal wovdd vithcimw the limb Part 1. - Ctrisoprodol promptly in response to painful s '=Ldus, but would not 1. Effect of Single Oral Doses in ,N:ott-addicted Patients show dilatation of pupil usually noticed in response to pain (i). Evidence has also been provided that =risoprodol may elevate Vethods. - Single doses of carisoproclol were administered the pain threshold in man using (a) high frequency electronic orly in capsules to f@sting, n2on-coleranc addicts at 8.30 a.m., sdmulacion to the tooth (Margolin, 2) and (b) an ultrasonic and observations were carried ouc at hourly intervals for stimulus to induce deep, aching pain to the hand (Holliday six hours, using the single-dos4: ooiare questionnaires (patients' & DiUc, 2).2 ancl observers' ratings). Phenyr=-iidot (2-[Bcm-hydro.-cyphenerhyl=iinol pyridine) Restilts. - Prelin@ experiments indicated that doses is also a CNS acting muscle relaxant, but in'contradis@cm-on below 1,000 mg induc2ed no significant subjective effects, to carisoproaol, it is e&cdve as an analgesic by orthodox but with higher doses certain effects were demonstrated, as withdmnv-al reflex tests, and its potency in anixrws is compa- shown in table 1. It was not, however, until a. dose of 2,000 mg rable to that of codeine -(12).2 Both compounds are being marketed as muscle relaxants, TAZLF I- Effects oi sinflie or-.tl doses of enrisoprodol effective in the relief of pain due to muscle spasrrn (11, 2). (putleiit rtting-3) Since both compounds represent new structural departures for analgesics, experiments were carried out at the Addic- ;u=btr tion Pescarch Center to ascertain if either possessed nior- of paUenLs pyindpa effects phine-lik-c addictive qualities in mam 4 1 050 3 - -- blank Genernl metliods .1 - c=nquil)L-er The subjects used in these studies were healthy adult negro 4 1 I-W 3 - , blank " or Nxliite males serving sentences for violation of state or I - rcl=cd federal narcotic laws, who volunteered for the experiments. 4 1 600 2 - bi3nk " AU -,vere former opiatc addicts. Since bodi drugs are be@ig 2 I - dope of 6 rc"tiscs) marketed for clinical tise by the oral route, and since addicts would have difricuit-y c.-ctracting these drugs for injection 5 2 ow 2 - dope from the @iert iiigrcfliciits with %vliich thcy are mixed, they 2 3 - barbicuracfs were evaluated orally only. The tcsts employed to asc-.rtzin is 2 500 1 - 11 dope " (2 of 6 rtspotiscs) addictiveiiess were: 6 - b2rbiturates 2 3 - 11 blank 1. Adiiiinistr-ition of siii@,le doses to noii-tolerant subjects I - I)clizcdritic for the detccdoti of iiiorpli@ic-like efflcts. This was ev-alu-.ited 4 - 8iiiisccilaticous by mcans of the single dose opiate. qticsrioruiaires (pariezits' 5 - slccpy and obscrvers' raciiigs k7 I 3 L@ Co- O", 0 0 2 g00. n"00ut el, rrnC: -0 oO Co,@n v; 2 0 P0 0 93 2 17' 0fol 54 INTENSITY OF ABSTINENCE - tiOURLY POINTS I a@ -, ;3 5ow , -W 0 fli Ca n C,0 -. 2 -4 O :tj tA 0 0 4A 0 0 2 0 L, 0. !-I 4r"i00 2 n 0 0 ew CoO 0 0 2 -4 @= ri.OO r 4D 420 &4 0 0 P 0 0 2 0 n -0 C]. cr0-a O 0 -0a- Pa. r- CL CLI 0 0 v 00 00 0 2 C;a cr 0:3 M 0 aM- -, It 'a 2 0 r.0 z r rb R n.2 Ul.< 0 'a Cy- ii @s 4 @; " .0- O 2 -0 0 CD 0 1-11 ".@ 4 a- t,O"- I 9: C., EtO 2 0 n.2 w ;-; -U-g 0 O S@: 0 0 .0 2 :!O . -0t n--0 0 0 0 M 0 0 2 P- 0 relo. )> C) r 0 C) 2 0 S. 5- fl- 0 0 2 1+ C: 6 0% @i. I 0 ;a 3 2 Z- 00cr 0 " ii. n 0ck@,@ 0 S.0 (r :j :I. cr 'O .Oo 2Ln na ;0, lo-r 2 O, 0 2 QQ @i, (b -r.. vnl 2 0 Co -O ; L: I) a ;g 0-1 t\ (n0 91 E; R' n8(n" 2 O- M - 0 0 0 ti., H n 2 iL 0 to 0 ;3 I ab 2 0 0th i, z 0 P3 at, r= 0 M 0 el 2 ;I- 91. 0C. , O- 3 P -r 2 -L 0 N 0 CA V Si 10 2 00 0 n0 o2 4 2 O r,3 0 0 -0 2 a-- LL 0 t;- - cr It 0 cr ---I C: - 9O 2 0 0 n:3 0UQ 2 0O or. :3. 2 0 n tr" 0 2 'A ij .4 aE C? a-8 2 VQ r u;i5 0 C(i- &3 r ncr 2 0 -C:) LO 5 t.,J 0 la Ul P, 0. abo suppressed partially by pcncobarbital (figure 1), but not had an additional F-EG after 45 days on the drug. During to a statistically sigiatcant degree (P <.l and >.05). The withdrawal, each of die 5 patients that had taken carisopr,),Il 3 patients rcctiving d2ie 4,300-ing substitution dose of cariso- for 18 days had an EEG 13 and 36 hours after the last .I()ic. prodol were quite sedated and somewhat diffici@t to arouse, and the patient that had carisoprodol for 34 days had one but showed only a. slight degree of'dysarduia and ataxia. EEG 13 hours 2and another at 24 hours after die last (to,,c. AU patients who received penrobarbimi were sedated and Revilts. - During chronic z&ninistration of carisoprodul, showed a slight to moderate degree of ataxia and dys'rthra; except for changes in the EEG pattern, tltc outstanding f@actir'e. certain subjects were confused. was a complete absence of any significant subjective eftcc-,s even when the dosage was increased to 4,800 ing-daly. in 3. Dimci Addictiort to Carisoprodol Other words, it was2 not possible to diarcntiatc carisoprodtl iwethods. - Five non-toicrant subjects were used in % from a'placebo (figur'e 1). single-blind " test - i.e., patients but not observers were FoHowiiig abrupt withdrawal of carisoprodol, the 4 patients unaware of the nature and schedule of mcdicatio2n. Starch that received it for 18 days showed no aucononiic signs of placebos and carisoprodol powder were cpared in identi- abstinence, and did not realize that their medication had bellti Pr cally appearing capsules, and all medication -%%-as dividbd changed. TAS scores (total scores under the rime-acrion equally among four doses daily. AU patients initially received curve during the 10 days of Nvithdrawal) averaged 77.3 during placebo capsules for 12 days, 4 received carisoprodol tor 18 withdrawal as compared with an average TAS score of days and one for 54 days. Carisoprodol was withdrawn 41.0 obscived during their lasc 10 days on carisoprodol. This abnipdy and replaced by identically appearing capsulei. The increase in thc@ absdlicnce scores during withdrawal is insigni- initial daily dose of carisoprociol was 1,200 mg; I this was fic=t, particularly in Nie,.v of the Ect that 2 the maximum increased at a rate of 200 mg daily for 16 days to 2 daily daily score was only 10.3 points during withdrawal. The dose of 4,200 mg, and then by 300 mgon the 17th and 1$th patient who received cuisoprodol for 54 days showed no days, attaining a dailv dose of 4,SOCrmg. The patie2nt receiving signs of abstinence .vhcn the drug was discontinued abruptly; cafiwprodol for 54 days received 4,800 mg daily from the tELe TAS score .vas 38 points, and the maximum daily score 18th to die 54th day. w2s only 7 poincs. This patient lik2ewise stated that at no time did he feel the medication, and he was completely unaware Observations were made three times daily throughout the odol had been discontinued. experiment, and the degree of abstinence was calculated by of the fa2ct that carisopr the daily point scores of Kolb & qin=clsbach (10). In one The EEG pattern after single doses of Y)O mg showed questionable barbiturate-like cttects as compared with the patient, mdcicc of physical dependence also evaluated (5) 2 by administering 2 mg of nalorpliine subcutaneously on the pre--drug EEG, but after single doses of 1,000 and ') 000 mg, 44th day, and 5 mg on the 48th day of cuisoprodol ach-iiinis- and during chronic intoxication (4,200-4,800 mg da@y), =don. Throughout the'@,est, patients and2 aides independently barbiturate-like effects were obtained. These changes consisted completed a chronic dosage opiate quescionnaire (7) at 7 p.nL of rhydunic and non-chydunic low- and mcdiuzn-voltage f@st daily. Clinical toxicity was evaluated by obsgn-adons and by activity (18-32 cps) seen more prominently in the fronml laboratory tests made prior to drug oLdminis=cio4.and repeated leads. In the 4 men who received carisoprodol for 18 days, at bi-wcelly intervals, when carisoprodol was administered, the EEG patterns 17 and 36 hours after the last dose of the as follows: routine analysts2 of urine, red and white blood cell drug were normal. In the case of the patient who took- cariso- counts, hemoglobin content, hemarocrit and liver function prodol for 54 days, the first EEG, taken 14 hours after the tests (diymol turbidity cephalin flocctdatioti and evidence of List dose of carisoprodol, showed a 2barbituratc-like effect, bifirubin in the urine). An electrocardiogram was made on but the one taken 36 hours after the last dose was normal. each patient while receiving placebos, and again.aftcr a high None of these patients showed focal or generalized abnor- ,dosage of carisoprodol had been rcached-i2.e., 4,200 or nialitics of the paroxysmal type during withdrawal, such as those seen following withdrawal of barbicurates (9, 13, 4). 4,800 mg EEGs were obtained using an eight-ch=icl resistance None ofthe clinical observations or laboratory tests shonved capacitance coupled Grass apparatus. Using needle electrodes, significant deviations from pre-.drug observations.' one bi-polar and three mono-polar tracings (linked and Chronic administration of carisoprodol on a progressive grounded) were obtained from frontal, temporal, parictal dosage schedule did not indu2ce a characteristic bar'Dicuratc and occipical areas (4) prior to achiiiiiistering drugs co die intoxication pattern (iiyscagnitis, dysartliria, ataxia in gait and 5 patients used in this direct addiction tcsr- in 3 of tlicse, die station, cotift*ioti, poor jtidgeiiienc and loss of c2liiotional subsequent eifccc of a single 300@-iiig dose of carisoprodol control), and wlicn carisoproliol was abruptly witlidrawn, no v,ru ascermiiied about one liour after c-.irisoprodol Nvas atiiiiiiiis- signs of b-.irbitLiratL-like abstinence (atLxic,-y, ine tremor,2 tered orally. In a similar niaiuier, the eff@cts of a single dose wcakiilss, coiivtasiotis iii@l delirium) were observed (9). of i,ooo mg were determined in one pitictit, atiki those of I-lo%vcver, it re.,il-.iiiis to be seen wlictlier adminis2tering cariso- ZOW mg in miodier patient. During die direct addiction test, prodol C011tilltlOLISly III larger DOSI-@S NVOtIll-I induce a. chronic EEGS; were taken on all 5 p-.icicnts one tiolir after die 10 state of iiicoxic-itioti a2nd Nvlictlicr abrtipc withdrawal under medication, wlicii a daily dos'age of 4,2CK) ot 4,800 iii.- liad such circttiiistaiices Would provoke a barbiturate or mcpr(,- bcl-n atrained. The piticiie receiving carisuprodol for 54 days baniate type of Ibstiiieiicc. Such possibility Is st5igglsced w by the fact that carisoprodol is a cons %vas %a absence of detectable objcc .zcncr of meproban=tc most inipri- and exl-@bits niatiy barbiturate-a-c pliarinacolot these tests. ,:ical citects. tive or subjective pliiriiiacoloei2cal effects in Part 11. - lllii-iiyr-.titiitiol 2. 24-hotir Sitbstittiti,,;t if Plicityrasitidol for Aforplitte 1. Efects of Sitigle Doses illetitods. - TliLse were die satiic as those oucliiiecl loc ,Irct2lzods,-Thcsc were the same as those described for carisopro@ol. carisoprodol Re5tilts. - lllienyraniilot in a total dosage of 1,500, nig- Restilts. - Scvenccen tests in a dose range of 100-730 mg (divided itico three equal dos,.-s) %vas substituted for 2240. iiig were conducted using non-colemiit subjects; 6 patients received of niorpwiic stdface in 9 patimics, alid was compared ,vith the =26mum dose of 750 mg. No cffccts -were reported aiter morpliine (coiitiiitied iii' the customary dosage) and with a any of these doses by any patient o2r observer, except sleepi- placebo substicutcd iii other tests using the s=nc patiencs. ZICSS, which was noticed by one patient after a 750-mg dose. As compared -,Vidi a placebo, phetiyr=iiidol slightly depressed The pupils were not consuicted. Neither the padencs nor s2ymptoms of abstinence from inorplliiiq, bur the degree of observers identified phcnyramidol as an opiate; in fact, the suppression was smtistically insignificiiic (figure 2). FE;!T DPUG IDENNFMD AS 'DOPE" 100 80 -J 2 0 0 0 a: 03 60 LU M C13 z a. LLI z a. 0 M 0 V) >- 2 z z 0 cr. w 40 a. < CL L) CL z CL .< 20 0 0 z 0 ;a 2 100 z u 8 0 e. 0 0 0 0 0 LLJ 0 LLJ cn 60 z cr_ z a. 2 CL u w 0 cr. w 0 tn >- > 0 U) z z 0 0 40 Q, w w CL a. 2 CL 20 0 t I I t I Yes Doii't care' NO Li 'WOULD I= TO TAKE DAILY "I:EEL BAD r-igurc 2. R,trit@gs E!J'p,itictii5 2ditriisg direct adlicti4,ti tests. A cotitp3ris4)n of itic average percctici,,-c rt.-spcliiscs tits' for ctiticiuc, carisuprodL)I, pliciivraiiiidul aiiti .2 piat:cb to the sinl 0 ,2.le dose (iticstiotiti.2irc (patic for the paratticters " feel dr%,L, idcntitic:Ltit)ri s , d(ipe %votilti like to take d.iilv ". atid ' l;:ci bad a The coiiiparisuti bctweezi coticitic alid a p2i.ia:cbo 6vas iiiide witli t'ite saille stib.iccts ill the Sallie cxpcriiiielit, but other cotitparis(itl,.i LLtween drtio %%-ere iiiade iii an-.ilo@,,otis btic @litt'4:rt,-tit exp,.riiiielits 7usiti,,- Lliti@rctit stibiet-ts. face fcci numb, I got a btizzitig in both cars, and I had trtittl)lc 3.- Direct A(ldictioll to Pliel'Y lid0l -tolerant subjects were used in -.i double- hearing. H2e also described 2 sensatiott at tiincs resciitbl' Afethods. - Four iit)n effects of bciizcdrilic or cocune, which would last for oillv blind test - i.e., neither patients nor observers .vcrc aware of the nature and sclic2tiulc of medication. Starch placebo and a few minutes. On the other lian-3, he had a relaxed feeiiiii,, phenyrmrtidoi powder were prepared in identically appearing when he laid quietly in bed. Since these cffccts appeiref.1 2 n r2Ldictory to him, lie inquired -Ls to whether his inedici- capsules, and all medication ,.-as divided into four equal co t don had been changed from tiiiic to time. None of die paticiits doses daily. Initially all patients received placebo capsules liked the citccts of phenyr=nidol, and die higli incidt.-nce of for 7 to 10 days, then all .vere given plienyrlraidol for IS da@l, 2 -,vo days. feel bad " reports as compared to the zero incidence of sucli' after which the drug was abrupdv withdrawn for t reports during chronic into-.ccadon with codeine is note- Medication was then resumed for an additional 42 days. The 2 worthy (figure 2). initial daily dose of phenyr=iidol was 600 mg, which was progressively increased until a daily dose of 4,500 mg %vas After 61 days of chronic intoacadon, none of these patients attained by the 18th day, and an attemot was made to smbdize realized that pla2cebo ca@sldes had been substituted. Abstinence patients on uhi-s dosage for the remainder of die experiment. scores were irisignific2nt; in fact, they were sinauer than After a total of 61 days of chronic drug administration. comparably computed scores obtained -,vliile receiving phenyraLTtidol was Aitha'ra,%N-ii on 2 doul4c-band basis by phenyran-iidol.- replacing it with identically appearing placebo capsules. Discu.%sion Observations -were the same as those made for evaldting la 2 the tests employed, neither carisoprodol nor phenym- - and EKGs were not obmin@d c2risoprodol, except EECN . . .midol showed any addictive properties of an opiate type. Remilts. - One patient took phen@-r=-ddol for 16 days. The Although 'c22m' oprodol is pliar=cologically similar in certaiii experiment was tea=3.ted on the 1-ich day, wl=n 'i d6sage respects to barbiturates, it is not as rapidly acting as certain of 4,200 mg had be= armiiied, because he had diifuse urticaria- barbiturates. When the dosa2ge of cazisoprodot .v2s rapidly Prior to this, the only s)-mptom noted by this patient w2s increased from 1,200 to 4,800 mg. daily %vidiin z period of sleepiness ". No symptoms or signs o?'abstinence developed 18 days, no evidence of incoacation W'IS noted - 2 suggesting after phenyramidol was discontinued, and the urticaria gra- th.2t some tolerance developed to the sedative and hypnotic d=Uy subsided. CTCM. The other 3 patients attained a daily dose of 4,300 mg by Suminary and conclusioni the 18th clay, and when medication was withdrawn abruptly The adclictiveness of orally administered carisoprociol and for two days they showed no evidence ot'abstinence..MCdic2- phenyr=iidol has been studied in former opiate addicts. tion was resumed 2 on die 21sz day, bur it was necessary to The procedures included effects of single doses, substitution reduce the dosage of two patic.,its to 3,300 mg daily because tests to suppress abstinence From morphine, and direct addic- of such complaints as indigestion, sleepiness, dizziness 2 aa don tests. numbness of the skin (figure 2). One patient continued on 4,500 mg of phenyrmd@oi daily, but he had a miatipliciry It is concluded that neither carisoprodol nor phenyrirnidol of, complaints; for =ample, he stated It =de my p2ossesses addictive qualities of in opiate type. REFERENCES @vi., LUDWIG, B. J., MAPGOLIN, S. HIMMELSBACH. C. 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