Doc 0000151878

.. .. ." ... - ... I . ADD&~DUM ADDICTIVENESS OF NEW SYNTHETIC ANALGESICS I. Benzimidazole Derivatives: (a) 1-(Beta-di ethylaminoethyl.)-2• (benzyl-4-chloro }-S nitrobenzimidazole (NIH-7506, ARC I-G-1), (b) l-(Beta-dlethylam!noethyl)-2•(p-ethoxybenzylj-5- nitrobenzimidazole methane sulfonate (NIH-7607 1 ARC 1-G-2), (-)-3-Hydroxy-N-(3,3-dimethylallyl)-morphinan hydro ll. bromide (NIH-744~)]-B-/1 N-(1-Methyl-2-piperidi~~~thyl)-propio~nili~e hydrochloride III. (Phenampromi cl )§and (~ln-'1"" 2 ..J ,4 fl~ .J. -I-lj N•{ 2-([Ivlethyl] •phenethylamino )-propyl] -propioani llde sulfate (Diampromid~NiH-76()3 J AiC:: L.~J-i} By Drs. H. F. Fraser, Harris Isbell and A.. B. Wolbach NIMH Addiction Research Center Lexington, Kentucky ---- .. I. Benzimidazole Derivatives Data on the t~ benzimidazole derivatives (hereinafter designated NIH-7586 and NIH-7607) is abstracted from a report - ) 1 2 by Isbell and Fraser ( unpublished. Hunger ~!l· and 3 . Gross and Turrian have found that some basically substituted 'benzimidazole derivatives have analgesic activity. In addicted monkeys, NIH-7586 was twice, and NIH-7607 was 1500 times as pot~nt as morphine in alleviating abstinence.~ Since these compounds constituted a completely new chemical class of analgesics, N!H-7586 and NIH-7607 were referred to the u. s. Addiction Research Center, Public Health Service Hospital, Lexington, Kentucky, for determination of their addictive potentialities in man. -- Page 2 Methods Because of reports of respiratory depression after parenteral administration, the oral route was used exclusively. NIH-7586 was given in the form of. compressed tablets, each containing 25 mg. NIH-7607 was administered ·in a solution in distilled water in concentrations of 0.01 and 0.1 mg/ml. 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 Slnqle Doses or NIH-7586 and NIH•7601. Observations were made one, tvro, three, four, ·six, eight, ten, twelve and fourteen hours after medication and included subjec• tlve effects as tabulated from questionnaires, measurements of pup11·1ary diamet-er and recording of morphine•like behavior.S Thirteen subjects received NIH-7586 and 7 subjects received NIH~7607 and the eff~cts 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) in another experiment. ~.·- ·~ Page 3 Suppression of abstinence was evaluated ln S patients who were stabilized on 60 mg of morphine sulfate administered 5 subcutaneously four times da!ly. NIH-7586 and NIH-7607 were substituted orally for morphine in amounts thought, 6n the basis or preliminary experiments, to be approximately equivalent to 10 to 40 percent (18 to 72 The image displays a graphic with the words "THE BLACK VAULT" in a stylized font at the top, set against a dark background with blue neon accents. To the left, a portion of a large, circular vault door is visible, rendered in metallic tones and featuring various complex mechanical details like gears and a central dial. The right side of the image contains white text on a black background, explaining that the document was obtained from The Black Vault, an online database of declassified government documents, specifically referencing the MKULTRA/Mind Control Collection. Below this text, a yellow hyperlink is prominently displayed: "http://mkultra.theblackvault.com". There are no photographs, handwritten annotations, official stamps, forms, diagrams, tables, redactions, or visual evidence of experimental procedures on this page. This document is a typed page with handwritten annotations made on it. At the top right, a circled handwritten number "158" is visible. The text begins with the heading "ADDENDUM" and then details "ADDICTIVENESS OF NEW SYNTHETIC ANALGESICS." Several chemical compounds are listed by name and alphanumeric identifiers, some of which appear to have been handwritten and are thus partially obscured, making full transcription impossible. The document concludes with the authors' names and institutional affiliation. A handwritten number "B-229" is present in the bottom right corner. abstinence was evaluated ln S patients who were stabilized on 60 mg of morphine sulfate administered 5 subcutaneously four times da!ly. NIH-7586 and NIH-7607 were substituted orally for morphine in amounts thought, 6n the basis or preliminary experiments, to be approximately equivalent to 10 to 40 percent (18 to 72 mg) of the patient·•s accustomed . dose of morphine. In the case of NIH-7586, the dosages selected were 75 and 150 mg divided into three doses during the 24 hours. in the case of NIH-7607, the dosages chosen were 0.15 and 0.3 mg, 24 likewise divided into three doses during the hours. Data were compared with those obtained in another experiment in which 9 patients received 18 mg (10 percent of their accustomed dose), 36 mg (20 and 90 mg (50 percent) of morphine sulfate percen~), subcutaneously in similar tests. Regression lines, estimates or potency of·NIH-7586 and NIH-7607 give·n orally as compared with the potency or morphine given subcutaneously, and 95 percent confidence limits wera calculated according to the method . . 6 described by Bllss. A "short" (18 day), "double-blind,n direct addiction test was carried out on NIH-7607, and its addictiveness by the oral route was compared with that or morphine, heroin and a placebo, the latter three medications being administered subcu taneously. The methods employed are described elsewhere by 4 Page 7 Fraser, Isbell, Van Horn and Martin. Eight nontolerant former opiate addicts were used, and each was exposed to all drugs. The average initial daily dosage of each drug was as follows: morphinl3 30. 6; hero in, 13.0; and NIH-7607', 0 • .383 mg. 1 The dosage of each drug was progressively accelerated and the f'lnal average daily dosage attained on the 18th ·day was as f'ollows: morphine, 207.0; heroin, 86.8; an~ NIH-7607, 2.95 mg. All drugs were abruptly withdrawn and identically appearing placebos substituted. Observations for intensity of abstinence were made for ten days according to the method of Kolb and Himmelsbach employing a "st.andard" and a "modified" Himmelsbach scoring procedure.5 Once daily throughout the experiment, a "Chronic Dosage Attitude" questionnaire tor opiat.es (patie.ntst r-atings) and a parallel "Chronic Dosage A~tltude11 questionnaire 8 (obser~ers• for' aides ratings) were eompleted. - . Results Effects of Single Doses. The results as presented in Tables· 1 and 2 are co:npared w! th those obtained with 20 and 30 mg ot morphine sulfate orally, and with 60 and 90 mg a parallel "Chronic Dosage A~tltude11 questionnaire 8 (obser~ers• for' aides ratings) were eompleted. - . Results Effects of Single Doses. The results as presented in Tables· 1 and 2 are co:npared w! th those obtained with 20 and 30 mg ot morphine sulfate orally, and with 60 and 90 mg of codeine Both drugs induced typical sulfate orally ln another experin1ent.. morphine-like "euphoria" ancl behavior. NIH-7586 appears to be roughly one-third to one-fifth as potent as morphine, and roughly equivalent to codeine in this respect. NIH-7607 appears to be more than 80 to 120 times as effective as morphine orally as an "euphoriant." -- .... Page 5 Suporession of Abstinence. Both NIH-7586 and NIH-7607 · partially suppress~d abstinence from morphine in the doses used. The results shown in Figure 1 indicate that 1 mg ot morphine subcutaneously was equivalent to 2.62 (l.00-6.59) mg'of NIH-7586 orally, and 1 mg of NIH-7607 orally was equivalent to $9.3 (15.55 to 136.$) mg of morphine subcutaneously. ·The curves met the standard requirements for significance of slope and parallelism. The figures in parentheses are the 95 percent confidence limits. "Short," "Double-Bl!nd,u Direct Addiction Tests (NIH-7601 Orally; Morphine and Heroin Subcutaneously). In 6 of 8 patients, no difficulty was encountered in progressively accelerating the dosage of drugs. However 2 patients were quite intolerant to all drugs when the dosage was augmented. For example, the maximum dally dosage of heroin attained by the 18th day for one patient was 41.5 mg, and the other 48 mg; whereas 5 other patients reached a dose of 103 mg daily, and one 90 mg daily. The result~ of tabulating the RAtt1tude" questionnaires for opiates, employing both patients' and aides' ratings, are shown in Figure 2. ~ Whereas heroin and morphine were consistently as ~dentified 11dope," NIH•7607 was frequently not·so classified and many of the patients 1dentii'1 ed 1 t as being "dope" and _"goof balls" (barbiturates) concurrently. It is noteworthy however that. t.he -- Page 6 aides considered that the pattern of effects objectively resembled those o~ an opiate and were not impressed by the nnon-oplate" characteristics of NIH-7607. Insofar as "estimate ot strength" is concerned, patients considered the effects of NIH-7607 quite weak, since the average score on the weighted scale was only 1.0, whereas morphine and heroin.rated about - 3.5. In response to the question, "would you like to take the drug daily?" only 16 percent of the The document is a typed page from a report. There are no photographs, diagrams, or forms present. There is one handwritten annotation in the bottom right corner that appears to be "B-228". There are also very faint, scattered dots that might be remnants of a stamp or a watermark, but they are not legible enough to identify. A few small, dark circular marks are present near the top of the page, possibly from a hole punch. There are no visible redactions or obscured content. This is a scanned page from a declassified document. The content is text-heavy, with no photographs, diagrams, or forms. There are no official stamps visible on this page, nor are there any handwritten annotations or marginalia aside from a document identifier "B-227" in the bottom right corner. The text describes a scientific experiment involving drug administration and observation of subjects, detailing the methods and effects of various substances. There are no visual cues indicating experimental procedures or facilities beyond the written description. as "estimate ot strength" is concerned, patients considered the effects of NIH-7607 quite weak, since the average score on the weighted scale was only 1.0, whereas morphine and heroin.rated about - 3.5. In response to the question, "would you like to take the drug daily?" only 16 percent of the res?onses indicated they 'would llke to take NIH-7607 daily, whereas 32.6 percent indicated they would like to take heroin daily, and 42 percent, u.s. morphine daily (It should ·be pointed out that aci'dicts prefer to take their drugs by injection, and this may account in part for the subjectst relatively low acceptance rate for NIH-7607, which was administered orally in this study). The low incidence ot positive responses following a placebo, !n the ratings by both patients and aides, is noteworthy since no attempt was made to ·eliminate placebo responders in the selection of subjects.7 When all three drugs were abruptly discontinued and replaced by a placebo,. a moderately severe abstinence syndrome ensued during the next ten days and, as shown in Figure 3, the severity of abstinence as Judged by the total daily point scores was very similar for morphine, heroin, and NIH~7607. The patients, however, considered that abstinence 8-223 - --- Page 7 from NIH-7607 was somewhat less severe than that which followed withdrawal of subcutaneously 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, comparable to that produced by morphine and heroin, develops when NIH-7607 is administered chronically on an abusive schedule. Summary; 1. The addiction liability of orally administered l•(Beta-di ethylaminoethyl )··2•( benzyl-l.t.-chloro) -.5-ni trobenz imi dazole (NIH-7586) and l•(Beta-diethylaminoethyl)-2~(p-ethoxy­ benzy1)-5-nitrobenz1midazo1e methane sulfonate (NIH-7607) has been investigated in man. 2. ln single doses both NIH-7586 and NIH~7607 induced morphine-like subjective effects and behavior in nontolerant former morphine addl~ts~ NIH-7586 is one-fifth to one-third as potent as oral morphine in inducing subjective effects, whereas NIH-7607 is 80 to 120 times as potent as morphine in this respect. Both drugs constrict the pupil•. 3. Both NIH-7586 and NIH-7607 sup?ress symptons of abst!nence.from morphine. -- Page 8 4. When NIH-7607 was given in a direct addiction ~tudy the overall pattern observed during chronic administration and following withdrawal resembled that of patients gl ,,en morphine or heroin. Although ldenti!"!ed as an oplat.e, patients or were 3. Both NIH-7586 and NIH-7607 sup?ress symptons of abst!nence.from morphine. -- Page 8 4. When NIH-7607 was given in a direct addiction ~tudy the overall pattern observed during chronic administration and following withdrawal resembled that of patients gl ,,en morphine or heroin. Although ldenti!"!ed as an oplat.e, patients or were much im?ress~d b~/ the hypnotic nettons this drug. It is concluded that NtH-'7.5G6 and NIH-7607 have addictive potentials co~nparable to that of morphine. 11. JL-3~vdroxy-N-(3,3-dimethylallyl)-morphinan hvdro bromide. This compound, developed by Hoffman-La Roche and herein after designated as NlH•7446, is structurally related to levallorphan. Nalorphine, although an effective analgesic, provokes distur.bing 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 NIH-7446 was as potent as morphine as an analgesic in relieving postoperative pain, but, when given in equivalent analgesic doses to normal subjects, was only half as po~ent as morphine in depressing resplration.9 However in another experiment, in 3 patients, high doses (1 mg/kilo) of NIH-7lt46 provoked ·respiratory depression whicl'i was equivalent to that induced by morphine and which was dramatically anta~onized 9 by nalorphine. Page 9 In comparison with nalorphine, the morphine-antagonistic properties of NIH-7446 are not prominent. Thus Keats found that NIH-7446 produced little antagonism in 3 patients who had .. 9 received morphine (1 mg/kg). In the following presentation, the addietiveness of NIH•7446 will be evaluated from the viewpoints of (1) the effects of single doses, (2) its antagonistic properties ln morphine-dependent subjects, and (3) its ability to suppress symptoms of abstinence in morphine-dependent patients. Methods - Effects of Single Subcutaneous Doses of N!H-7446 (10 and 15 mg) as Compared with Doses of Mornhlne Sulfate. Corres~ond!ng Effects were evaluated ln a "single-blind, 11 cross-over expert• ment.employing 9 nontolerant former opiate addicts, each of whom received in a randomized order at weekly intervals 10 and 15 mg of and 10 and· 15 mg of morphine sulfate. Observations t~IH-7446, . . were made 1/2, lt, 2i, 3!, st and 7t hours after medication. These included responses to the "Single Dose Attitude~ question~ 8 naire (patientst ratings), "Single Dose Attituden questionnaire 8 (observerst ratings), and measurements of the pupillary diameter -- 5 made !n a room with controlled lighting. In tabulating the data emphasis wag placed on the incidence of This page contains no photographs, stamps, forms, diagrams, tables, or evidence of experimental procedures. It is entirely text-based, with the exception of a handwritten annotation in the bottom right corner that reads "B-226". There are also two dark circular marks at the top of the page, possibly from a binder or hole punch, and a faint smudge in the top right corner. The content discusses suppression of abstinence and the administration of morphine to patients. The document page contains typed text and handwritten annotations. It appears to be page 4 of a report, as indicated by "Page 4" in the upper right corner. A handwritten annotation "B-225" is present in the lower right corner. There are also some stray marks and dots scattered across the page, some of which may be artifacts of scanning or printing. No photographs, stamps, forms, diagrams, tables, or redactions are visible. 7t hours after medication. These included responses to the "Single Dose Attitude~ question~ 8 naire (patientst ratings), "Single Dose Attituden questionnaire 8 (observerst ratings), and measurements of the pupillary diameter -- 5 made !n a room with controlled lighting. In tabulating the data emphasis wag placed on the incidence of "opiate" symptoms and the extent to which these former addicts 1111kedn the medication, as evaluated !n a weighted scale. ··~ -- Page 10 ?4~our Substitution of NIH·7446 for Morphine, as Compnred with Morphine Continued: and with a Placebo. Nine addicted patients, who were stabilized on an average of 240 mg or morphine sulfate daily, received as a substitute an average . . of 200 mg of NIH-7446 (divided among four equal subcutaneous doses). This was compared with 180 mg of morphine sulfate and a placebo continued in ~he same patients~ (Note that only three injections or 60 mg each of morphine sulfate, or a total 'at 180 mg during the interval of substitution, is equivalent to 240 mg or morphine sulfate daily, since the fourth injection or morphine is due ~t the end of the 24 hours). Observations tor intensity of abstinence were made from the 14th through the 24th hour of substitution, and the total abstinence scores for eleven hours (TAS~ll) were calculated according to the method of Winter and Flataker. 1~ The paired t•test, using each individual as his own control, was employed to determine whether _there was a significant difference ln the 11 TAS•ll scores for NIH~7446, morphine, and placebo. Antagonistic (Nalor?hlne) Characteristics were evaluated by administering 2 to 20 mg or NIH-7446 subcutaneously to 5 patients chronically receiving ~0 mg or morphine sulfate daily. NIH-7446 was given two to three hours after the la~t subcutaneous injection of morphine and patients were observed for signs of abstinence from morphine.· .8-219 Page 11 Results .. ., Effects of Single, Subcutaneous Doses of NIH-7446 (10 and lz mg) as Comoared with Corresponding Doses of M. orphine 2 Sulfate. All 9 patients identified both morphine sulfate and 4, NIH-7411.6 as being "dope," and, as shown in Figure the incidence or "opiate-l!kert symptoms and degree or "liking" for · both drugs were very similar when the same doses were given ,(These observations are in accordance wl th those of Keats in respect to the relative analgesic potency or· morphine and NIH-7446). 24-Hour Substitution of NIH-7hlL6 for Morph1ne as 1 Compared with The document page contains typed text discussing the suppression of abstinence from morphine and the results of direct addiction tests. There is a handwritten annotation "B-224" in the lower right corner. No photographs, stamps, forms, diagrams, tables, or redations indicating experimental procedures are visible. "opiate-l!kert symptoms and degree or "liking" for · both drugs were very similar when the same doses were given ,(These observations are in accordance wl th those of Keats in respect to the relative analgesic potency or· morphine and NIH-7446). 24-Hour Substitution of NIH-7hlL6 for Morph1ne as 1 Compared with Morohin~ Continued, and with a Placebo. NIH-7446 substituted very sat! sfactori ly for morphine in a relati ~re dosage of 200 mg. of NIH"7446 for 180.mg of·morphine. However the curve was not as flat as that observed when morphine was continued, and the difference between these curves is signiti- . 5). cant (P =<0.001, Figure On the other hand, NIH~7446 suppressed abstinence significantly better than did a placebo 5). (P < 0.001! Figure It is concluded that in the dosage • employed NIH-7446 effectively, but incompletely, suppressed symptoms of abstinence from morphine. /.} -2.1 JY - ... Page 12 Antagonistic (Nalorphine) Characteristics. No evidence ot any effect was observed when 2 to 10 mg or NIH-7446 was administered to morphine-dependent pat1~nts. However, the patients stated that when the dosage was increased to 20 mg there might have been a slight nboost" in op1ate•like effects. There was no evidence o~ precipitation of abst!n~nce by admin- istration of NIH-7446 in any of the tests. Summary It is concluded from these studies that the qualitative and quantitative effects of NIH-7446 are very similar to those or morphine, and its addlctiveness probably approaches that of morphine. III. (a) N-(1-Methyt-2-piperidinoethyl)-oropioan!lide · _hydrochloride (Phenampromid), and . (b) N•[2-([Methvl]-phenethvlam!no)-proovl] . pro.ploan! llde sulfate (Di ampromid). These drugs (Phenampromid and Diampromid) were developed 12 by Wright, Brabander and Hardy. The analgesic potency of Phenampromid equalled that of codeine in mice, and meperidine in rats_. Diampromid approximated the analgesic potency or . 13 meperidine in mice, and or morphine in rats. Nalorphine antagonized the analgesic and respiratory depre~sant actions of 1 both compounds, 3 and both were effective analgesics in prelim• 1 .!nary trials in man. 4 -- Page 13 The methods used tor evaluating the addictiveness of these compounds 1n_man were similar to those enumerated tor NIH-7446, except that when single doses were administered incomplete comparisons were made with morphine administered to the same subjects. For convenience in presentation, the results obtained with the two drugs will .be presented-separately. Results. (a) Phenamprom!d Effects of S1nple Subcutaneous Doses of Phenamprom!d. 1 These were evaluated using the "Single Dose Attitude" This page contains text from a declassified document. There are no photographs, stamps, redacted content, diagrams, tables, or handwritten annotations visible. The text appears to be a report describing the results of an experiment related to drug effects and patient responses. The page is numbered "Page 6" at the top right, and a handwritten notation "B-223" is present at the bottom right. that when single doses were administered incomplete comparisons were made with morphine administered to the same subjects. For convenience in presentation, the results obtained with the two drugs will .be presented-separately. Results. (a) Phenamprom!d Effects of S1nple Subcutaneous Doses of Phenamprom!d. 1 These were evaluated using the "Single Dose Attitude" question• . 8 naire (patients' ratings) in sixteen tests in a dose range or 10 to 200 mg. Observations were carried out 1/2, tt, 2!, 31, 5t 1t and hours after medication. Definite opiate-like subjective effect.s were reported with doses of 75 mg. Six patients received 200 mg. In this dosage, one patient liked the drug "slightly," four, "moderately," and one, "an awful lot." Suppression of Abstinence from Morphine with Phenamprom!d was evaluated in the same 9 subjects used ln the studies on NIH-7446. For comparative purposes, 24-hour substitutions were also carried out with morphine (positive control) and a placebo (negative control) on each subject. The average dosage 14 Page administered during the 24 hours was 1135 mg, divided·among three approximately equal subcutaneous doses. At the conclusion of the substitution each patient completed the "Chronic Dosage 8 Attitude" questionnaire (patients' rat1ngs). The intensity of abstinence was measured hourly from the 14th through the 24th 1 hour during the interval or substi tut.!on, using the "modif1ed ' 5 Himmelsbach hourly point score. Although·, during the substi tution, 4 of the 9 patients identified Phenampromid as being "dope," all emphatically stated they did not like the effects ot the medication. They complained that it gave them a ttweird feeling" which they had not experienced previously, and compared lts effects with those of lysergic acid diethylamide (LSD-25), cocaine, or marihuana. Abstinence phenomena were pa~tially, but significantly, . suppressed by Phe11-ampromid (Figure 5). · Because or the disturbing side effects it was not feasible to employ larger .. doses· of Phenampromid in order to evaluate the pharmacological equivalence or morphine and Phenampromld more completely. --- Page 15 Results. (b) Dlamorom!d Effects of Sinqle Subcutaneous Doses of D!amprom!d were evaluated in t~lve tests in a dose range of 5 to 75 mg, using the "Single Dose Attitude" questionnaire (pat!entst ratings) and the parallel questionnaire for observers' With r~tings. doses of 50 and 75 mg, very typical "subjective" 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 Dose Attitude" questionnaire (pat!entst ratings) and the parallel questionnaire for observers' With r~tings. doses of 50 and 75 mg, very typical "subjective" 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 tllose or morphine, all patients complained that the medication had a short duration of action, and this was substantiated by pupillary measurements, which indicated that maximum miosis persisted for o~ly two and one~half 'to three hours • • Effects of.S!ngle Intravenous Doses of Diamoromid were evaluated in a pilot study using dosages as follows: 20 mg . (1 subject}, 25 mg (2 subjects}, and 75 mg (1 subject). 0 S1ngle Dose Attitude'' questionnaires were completed by both the subjects and and the pupillary-diameter obser~ers, w~s measured at intervals as described ·for single subcutaneous doses. - ln these doses, all subjects consistently identified the medication as 11dope" and the extent to which they liked the -· Page l6 medication ranged from "slight11 to 11a lot." The patient who received 75 mg ofDi~~promid became pale one minute after the ... •· injection and had difficulty walking to the observation room. He sat on a chair and very promptly fell asleep. He'was given 10 mg of' nalorphine intramuscularly about !our minutes after the injection of Diamprom!d, ~'d recovered rapidly. No further inJections of nalorphine 11rere required. Suppression of Abstinence from Morphine vti th Diampromid was evaluated in the same 9 subjects employed for Phenampromid, using the same controls and methods o! observation. A dose ot 750 mg {divided among four equal doses) was substituted for morphine in 8 of t~ese· subjects, and 1n one subject a dose of 625 mg, simllar~y divided, was used. Diampromid substituted quite adequately tor morphine in this dosage, but the chief complaint of th~ patients was: 0 1t only holds you for about two hours. This observation is confirmed by the intermittent 11 peaking of the abstinence scores, and in each instance abstinence symptoms were promptly relieved by medication (note 5). the arrows in Figure In the case of D1amprom1d, the total TAS-11 score was significantly greater than that observed when morphine was continued in the same patients, but the ability fl-:;2.13 I Page 17 of Dlampromid to abstinence from morphine was ~uppress inadequately tested,·since medication would The page is a typed document with a handwritten annotation at the bottom right corner that appears to be "B-222". There are also a few small black dots scattered across the page, which may be ink smudges or part of the printing process. A slightly larger black circular mark is present near the top center of the page, possibly an artifact from scanning or printing. No photographs, stamps, forms, diagrams, tables, or redactions are visible. by medication (note 5). the arrows in Figure In the case of D1amprom1d, the total TAS-11 score was significantly greater than that observed when morphine was continued in the same patients, but the ability fl-:;2.13 I Page 17 of Dlampromid to abstinence from morphine was ~uppress inadequately tested,·since medication would need to be given at more frequent intervals. a Summa - Both Phenampromid and Diampromid possess addiction liability. These experiments, however, are insufficient to 'assess their relative addlctiveness as compared to morphine and codeine. :z. ;3-21 -· Page 18 References 1. Isbell, H. and Fraser, H. F.: data. Unpubllshe~ 2. Hunger, A. J., Kehr1e, J., Rossi, and K.: A~, Hoffm~, Synthese basich substiturirter, wirksauer ana1get1~ch Benzimidazole-Derivate. Experientla, 11: 400, 1957. 3. Gross, F. and Turrian, H.: Benzimidazole Derivatives with !l= Marked Analgesic Action. Experientia, 401-403 (Oct.O 1957. 4. Deneau, G. A., McCarthy, D. A.,.and Seevers, M. H.: Physical Dependence Liability Studies !n the Monkey. Addendum 1. Min. 20th Meet., Comm. Drug Addiction and c. Narcotics Natf. Res. Counci 1. Washington, D. Natl. 1 Acad. Sci. (Jan.) 1959. S• f'_raser, H. F. and Isbell, H.: Addiction Liabilities of Sl-2t-Hydroxy•5,9-dimethyl-2-(2-phenethyl)-6,7-benzmorphan HBr (NIH•7519) and 1-3-Hydroxy. ..N -phenacylmor.phinan methane sulfonate (NIH-7525). Addendum 3. Min. 20th Meet •• Comm. Drug Addiction and Narcotics: Nat!. Res. Council. c. Washington, D. Natl. Acad. Set. (Jan.} 1959. 6. Bliss, c. I.: The Statistics of Bioassay. With Soecial Reference to the Vitamins. New York. Academic Press. 1952. 7. Fraser, H. F., Isbell, H., Martin, w. R. and Von Horn, G. D.: Unpublished data •. Page 19 .. t 8. Fraser, H. F. and Isbell, H.: Human Pharmacology. and Addietiveness of Ethyl 1-(3-Cyano-3,3•pheny1propyl)-~­ phenyl-4-piperldlne carboxylate hyd~oehlorlde (R-1132, Min. 21st Meetlnq Comm. on Diphenoxylate). Addendum • - Drug Addiction and Narcotics. Natl. Res. Council. c.