ADDEIII)U,A ADDICTIVENESS OF NEW SYNTli,-TIC ANALGESICS 1. Senzimidazole Derivatives: (a) 1.(Beta-diethyla-minoethyl.)-2-(benzyl.4-chloro)-5- nitrobenzimidazole (NIH-7586* ARC I-Cs-1), (b) 1-(Beta-diethylaminoethyl)-2-(p-e'%.hox2ybenzYl)-5- nitrobenzimidazole methane sulfonate (NIH-7607s ARC 1-0-2)s II. (-)-3.4iydroxy-N.(3.3-dimethylallvl)-morphinan hydro- bromide (NIIi-744'k-- Afie ,---; 7- 6- 1 III. N-(l-?Aethyl-2-piperidi4pet7hV ).pro2plo e hydrochloride d iY--7 -Z I (phenampromid @aii@ A ff 4 /) N-[2.([i%,'tethyll- lamino)-propyll-propioanilide phenethy sulfate (Diampromid.L---@Nii4-'71-03@) A1j?d T-7t7-i) BY Drs. H. F. Fraser., Harris Isbell and A. B. Wolbach NIMH Addiction Research Center Lexington, Kentucky 2, J. Benz>2pimidazole Der>2pivat>2pi>2pyes Data on the >1pt>1pwo benzimidazole >1pd>1pe>1pr>2pi>1pv>1pa>1pt>1pi>1pv>1pe>1p3 (hereinafter designated NIH>2p-7586 and NI>2pH>2p-7607>1p) is abstracted from a report 2 d>1p)>1p. Hunger et al. and by Isbell and Fraser unpubl>2pishe 3 Gross and2 Turr>2pia>2pn have found that some basically substituted >2p,benzimidazole derivatives have analgesic act>2piv>2pi>2pt>2py>1p. In addicted monkeys, Nll>2pi>2p-7586 was twices and >2pHI>2pl>2pi>1p-7607 was >1p1>1p5>1p0>1p0 >1pt>1pi>1pm>1pe>2ps as potent as morphine in alleviating abstinence>1p.>2p4 Since these compounds constituted a completely new chemical class of analgesics, N>2pI>2pH-7>2p586 and NIH>2p-7607 were referred to the Ad>1pd>2pi6ctio>1pn Research Center, U>1p, S. Public Health Service Hospital, Lexington, Kentucky$ for determination of their addictive potentialities In man, 2>2p. Page 2 Methods press>2pion after Because of reports of respiratory de parenteral administration* the oral route was used exclusively* NIH>2p-7586 was given In the form or compressed tablets, each containing 25 mg, NIH>2p-7607 was administered>1p'>2pin a solution in distilled water I2n concentrations of >1p0>1p.>1p0>1p1 and >1p0>1p.>2p1 mg/mi. Drugs were administered to patients in a fasting state. Identity of the drugs was unknown to the patients but was known to the observers ("single-blind"), Effects of >1pS>2pin>2pg>1ple>1p-Doses>2p-of NIH>2p-7586 and NIH>2p-7>2p=>2p. Observations were made one, t>2pv>2pio>2ps three, four>2p.>1p'six>2p, eight, ten, twelve and fourteen hours after medication and Included subjec>12p- tive effects as tabulated from questionnaires, measurements of pup>2pi>1pllary diamet>2pvr and recording of morphine-like behavior>1p.5 Thirteen subjects received NIH-7586 and 7 >1ps>1pu>1pb>1pj>1pe>1pc>1pt>2ps received NIH>2p-7607 and the ef>2pf>2pqct's observed were compared with those obtained In 14 subjects who received 20 and 30 mg of morphine, 60 and 90 mg of codeine, and a placebo (all orall y>1p) in another experiment. 2 >1p->2p. z>2pZ >2p-7 Page 3 Su>2pD>2ppress>2pion of abstinence was evaluated In p>2pat>2pient>2ps who were >2ps>1pt>1pa>1pb>1pi>1pl>1pi>1pz>1pe>1pd on 60 mg of morphine sulfate administered >1p5 subcutaneously four times daily. NIH>2p->2p7586 and NIH-7607 were substituted orally for morphine in amounts thought>2po >1p6>1pn the bas2is of preliminary experimentss to be approximately equivalent to >1p1>1p0 to 40 percent >1p(>1p1>1p8 to 72 mg) of the patient-Is accustomed dose of morphine. In the >1pc>1pa>2ps>1pe of NIH>1p-7586>1p, the dosages selected were 75 and >1p1>1p5>1p0 mg div>2pided Into three doses during the 24 hours. in the c>2pase of NIH>2p-7607>1p, the dosages chosen were >1p0>1p.>1p1>1p5 and 0>2p.3 mg, likewise divided Into three doses during the 2>2p4 hours. Da2ta were compared with those obtained In another experiment in which 9 patients received IS mg >1p(>1p1>1p0 percent of their accustomed dose), 36 mg >1p(20 perce>2pi>2pit>2p.>1p)>2p. and 90 mg >1p(>1p5>1p0 percent) of morphine sulfate subcutaneously In similar tests. Regression lines, estimates Of Poten>2pc>2py >1pof>2p-N>2pIH>2p-7586 and NIH>2p-7607 giv>2pen orally as compared with the potency of morphine given subcutaneously, and 95 pe2rcent confidence limits were, calculated according to the method 6 described by Bliss. A "short" >1p(>1p1>1p8 day),-"double-blind.* direct addiction test was carried out on NIH-7607>2p0 a>2pnd >2pIts add>2pictiveness by the oral route was compared wit>2ph that of morphine, heroin and a placebo, the latter three med>2picat>2pions being adm>2pin>2pistered subcu- taneously. The methods employed are 3described elsewhere by Page 7 Fraser>2ps Isbellp Van Horn and >2p1>2p4artin>1p. Eight nontolerant former opiate addlats were used, and each was exposed to all drugs. T>2pne average initial daily dosage of each drug was as follows: morphine>2pp 30>1p.6>1p; heroin, 13>2p.0>2p;>2p- and Nll>2pi>2p-7607>1p'>2p. >1p0>1p. >2p">2p->2p83 mg. The dosage of 2each drug was progressively accelerated and the final average daily dosage attained on the >1p1>1p8>1pt>1ph 'day was as follows: morphine, 207>1p.0>1p; heroin, 86>1p.8>1p; a.,id NI>2pE>1p-7607>1p, 2>1p.95 mg, All drugs were abr>2pup>2pt>2p*>2p.ly withdrawn and Identically appearing placebos substituted. Observations for >2pIntens>2pity of abstinence were made for ten days according to the method of Kolb and Himmelsbach employing a >2pi>2pt>21psta>2pndard>1p" and a "modified" H>2pi>2pnmelsbach >1p5 scoring pr>2pocedure>2p4>2p, Once daily throughout the >1pe>1px>1pp>1pe>1pr>1pi>1pm>1pe>1pn>2pt>2p4>2pa>2ps a "Chronic Dosage Attitude" quest>2pio>2pn>2pnaire for opiates >1p(patie>2pi>2pitst ratings) and a parallel "Chronic Dosage Attitude" questionnaire >1p8 for aides (observers' ratings) were >2pcompleted>1p. 2 Results Effects of>1p.S>2pin>2pgle Doses. The results as presented la Tables>1p'l a>2pid 2 are co>2p:>2pnpared with those obtained with 20 and 30 mg of morphine sulfate orally$ and with 60 and 90 mg of codeine sulfa>2p*>2p.c or--ally >2pI>2p.>2p->2pi another experi>2pn>1pie>2pn>2pl>2pk>2p.>1p. Both drugs induced typical morphine-like "euphoria" and behavior. NIH>2p-75>2p86 appears to be roughly o>2pi>2p4ie>1p-t>2phird to one-fifth as potent as morphine, and roughly equivalent to codeine in this respect. NIH>2p-7607 appears to be more than >2p8>1p0 to 120 t>2pi>2pm>2pe>2ps as effective as morphine orally as an >2pl>2pieuphor>2piant>1p.>1p" Page aides considered that the pa ttern of effects objectively resembled those of an opiate and were not impressed by the "non-opiate' characteristics of NIH>1p-7607>2p, Insofar as "estimate of strength" is concerned, patients considered the effects of NIH-7607 quite weak, since the average score on the weighted scale was only >1p1>1p.>1p0>2p, whereas morphine2 and heroin>1p,rated about 3>2p.5>2p. In response to the question, "would you like to take the drug daily?" only 16 percent of the responses >2pInd>2picated they 'would >1pl>2pike to take NIH>2p-7607 daily>2ps whereas 32>1p.6 percent Indicated they would like to take heroin daily., and 42 percent., morph>2pine daily (It should>1p'be pointed out that U.S. addicts prefer to take their drugs by Injection, and this may account in part2 for the subjects>2pv relatively low acceptance rate for NIH>2p-7607>1p, which was administered orally In this study). The low incidence ot positive responses following a placebos In the ratings by both patients and aides, Is noteworthy since no attempt was made to>2p'e>2pl>2pim>2pinate placebo responders In the selection of subjects>1p.7 When all three drugs were abruptly discontinued and replaced by a placebo>2p,>2p$>2p.a moderately sever1e abstinence syndrome ensued during the next te>2pn days ands>1p, as shown In Figure 3>1p. the sever>2pity of abstinence as judged by the total daily point >1ps>1pc>1po>1pr>1pe>2ps was very similar for morphine, heroin, and NIH>1p-7607>1p. The patients$ however>2po cons>2pidered that abstinence Page 7 from NIH>1p-7607 was somewhat less severe than that which followed withdrawal of sub>2pcutaneously administered morphine and heroin; this might be In part due to a more gradual onset of symptoms when drugs given orally are discontinued. These experiments indicate that a very high degree of physical dependence, co>2pmpar>1pable to that produced by morphi2ne and heroin,, develops when NIH>2p-7607 Is administered chronically on an abusive schedule. Summary >1p1>2p0 The add>2pict>2pion liability of orally adm>2pin>2pis>2p">2ptered 1>2p->2p(Beta-diethylam>2pinoethyl)>2p-2>2p->1p(benzy>1pl>2p->2pk>2p-chloro)-5-n>2pitrobenz>2pim>2pi- dazole >1p(NI>2pE>1p-7586>1p) and 1>2p->2p(Beta-diethylaminoethyl>2p)>2p.2>2p.>2p->2p(p-ethoxy- benzyl>1p)>2p-5>1p-nitrobenzim>22pidazole methane sulfonate >1p(NIH>2p-7607>1p) has been Investigated In man, 2>1p. In single doses both NIH>2p-7586 and NI>2pF>2p.>2p->2p-7607 Induced morphine-like subjective >1pe>1pf>1pf>1pe>1pc>1pt>2ps and behavior In nontolerant former morphine addicts'* NIH-7586 Is one-fifth to one-third as potent as oral morphine In Induc >2ping subjective effects, whereas NIH>2p-7607 Is >1p8>1p0 to 120 t>2pi>2pmes as potent as morph3ine in this respect. Both drugs constrict the pup>2pil's>1p. 3>1p. Both Nll>2pi>2p-7586 and NIH>2p-7607 suppress sy>2pmpto>2pms of abstinence from morphine. page 4. When NIH-7607 was given in a direct addiction study the overall pattern observed during chronic administration wid following withdrawal reseinbled that of patients gilien morphine or heroin, Although ldentiill--d a3 an opiate, patients were much impressed b,,-, the hypnotic nations of 2'6his drug. It is concluded that Ntli-'75'6 and NITI-7607 have addictive potentials co!nparable to that of morphine. @--a-Hydro=-N.(3, -dimethylaltyl)-morphinan hvdro- bromide. This compound, developed by Hoffman-Le Roche and herein. after designated as IiIH-7446$ 2is structurally related to levallorphan. Nalorphines although an effective analgesic, provokes disturbing mental effects which preclude its use as an analgesic. Therefore an effort has been made to find nonaddicting compounds of the nalorphine type with fewer undesirable side effects. One of these, NIH-7446, was referred for study. Keats found that NIIi-7446 was as potent as ,morphine as 2 an analgesic In relieving postoperative pain.-but, when given In equivalent analgesic doses to normal subjects, was only half as potent as morphine In depressing respiration.9 However in another experiment, In 3 patients) high doses (1 mg/kilo) of NIH-71@46 provoked-resplratory depression which %,,as equivalent to that induced by morphine and which was dramatically antagonized 9 7 by nalorphine. Page 9 hine>1p-antagon>2pi>1pst>2pi>2pc In comparison with nalorph>2pines the morp properties of Nll>2pi>2p-74>2p46 are not prominent. Thus Keats found that NI>2pf>2pi>1p-744 6 produced little antagonism In 3 patients >2pwho had 9 received morphine (I mg >2p9>2p)>2po In2 the following presentation# the add>2plctivenezs of NIH>2p-7446 >1pw>2pi>1pl>1pl be evaluated from the v>1piewpo>2pint>2ps of >1p(>1p1>1p) the effects of single doses>2ps >1p(2>1p) Its antagonist>2pic properties In morphine-dependent subjects$ and >1p(3>1p) >2pIts ability to suppress symptoms of abstinence >2pIn morphine-dependent patients. Methods Effects of S>2pin>2pgle>1p.Subcut>2pene>2pcus Doses of N>2pIH>22p-7>2ph>2pJ>2p@>2p6>2p@>2p->2p(10 and >1p1>1p5 mg) as Compared >2pv>2p4>1pi>1pt>1ph Corres>2pn>1ponding Doses of >2p?>2p,>2p,or>2pph>2pine>2p.Sul>2p.fate. Effects were evaluated In a >1p"single>2pwb>1pl>2plnd>2p#>2p" cross-over exper>2pi>1p- ment>1p.employing 9 nontolerant former opiate add>2picts>2pt each of >2p%>2pvhom rece>2pived in a randomized order at weekly >2pIntervals >1p1>1p0 and >1p1>1p5 mg of >2p1>2p41H>2p-7446>1p, and >1p1>1p0 and>2p-15 mg 2of morphine sulfate, Observations were made 1>1p/2>2p, l>2pi>2ps >1p2>2pi>2ps 31>2p, >1p5>2pi and 7>2p1>2p.hours after medication. These >2pIncluded responses to the "Single Dose Attitudea question>2pg>2pe na>1plre >1p(>2ppatientst rat>2pLngs>2p)>2p18 "Single Dose Att>2pitud>1pe>2p" que>2pst>2pio>2pnnaire >1p8 >1p(observer>2pa>2pt ratings>1p)>1ps and measurements of the pup>2pillary diameter made In a room with controlled1 light>2ping>1p.5 In tabulating the data emphas>2pis >1pw>1pa>2p3 placed on the >2pIn>2pc>2pidence of >2pv>2ptopiate>1p" symptoms and the extent to >2pi>2p;hich these former addicts "liked!' the med>2pica>2p*>2p%>2p.>2piono as evaluated in a weighted scale. >2pPa>2pg>2pe >1p1>1p0 24>2p->2pHour Substitution of Nll>2pi>2p-7>2p1 6 for Mor>2pphine>2pg as Compared with Mor>2pv Nine line Continued, and with>2p-a Place>2pb>2p-o>2p. addicted patientsp who were stabilized on an average of 240 mg of morphine sulfate da>2pi>1ply>2pp received as a substitutean average 2 of 200 mg of NIH>2p-74>2p46 (divided among four equal subcutaneous doses). This was compared with >1p1>1p8>1p0 mg of morphine sulfate and >1p5 a placebo continued in the same patients. (Note that only three Injections of 60 mg each of morphine sulfatet or a total ,of >1p1>1p8>1p0 mg during the Interval of substitution, Is e>2pqu>2pival>2pent to 240 mg of morphine sulfate daily, since the fourth 2Injection of morphine Is due at the end of the 24 hours). Observations for Intensity of abst>2pinence were made from the >1p1>1p4>1pt>1ph through the >1p2>1p4>1pt>1ph hour of substitution, and the total abstinence >1ps>1pc>1po>1pr>1pe>2ps for eleven hours >1p(TAS>2p.>2p->1pI>2pI>1p) were calculated >2p1>1p0 according to the method of Winter and Flataker>1p. The paired t>22p->2p-test>1p, using each individual as his own control, >1pw>1pa>2ps employed to determine whether there was a significant difference In the TAS-11 scores for NI>2pI>2pi>2p-74469 morphine, and placebo. >2p1>1p1 Antagonistic >1p(Nalor>2pph>2pi>2p,>2p->2p,>2pi>2pc>1p) Characteristics were evaluated by administering 2 to 20 mg of NIH-7446 subcutaneously to >1p5 patients chronically receiving 240 mg of morphine sulfate daily. NIH-74460 was given two to three hours after the last >1ps>1pu>1pb>1pc>1pu>1pt>1pa>1pn>1pe>2po>1pu>1ps Injection of morphine and patients were observed for signs of abstinence fro>2pn morphine., Page 12 Antagonistic (Nalorphine) Characteristics. No evidence of any effect was observed when 2 to 10 mg of NIH-7446 was administered to morphine-dependent patients. Howevers the patients stated that when the dosage was Increased to 20 mg there might have been a slight "boost" in OpLate-lLke effects. There was no evidence of precipitation 2of abstin;ance by admin- lstration of NIH-7446 in any of the tests. Summarv It is concluded from these 'Studies that the qualitative and quantitative effects of NIH-7446 are very similar to those of morphine$ and Its addlctiveness probably approaches that of morphine. III, (a) N-(I-Methyl-2-,P2IT)eridinoeth)rl)-oropioantlide hydrochloride (Phenamoromid)., and (b) N-(2-([22etEhyll-pheneth-vlamino)-proDvll,= flide sulfate iampromid). pro.pioan These drugs (Phenampromid an d Diampromid) were developed 2 by Wright, Brabander and Hardy. 12 The analgesic potency of Phenampromid equalled that of codeine In mice, and meperldine In rats. Diampromid approximated the analgesic potency of 13 meperidine In mice, and of morphine In rats. Ilalorphine antagonized the analgesic and respiratory depressant actions of both compoundssl3 and both were effective analgesics In prelim- 14 .1nary trials in man. Page >2pI>2pA The methods used for evaluating the addictiveness of these compounds In man were similar to those enumerated for NIH>2p-7446>1p, except that when single doses were administered Incomplete comparisons were made with morphine adm>2pin>2pi>1p-stered to the same subjects* For convenience in presentation, the results obtained wit2h the two drugs will>1p.be presented'separately>1p. Results. (a) Phe>2pnamprom>2pid Effects of Single, Subcutaneous Doses of P>2phena>2pm>2pp>1prom>2pid>1p. These were evaluated using the 'Single Dose Att>2pitudel>2pt question- >1p8 na>2pl>2pbre >1p(>2ppat>2pientst ratings) In sixteen tests In a dose range of >1p1>1p0 to 200 mg. Observations were car>2pr>2pied out 1>1p/2>2p2 l>2pi>2ps >1p2>2p2i>1ps >1p3>2pi>1ps >1p5>2p1 and if hour>2ps after medication. Definite opiate-like subjective effects were reported with doses of 75 mg. Six patients received 200 mg. In this dosage$ one patient liked the drug >2pnsl>2pightly>2ps>2p" four, "moderately," and one., Ilan awful lot>1p.>1pn >1pS>1pu>2pl>2p2>2pD>1pr>1pe>1ps>1ps>1pi>1po>1pn of A>1pbst>2pinence from >2pi>2pl>2p,>2p.>2pIor>2pphine with Phenam>2p->2poromid was evaluated In the9 same 9 subjects used In the studies on Nll>2pi>2p-7446>1p. For comparative purposes>2ps 24>1p-hour -substitutions were also carried out with morphine >1p(po>1pt>2pitive control) and a placebo >1p(negat>2pive control) on each subject, The average dosage Page administered during the 24 hours was 1135 mg>2pt divided>1p'among three approximately equal subcutaneous doses. At the conclusion of the substitution each patient completed the >2p"C>2phron>2pi>2pc Dosage Attitude" questionnaire >1p(>2ppat>2pientsf ratings).>1p8 The Intensity of abstinence was measured hourly from the >1p1>1p4>1pt>1ph through the >1p2>1p4>1pt>1ph 2 hour during the Interval of substitution.. using>2p,the >1p"modif>2pied>1p">2p. >1p5 H>2pi>2p=elsbach hourly point score& Although,, during the subst>2pi>1p- tut>2pion>1p, 4 of the 9 patients Identified Phenampromid as being >1p"dope>1p,>2pi>2pt all emphatically stated they did not like the effects of the medication. T>1phey complained that It gave them a >2pt>2ptweird feeling" which they had not experienced pr2eviously>1ps and compared Its effects with those of lysergic acid d>1piethylam>2pide >1p(LS>1pD>1p-25>1p)>2p, cocaine, or marihuana. Abstinence phenomena were partiallys but s>2pignificaatly>1p, suppressed by P>2pl>2p@enampromid (Figure >1p5>2p)>2p.>2p' Because of the disturbing side effects It was not feas>2pible to employ larger doses-of Phenamprom>2pid In order to evaluate the pharmacolog>2pical equivalence of morph>2pine and >52pPhenamprom>2pid more completely. Page >1p1>2p->2p->2p) Results. >2pt>2pb>2p) >1pD>2pi>1pa>1pm>2pi>2p3>1pr>1po>1pm>2pi Effe>2pcts of >1pS>2pi>1pn>2p2>1pl>1pe Subcutaneous Doses of D>2piampro>2pm>1pid were evaluated In twelve tests In a dose range of >1p5 to 75 mg, using the "Single Dose Attitude" questio>2pnnaire >1p(pat>1ple>2pnt>2p->2pst ratings) and the parallel questionnaire f2or observerst ratings. With doses of >1p5>1p0 and 75 mg, -very typical nsubjectiven morphine-like' effects were reported by the patients and characteristic ,morphine-like behavior was observed by the aides* A dose of 75 mg was considered to be roughly equivalent to 20 mg of morphine subcutaneously. Although peak effects were similar to t>2phose of morphine, all patients complained that the medication had a short duration of act>22pion>1p, and this was substant>2piated by pup>2pillary measur ements>1p, which Indicated that maximum mios>2pis persisted for only two and one,-half to three hours, Effects of Single intravenous Doses of D>2pia>2pmDromid were evaluated In a pilot study using >1pd>1po>1ps>1pa>1pg>1pe>2ps as follows: 20 mg (I subject>1p)s 25 mg >1p(2 subjects), and 75 mg (I subject). >1p"S>2pingle Dose Attitude's questionnaires were completed by both 6 the subjects a>2pnd observers, and the pupillary>1p-diameter was measured at >2pI>1pn>1pt>1pe>1pr>1pv>1pa>1pl>2ps as described for single subcutaneous doses. In these doses, all subjects >2pc>2po>1pn>1ps>1pi>1ps>1pt>1pe>1pn>1pt>1pl>1py Identified the medication as >2p"dopen and the extent to which they liked the Page >2p1>2p->2p'>2pO medication ranged from 'slight" to "a lot." The pat>2pi>2p'nt who >2pe received 75 mg of>1p.>2pDia>2pmprom>2pLd became pale one minute after the injection and had difficulty walking to the observation room. He sat on a chair and very promptly fell a>1ptleep>1p. He>2p'was given >1p1>12p0 mg of nalorph>2pine intramuscularly about four minutes after the Injection of D>2piamprom>2pid>2ps a>2pnd recovered rapidly. No further >2pIn>2pje>2pctions of nalorph>2pine were required. Suppression of A>1pbst>2pinence>2p->2p-f>2p->2prom >2p?>2pAorl>2pphine with D>2piam>2ppromi>2pd >2pwas evaluated in the same 9 subjects employed for Phenamprom>2pid>1p, using the same controls and methods of observation. A dose of 750 mg (di2vided among four equal doses) was subst>2pitu ted fof morphine in >1p8 of these' subject>2ps>2p, and in one subject a dose of 625 mg, similarly divided, was used. D>2piampromid substituted quite adequately for morphine in this dosages but the chief >2pco>2pm>2pp>2plaint of the pat>2pients was: "it only holds you for about two hours." This observation is conf>2pirmed by the >2pInt>2pe>2prmittent peaking of the abstinence scores, and I9n each instance abstinence symptoms were promptly rel>2pieved by medication (note the >1pa>1pr>1pr>1po>1pw>2p3 In F>2pi>1pgure >1p5>1p)>1p. In the case of D>2piampromLd>2p.>2p, the total TAS>2p-11 score was significantly greater than that observed when morphine was cont>2pinued in the same patients, but the abil>2pity Page Is References 1. isbellg H, and Frasers He F.: Unpublished data. 2. Hunger, A. J., Kehrle, J.$ Rossis A'.. and Hoffman, K.o. -Synthese basich substiturirters analgetisch wirksauer Benzimidazole-Derivate. Experientia, 13: 400, 1957. 2 3. Gross$ F. and Turriarrs H.: BenzLmidazole Derivatives with Marked Analgesic Action. Experientia, 11: 401-403 (Oct-0 ef7 4. Deneau, G. A.v McCarthy, D. A.t.and Seevers$ M. H.: Physical Dependence Liability Studies In the Monkey. Addendum 1. Min. 20th ?Aeet., Comm. Drug Addiction and Na2rcotics, Natf. Res. Council. Washingtons D. C. Natl. Acad. Sci. (Jan.) 1959. 54 Fraser# H. F. and Isbell# H.: Addiction Liabilities of dl@2t.-Hydroxyi5,9.dlmethyl-2-(2-phenethyl)-6,,7-benzmorphan HBr (NIH-7519) and 1-3-Hydroxy-N-phenacylmor'phlnan methane sulfonate (NIH-7525). Addendum'3. Min. 520th Meet.,-Comm. Drug Addiction and Narcotlcs.-Natl. Res. Council. Washington, D. C. Natl. Acad. Sci. (Jan.) 1959. 6. Bliss$ C. I.: The Statistics of Bioassa@r. With St)ecial Reference to the Vitamins. New York. Academic Press. 1952. 7. Fraser, H. F., Isbell, H.$ Martin, W. R. and Van Hornt 0. D.: Unpublished data. Page 19 >1p8>1p. Fraser, >2pH>1p. F. and Isbell, >2pH>1p.>1p: Human Ph armacology and >1p-pheny>1plpropyl>1p)>2p->1p4>1p- Addictiveness of Ethyl 1>2p->2p(3>1p-CYa>2pn>2pO>2p-3>1ps3 pheny>1pl>1p-4>2p-piperid>2pine carboxylate hydrochloride >1p(R>2p-11329 >2pDiphenoxylate2>1p)>1p* Addendum Min. >1p2>1p1>1ps>1pt >2pl>2pfeet>1p->2pin>2pg>1p-Co=>1p.>1p,on >1pD>1pr>1pu>1p2 Addiction and Narcot>2pics>2p.>1p->1p->1p->1p- Nati>1p. Res. Council. Wash>2pington>1ps D. C. Natl>1p. Acad>2p. Sc>2pi>1p. (Jan.) 1>2p,960>1p. >1p9>1p. Keats, A.: Personal communication. >1p1>1p0>1p. Winter, C. A. and Flataker>2pt L.: Studies on l>1pieptazone (6>2p->2pL>2p'orph>2pol>2pino>2po>2p-4,>2p4>1p->1pD>2piphe>1pnyl>2p-3>1p-Hepta2none Hydrochloride) In Comparison with other Analgesic Age>2pr>2pits>1p. J. Pharma>2pco>1p-1>1p. >1p& Exper>1p. Thera>2pp>2p.>1p,>2p,98>1p: 305>2p-317 (Mar.) 1950>1p. Edwards, A. L.: Statistical Analysis for Students in Ps>2pych>2polo>2pc>2pi>1p->2pY and Education. New York. Rinehart >1p& Co>1p.s Inc. 1946>2p0 12>1p. Wright, Bra>1pbander and Hardy: J. Am. Chem. So>2pc>1p.>2p, >1p8>1p1>1p: >1p1>1p5>1p1>1p8>1p, 6 1959>2p* 13>2p- Osterberg, A, C. -and Rauh,, C>1p.>1p.E>1p.>1p: The Analgesic Action of D>1piampromid and Phena>2p.>2p->2pipromid>1p; N>1p->1p(Tert>1p-amino alkyl>1p)>2p-PropLo>1p- an>2pilides>1p. Pharmacologist, >1p1>1p: >1p(2>1p) 78 (Aug-Sept.) 1959>2p- 14>2p- Place,, V. A.: Personal communication. Page >2p'e>2p@>2p-0 Table I >2p"Subjective>2pO characte>2pr>2pization of >2pK>1pI>2pR-7586 and NIH-7607 as compared with morphine, codeine and a placebos all adm>2pin>2pistered orally. >1p+ Number of Patients Res>2pDond>2pi>2pn_>2pq Positive Positive 2 Dose No. of for for other >2pQuestion>1p- D>1pr>2pu>2p-g>2p->2p->2p7 >2pm>2pq>2p- .--(Mg) Subjects 02>1p.>1pLates Drugs able Negative__ NIH>2p.>2p.>1p7586 >1p1>1p0>1p0 13 3 >2p4 Nl>2pH>2p-7607 0>1p.25 7 6 >2p1 >1p0 >1p0 Morphine >1p* 20 1>2p4 7 >1p1 El] 3 3 Morphine >1p* 30 2 >2p1>2p)>2pi>2p, 7 2 3 2 Codeine >1p* 60 it >1p5 >1p1 El] >2p4 >2p4 Codeine >1p* 90 >1p1 6 >1p1 >1p5 2 Placebo >1p* 1>2p4 >1p1 El] >1p1 12 >1p+ For met>1ph>2pod of scor>2ping>2ps see Reference No>1p. >1p5>1p. Figures in brackets represent patients wh4o also reported positively for op>1pia>2pte>2ps>1p. Data from another experiment. 1>2p3 >2p- Page 21 Table 2 Pupillary constriction after NIH-7586 and NIH>2p-760>2p1>2p,>2p1 as compared with morphine, codeine and A placebos all given orally. Dose No. of Mean Area Under Curve Drug (mg) Subjects O>2pL>2p% Hours >2pi S>1p.E>1p.>1p) NIH>2p-7586 2 >1p1>1p0>1p0 13 8>2p-14 >2pt >1p0>2p->1p8>1p1 NIH>2p->2p*7607 0>1p.25 T 10>2p-9 >2pi 1>1p.35 Morphine >1p* 20 it 11>1p.>2p4 2>2p.5 Morphine >1p* 30 >1p1 17>2p.1 3>1p.2 Codeine >1p* 60 1>2p4 9>2p.0 1>2p.7 Codeine >1p* 90 1>2p4 9>1p14>2p-4 >2p->2pi 2>2p.4 Placebo 14 0>2p-4 >2pi >2pi>1p.63 Data from another experiment. >2p:D >1p0 1>1p3 >1p0 7607 NIH MORPHINE IH>2p-7586 120 >1p1>1p1>1p0 L>2pL>2pJ >1p1>1p0>1p0 >1po >1p+ 2 90 co < Y=215>1p.18>2p-72>1p.91 log>1px >1p8>1p0 >1p0 >2p>>1p- 70 >2pl>2pmg>1p. NIH>2p-7607=59.3(15.6>2p-136.5>1p)mg.MORPHINE >1pZ 60 >2pL>2pi>2p->2pi >1pl>2pmg>1p. MORPHINE= 2>1p5.62>1p(1>1p.00>1p-6>1p.59>1p)mg>1p.NIH>2p-7856 >2pz >1p0 0>1p.25 0>1p.6 >1p1>2p8 36 >2p75 >1p1>1p5>1p0 LOG. DOSE >1p(mg>1p.TOTA>1pL>1p) IN SUBSTITUTION PERIOD Figure >1p1>1p. Addictiveness of >2pi>2pnew Synthetic Analgesics. >1pDAC Report, January 196o>1p. Page 23 Legend for Figure 2. Figure P-, Summary of the results of 'Chronid Dosage Attitude" Questionnaires Independently completed by patients (patients' ratings) and aides (observers' ratings) when they evaluated the effects of heroin, morphine, Nlli-7607, and a placebo during an 18-day,, ttdouble-blind," direct addiction study. TE OF "STRENGTH" OR POTENCY IDENTIFIED AS "DOPE" OR OPIATE ESTIMA P A P A P A P -A 2 >1p1>1p0>1p0 >2pw >2p8>1p0 4>1p.00 A >1p0 2 A co >2p:>2pD A 2 >2p60 >2p3>1p.00 co >2pt>2pn >2pi >2pP >2pL>2pL>2p) 2 >2p0 co >2p(>2pD F- >2pU>2p) >2pz co >2pw 40 2 >2pw >2pU>2p) >2p2>1p.00 >2p(>2pn YE>2p@>2p' >2pz >2pw >1p0 >2p0 >2pc>2pr >2pw 2 >2p9 o: >2pW >1p0 >2p0>2p. a. >2pw >2pZ >2p20 >2pz >1p1>1p.>1p0>1p0 2 >2pu n>1p. P A >1p0 >1p0 >1p0 2 >2pw >1p0 >2p(n >2p(n W >2pw IDENTIFIED AS NON-OPIATE >2pw WOULD LIKE TO TAKE DAILY" >2pC>2pL >2p>>2p- 2 >2pw >2pw P A P A P A P A P A P A P A P A >2pioo >12p1>1p0>1p0 D >2pw > >1p8>1p0 >1p8>1p0 >2pc 2 >2pw CD 60 co 2 >2p">2p1>2p(3>1p; to >2pr>2pa >1po >2pL>2pt >2pc>2pn >2p(>2pn >1p0 >2pw 2 >2p:>2pD >2p: >2pU>2p) NO$' >2p4>2p1>1pN>2pO>2pf>2pl >1p0 In >2pz 2 4 z >2pw 40 >2pw a a. 2 >1p0 >2pc>2pr_ cc >2pc>2pr >2pw >1p0 2 >2p:>2p:>2p">2pw >2ply >2p->2p' >2p.>2p:>2p:>2p">2p< 20 >1p0 >2pw >2p20 >2px E>2pS>2pr I!.,; 2 >2p2 >2pw >2pC>2pL YE>2pI>2p, > >1po >2pB>2p->2p0 2 >2p< >1p0 P =PATIENTS A =AIDES Page 24 Legend for Figure 3>1p. Figure 3>2p, Comparative >2pintensity of abst>2pi>1pnenc>2pi after abrupt withdrawal of morphines hero>2pin>2pt and NIH>2p-7607>1p. >2pDa>2pi>1pl>2py point scores were compu>2pt>2p,>2p-ed by using the averages>2p'for rectal temperatures respiratory rate# blood pressure and caloric intake observed during >1p71>1p0 days on placebo ("modified" Himmelsbach procedure>1p)s and the >2pl>2ptstandard>1p" Himm>2pelsbach pro ce>1p- dure in which the above variables were computed from those observed during the>2p'last seven days on drug. The TAS>2p-10 val>2pues represent the mean areas (total intensity of absti>2pnence for >1p1>1p0 days). ?age 25 Legend for Figure Figure Comparative effects Of 10 and 15 m- of morphine sulfate and 10 and 1.5 mg of NIH-74a.6 (patient3t ratings) In respect to t,,ie Incidence of Opiate symptoms (maxlmum possible positive an2swers hourly = 7.0),* and a weighted attitude score (maximum possible hourly score a 4.0). "TRS" v-"Iues represent the meaa-i areas (total response scores for 7i hours) -6 standard ,areas of the mean, It should be noted that morphine and iiIH-7446 showed very similar effects in respect to these variables. There was a tendency for the effects of ,aorphlne to develop more rapidly thar. did those of Nli'i-7L@46. OPIATE SYMPTOMS POSITIVE ATTITUDE SCORES POSITIVE ANSWERS >1p0 >2p@>2pn o >2p0 >2p0 >1p0 >1p0 >1p0 >1p0 >1p0 >1p0 LE >1po >2po 2 >1p0 >2pz >2p(>2p:7>1p) >2pr >2p90 2 >2pr>2pn >1p0 >2prn >2p0 >2p*>1p0 >2pZ ID 2 >2pr>2pr>2pi >2p3>2pm>2pz>2p> >2p->2p0 >2pm >1p0>2p0>2p- >2pm 2 >2pt>2pv >2pC>2p4 >1p0 >2p0 >2p0 >1p0 >2p1>2p+ >1p-4 2 >2p.>1p0 >2p0 >2pm >1p0 >1p0>2p- >2pc>2pn >2pL>2pj >2pz 2 >2p6 >1prn >2pu >2p4>2p->2p->2p' >2pi>2po >2pm >2p0>1p0 >2pr>2pn 2 >1pC>2p) >2pz >2pm >2p6>2p)>2p00 6 co co >1p0>2p0 L Page Figure >1p5>2p- Legend for Figure >1p5>2p, >1pC>1po>1pm>1pp>1pa>1pr>2pi>2ps>1po>1pn of average>1p.>2pintens>1plty of-abstinence during a >2p2>2p4>1p-hour substitution of >1p(>1p1>1p) a placebo, >1p(2>1p) NI>2p]i>2p-7446s >1p(3>1p) >1pPhenampromid>2ps >1p(>2p4>1p) D>2piampr>2pom>2pid>1p, and >1p(>1p5>1p) morph>1pi2nes continued in the same 9 subjects addicted to morphine evaluated by the 'modified' Hlmmelsbach hourly point syste>1p'>2pm>2p. The TAS-11 values represent the total abstinence hourly scores for eleven >1po>1pb>1ps>1pe>1pr>1pv>1pa>1pt>2pi>1po>2pn>2ps>2p, starting from the >1p1>1p4>1pt>1ph and continuing through the >1p2>1p4>1pt>1ph hour of abstinence, >2pi the standard error of the means. In the case of D>2piamprom>2pid>1p, arrows >2pI>2pndi>52pcate that medication was given >2pI=ediatel>1p,y following the abstinence score Illustrated.