THE ADDICTION LIABILITY OF SYNTHETIC SUBSTITUTES FOR CODEINE -- (PROJECT DESCRIPTION) - REQUEST TO THE OFFICE OF NAVAL RESEARCH FOR RENEWAL OF CONTRACT NR 101-149 WITHOUT ATTACHMENT

• Document Type: SPECIALCOLLECTION
• Collection: General CIA Records
• Document Number (FOIA) /ESDN (CREST): 00151827
• Release Decision: RIPPUB
• Original Classification: U
• Document Page Count: 6
• Document Creation Date: January 21, 2025
• Document Release Date: September 8, 1976
• Publication Date: January 27, 1958

Page 11
.favorable. There is also insufficient information concerning
the toxicity of propoxyphene. It is, therefore, uncertain
that a satisfactory substitute for codeine for relief of pain
has been found. For this reason, it Is essential to continue
the search for other synthetic substitutes. In addition, tile
larger the number of compounds tested the greater would be the
chance of finding a completely adequate substitute for codeine.
4. Work Proposed.
During the period from 1 July 1958 to 30 June 1959 we
propose to test the clinical pharmacology and addictive proper-
ties of narcodeine, 1-3-methoxy-morphinan, d-methadone�
di.piperidyi methadone, d-3-methoxy-N-phenethylmorphinan, and to
undertake preliminary examination of SOMA compounds in the
meperidine'series. In addition, studies of other substances
regarded as potential codeine substitutes by the Committee on
Drug Addiction and Narcotics will be carried out, as advice
concerning possible compounds for testing is received.
5. Methods.
Methods used are the standard addiction-liability testing
methods of the NINH Addiction Research Center. The methods are
accepted as standard by the Committee on Drug Addiction and
Narcotics and have been described in previous prOject descrip-
tions, which should be consulted for details.
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9. Estimated Cost.
The estimated costs are shown on the attached sheet. It
will be noted that the amount of money requested is higher
than in past years. The increase is due to increased costs in
the personnel services account; to within-grade promotions for
persons who have been with the project since its inception in
1951; need to provide money for Civil Service retirement (which
was formerly not paid from operating funds); and to provide for
, Civil Service pay raise anticipated during the current fiscal
year (1958). If the Civil Service pay raise does not eventuate,
this item could be eliminated from the budget. On the other
hand, if the raise is greater than that provided for in the
budget(6) the figure will need to be increased accordingly.
Harris Isbell, M.D.
Director
Attachment
27 January 1958
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THE ADDICTION LIABILITY OF SYNTHETIC SUBSTITUTES FOR CODE=
(Project Description)
Request to the Office of Naval Research for Renewal of
Contract NR 101-149
. NAonr -11 .57
(ONR:441:24JG:set).
1. Backqround Informltion.
Since July 1951 a project designed to develop a synthetic
drug which would be as safe as codeine with respect to toxicity,
antitusaive activity, and addiction liability has been carried
on within the National Institute of Vtntal Health Addiction
Research Center, U. S. Public Health Service Hospital, Lexington,
Kentucky. This project has been financed In large part by funds
from the Office of Naval Research, and this description consti-
tutes request for renewal of the project for the period
1 July 1958 to 30 June 1959.
A synthetic substitute for codeine is badly needed since
opium, or morphine ftrived from opium, constitute the only
sources of codeine. Unless a synthetic substitute for codeine
is found the United States must continue to stockpile opium in
order to provide adequate supplies of codeine for both the
civilian and military population in the Event of war. Facilitie3
Of the Ninu Addiction Research Center are not sufficient to
carry out this work, in addition to routine drug testing required
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for the evaluation of all new analgesics, unless additional
funds are supplied, through the Department of Defense.
2. Work Accomplished to Date.
Previous work has been summarized in the annual progress
report sent to Captain F. H. Quimby and Captain T. It.-Rlifebush,
Head of the Physiology Branch, Office of Naval Research.
Two drugs have been developed which are promising substi-
tutes for codeine for relief of cough. These drugs are:
i) dextro-methorphan, and 2) narcotine. Neither drug possesses
any significant addiction liability and both have relatively low
toxicity. Continuing reports to the Committee on Drug Addiction
and Narcotics, National Research Council, and clinical reports
appearing in the literature indicate that these drugs are
� effective cough suppressants. The antitussive phase of the
� problem has, therefore, in a sense been solved.
Although the antitussive problem is no longer as pressing
there are still no compounds available which are known to be as
effective and as safe as codeine for the relief of mild grades
of pain. Over 46 new drugs or mixtures of drugs have been
screened for this purpose. The outstanding substances so far
developed are dl. and d-alpha-4-dimethylamino-1,2-dipheny1-3-
methyl-4-propionoxybutane, or dl. and d-propoxyphene. The
addictiveness of these compounds is 30 low that the Committee
on Drug Addiction and Narcotics has ruled that they need not be
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6. Evaluation of Data.
Evaluation of data obtained in the addiction-liability
program has also been discussed in previous project descriptions.
7. Location of Project.
The work will be carried out in the NII-11 Addiction Research
Center, P1-IS Hospital, Lexington, Kentucky. This institution
provides the two necessary facilities for the type of work to
be undertaken: 1) a pool of patients who will volunteer for
experiments with drugs, and 2) strict environmental control
which prevents the introduction of drugs other than those under
study in an experimental situation.
8. Exverimental Personnel.
Work will be carried out under the direction of Harris
Isbell, M.D. Director, NI MH Addiction Research Center. This
investigator has had Lti. years of experience in research on
narcotic drug addiction and has published many papers .in the
field. He will be assisted by two other experienced physicians,
Dr. H. F. Fraser and 61.. Abraham Wikler, both of whom have had
extensive experience in research on drug addiction, with many
publications. The part-time services of a biochemist, neuro-
pharmacologist, and research psychologist are also available.
A special ward for the conduct of these studies is currently in
operation.
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*subjected to the controls imposed by the Harrison Act. Prelim-
inary clinical data indicated that they were nearly as effective
as codeine for the relief of pain. Complete data on toxicity
and clinical use are still not available, and momrecent reports
indicate that their analgesic potentialities may not be as
great as was originally claimed.
During the past 18 months important leads have been
developed concerning the demethylated derivatives of morphine
and morphinan. Normorphine has been shown to be an activ, agent
for inducing sedation in man. It suppresses abstinence from
morphine completely, but, unlike morphine, abstinence following
withdrawal after direct addiction is quite mild. These studies
are now being extended to include norcodeine, 1-3-hydroxyd.
morphinan (1-nordromoran) and 1-3-methoxy-morphinan. Evidence
of some activity in d-isomers in the methadone series has also
been obtained. We'hope to develop and complete studies on these
compounds within the next 18 months.
3. Need for Continuation of the Project.
The chief need for continuation of the project is related
to conflicting reports concerning the analgesic potency of
dl- and d-propoxyphene. Original clinical trials for relief of
chronic pain were promising. sore recent trials against post-
partum pain and chronic pain due to cancer have not been