A Review of the Chemical Features Associated With Strong Morphine-Like Activity - Paul a. J. Janssen - Br J Anaesth, Apr 1962, 34(4), 260-268

Brit. J. Anaesth. (1962), 34, 260

A REVIEW OF THE CHEMICAL FEATURESASSOCIATED WITH STRONG MORPHINE-LIKE ACTIVITY

BY

PAUL A. J. JANSSEN

From the Research Laboratorium Dr. C. Janssen (Beerse, Belgium)

In spite of quantitative differences known toexist and that are, not infrequently, quite im-portant in medical practice, all morphine-likenarcotics have a certain number of properties incommon. All potent narcotics will produce—atleast to some degree and at varying dose levels—relief from pain, respiratory depression, emesis,constipation, physical dependence, sedation inman, dogs, rats and monkeys, excitation in mice,cats and horses, miosis in man, mydriasis inmice, etc. Their respiratory depressant effects areeffectively antagonized by small doses of nalorphineand their emetic effects by potent neurolepticdrugs such as Haloperidol or chlorpromazine.The spectrum of these properties is so typical andhomogenous that it appears safe to presume thatall potent narcotics exert their effects by a commonmechanism of action.

If this is true, then it appears reasonable tolook for chemical features that are associated withmorphine-like activity, particularly among nar-cotics producing their effects at low dose levels.There might indeed exist something like acommon specific receptor area, somewhere in thebrain, possibly in the thalamic area, to which anarcotic molecule must be able to fit before it canact. No one has ever demonstrated this hypotheti-cal area, of course, and there is no serious reasonto believe that anyone will be able to do so in thenear future. We might, therefore, try to approachthe problem from the opposite angle and ascertainto what extent molecules with powerful narcoticproperties look alike chemically.

The three-dimensional structure of figure 1represents the absolute configuration and con-formation of the laevorotatory natural alkaloid(—)-morphine. Certain chemical features of thisrather complicated five-ring (rings A to E)T-shaped molecule (D-ring above and C-ringbelow the plane of the paper) are important for its

narcotic properties, whereas others are relativelyunimportant.(6' 16)

(A) Certain stereochemical features are veryimportant: the mirror image, (+)-morphine, isdevoid of analgesic activity and all known partialstructures related to morphine that are potentnarcotics have certain important stereochemicalfeatures in common (see further).(9)

(B) The C-ring of (—)-morphine is a six-membered ring of carbon atoms (cyclohexene),extending below the plane of ring B (fig. 1),having a double bond between C7 and C8 and afree hydroxyl group below its plane in C6. Allthese features are relatively unimportant.

FIG. 1(—)-Morphine

(absolute configuration and conformation).

(Ba) Removal of the G-OH group and saturationof the double bond leads to (—)-desomorphine-D(fig. 2), the simplest C-ring variant of morphine,which is roughly ten times more potent thanmorphine itself.(6) Its C-ring is a chair, thusdemonstrating the relative unimportance of theboat-conformation of the C-ring of morphine.

260

sFIG. 2

(—>Desomorphine-D(absolute configuration and conformation).

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CHEMICAL FEATURES ASSOCIATED WITH MORPHINE-LIKE ACTIVITY 261

(Bb) A large series of other C-ring variants ofmorphine has been synthesized. Many of thesestructures are potent narcotic analgesics (table I).

TABLE I

"C-ring" variants of morphine.Only the chemical structure and the probable conforma-tion of the C-ring are shown, the rest of the moleculebeing identical with morphine, including the stereo-chemical features. All these compounds are typicalmorphine-like narcotics; their potency (P.R.) is expressed

in terms of morphine = l."'14)

a=OH, p=H:(—>morphine(P.R. = 1).

ot=H, p=OH:a-isomorphine(P.R. ~ 1).

a=OH, p=H: dihydro-morphine or paramor-phan (P.R.=2±1).

a=H, P=OH: dihydro--isomorphine (P.R.=2±1).

a = p=H: desomorphine-D, P.R. = 8-5±3-5.

a=OCH,, P=H: dihydro-hetero-codeine: P.R. =4±0-5.

5 = 14 = H: hydromor-phone or Delaudid®:P.R.=5 ±2.

5=CH,; 14 = H: metopon:P.R.=7±4.

5 = H; 14=OH: oxymor-phone or Numorphan ®:P.R. = 1I±3.

Methyldesorphine orMK-57: P.R. =9±3 .

(C) The free phenolic hydroxy-group of mor-phine and its C-ring-variants cannot be muzzledwith an alkyl group (e.g. a methyl-group; pro-ducing a CH3O-ether like in codeine) withoutgreatly reducing analgesic potency (table II).Higher analogues of codeine (e.g. ethylmorphineor benzylmorphine) become increasingly inactive,whereas acetylation of the phenolic OH-group inposition 3 of morphine and its C-ring-variants(e.g. diacetylmorphine or heroin) is compatible

TABLE IIMethylation of the 3-OH group in (—)-morphine or itsC-ring-variants produces (—)-codeine or other 3-OCH,-derivatiyes of these C-ring-variants. The phenols are10±5 times more potent as analgesics than the corres-ponding methyl ethers, as shown by the following

data.11' '• '*»

Name Morphine = 1 Ratio

OHOCH,

OHOCH,

OH

OCH,

OHOCH,

OHOCH,

OHOCH,

OHOCH,

OHOCH,

MorphineCodeine

-Isomorphine-Isocodeine

Dihydro- -iso-morphine

Dihydro- -iso-codeine

DihydromorphineDihydrocodeine

(paracodine*)

1.00.15 ±0.05

0.9 ±0.30.2±0.15

2.0 ±1.0

0.3 ±0.1

2.5 ±1.50.2 ±0.1

Dihydrohetero-codeine 4.0 ±0.5Dihydro, methyl ether 0.7 ± 0.2

HydromorphoneHydrocodone

(dicodid*)

Desomorphine-DDesocodeine-D

OxymorphoneOxycodone

(encodal*)

5.0+2.00.7 ±0.1

8.5 ±3.50.6±0.2

11 ±3.02.0 ±1.5

1/6

1/5

1/7

1/13

1/6

1/7

1/14

1/5

with very high analgesic potency. All otherknown chemical changes on the aromatic ringhave invariably produced very striking loss ofactivity.15-16)

(D) The secondary amine normorphine (re-placement of NCH3 by NH) as well as all otherknown secondary or quaternary amines derivedfrom five-ring T-shaped molecules related tomorphine are either inactive or very weak anal-gesics. Replacement of the NCH3— moiety byother chemical groups (NR) reduces analgesicactivity as a rule, but there are a few importantexceptions. For example, (—)-N-2-phenetyl-morphine is about 15 times more potent than (—)-morphine itself<».16) (NCHj CHj Q H6). Replace-ment of this methyl-group by a few other groupsof low molecular weight may even produce potentantagonists of morphine-like compounds. Nalor-phine or N-allyl-normorphine (CH3 replaced byallyl or CH2CH=CH;>) is the classical prototypeof these antagonists.15- ••15-16)



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262 BRITISH JOURNAL OF ANAESTHESIA

Thus the C-ring of morphine possesses at leasta few relatively unimportant chemical features.Moreover, the E-ring or the ether linkage betweenrings A and C is also a "useless complication" inthe (—)-morphine structure. Its removal from(—)-desomorphine-D or its N-R derivativesactually leads to the four-ring (—)-morphinans(fig. 3) that are, as a rule, more potent than thecorresponding five-ring structures from which theyare derived. The active morphinan-isomers haveall the same configuration as (—)-morphine, themirror image of the isomers shown in figure 3being inactive or very weak. Removal or alkyla-tion of the OH-group in C3 again reducespotency.*4- "• 7>10) Dextromorphan or RomilarR,(+)-3-CH3O-N-CH3-morphinan, is said to be anantitussive compound with very little analgesicactivity, its mirror image a weak narcotic.

The morphinans are ring B/ring C- cis struc-tures. A few B/C- trans isomers have beenprepared (iso-morphinans, fig. 4) and, surprisingly,found to be somewhat more potent than thecorresponding isomeric morphinans.<8) The un-known B/C- trans isomer of (— )-morphine maytherefore, by analogy, be suspected to be moreactive than (—)-morphine itself.

— O-ring

R

CH,

CH.CH.—/

CH.-C—^

CH.CH,— ^

CH,CH=CH,

H

>

D

'otency

8

20

100

200

low

low

Name

Levorphanol

(—)-Phenomorphan

Levophenacyl-morphan

—

Levallorphan (potentantagonist)

Norlevorphanol

C ring

FIG. 4The skeleton of the iso-morphinans."1

The high potency found among several membersof the benzomorphan-series (fig. 5) shows againthe relative "unimportance" of at least somechemical features of the C-ring in the 4- and 5-ring structures already described, but furtherremoval of part of the C-ring (e.g. removal ofone or both methyl-groups attached to ring B ofmetazocine or phenazocine) reduces activity.16- M

FIG. 3Analgesic potency (morphine= I) of the (—)-morphinans

(absolute configuration as shown).'71

CH3

FIG. 5Absolute configuration of the CH,/CH,-cis and -transisomers of the benzomorphan-series (potency: morphine= 1); cis, L=CH,: (—)-metazocine (potency =1);cis, L = CH,CH,C,H6: (—)-phenazocine (potency=20).The trans-isomers are more active than the correspondingcis-isomers; methylation or removal of OH reduces

activity.The mirror images have very low potency."' Ul

- C H 2

rlnflC

FIG. 6Essential chemical features and absolute configurationof the 3-, 4- and 5-membered potent narcotics derivedfrom (—)-morphine, and shown in figures 1 to 5.IU)

Figure 6 therefore depicts the essential chemicaland stereochemical features associated with highactivity among these compounds, i.e.:(a) An L-shaped 3-ring skeleton, consisting of a

piperidine-ring to which a phenyl-ring isdirectly attached in position 4 (axial) andindirectly through a methylene bridge (ring B)in position 2.



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(*)

to

With the phenyl-nucleus to the left, thepiperidine-ring extends above the place ofthe paper in all potent isomers.A free or acetylated phenolic hydroxy-groupin position 3'.A tertiary basic nitrogen in the piperidine-ring, substituted with a moiety of the typeCH,-X in which X is hydrogen, or, preferably,CHaQHy COCgH6, CH2-2-furyl and similarmoieties.At least two further substituents on thepiperidine-ring, i.e. one equatorial methylenegroup (CH2X) in position 4, and one similarCHjX-group in Q , preferably but notnecessarily, in axial position. A secondsubstituent in C3 (e.g. OH) is compatiblewith high potency, but is not required. Thetwo methylene groups may be part of ring C.

Phenyl ring axial. Phenyl ring equatorial.

FIG. 7Isomer obtained by removal of the methylene-bridge of

(—)-metazocine.

Removal of the methylene-bridge between ringsA and D in (—)-metazocine (fig. 5) leads, withretention of configuration and conformation, to anisomer of 1 : 3-dimethyl-4- (3'-hydroxy) phenyl-piperidine (fig. 7). This particular compound isunknown. However, the stereochemical featuresof a closely related series, known as the "prodines"(fig. 8), have been adequately determined. One ofthe optical isomers of betaprodine, probably themost potent one, i.e. (—)-betaprodine, has thesame stereochemical features as (—)-morphine,levallorphan and (—)-phenazocine.<2'3) This iso-mer, therefore, may be said to "imitate" most ofthe typical chemical features of (—)-morphine.Unlike the other narcotics discussed thus far,however, a prodine is not a "partial structure"related to morphine. A very large series of relatedtwo-ring derivatives of 4-phenylpiperidine hasbeen prepared, and pharmacological investigationhas shown that the general structure of figure 9represents the most potent narcotics found in thisgeneral series. The prototype of these simple4-phenyl-piperidines is pethidine or meperidine

(-)-Beta-CH3 prodine

Does notexist(a—CH,)

Does notCH3 existH (a-CH,) CH3 (-)-Alpha-

prodine

-Beta-prodine

Does notexist(a—CHa)

„ Does not"H3 existH (a—CH3)

FIG. 8Stereochemistry and conformation of the four opticalisomers of 1 : 3-dimethyl-4-phenyl-4-propionoxy-piperi-dine (P=OCOC,H,), known as the "prodines".(±)-Betaprodine is several times more potent than(±)-alphaprodtne or (—)-morphine. In each racemate,one optical isomer (probably the (—)-isomer) is many

times more active than the other."' "

Umibttlmtcd

boncncrinj

CHOH or CO of NH of oxyicii or CH. (or cjonnnrO

H or lower iftyt or tllyl-

FIG. 9Chemical features associated with maximal analgesicpotency among "simple" 4-phenylpiperidine-derivatives

(conformation largely unknown).'1' '•'



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(fig. 10), the first synthetic narcotic, described in1939 by Eisleb and Schaumann. In figures 10, 11and 12 the relationship between the structure ofpethidine-like compounds and analgesic activityis briefly illustrated.''• »•6- "•1 2-1 3 .1 6 )

Maximal analgesic potency among thesedrugs is associated with the following chemicalfeatures.'1'131

(a) An unsubstituted phenyl nucleus (or anisosteric ring such as thiophene) attached to thebasic nitrogen atom of the piperidine ring byan unbranched chain of three atoms (figs. 9and 10).

(b) A substituent of the type R-CHjCH2 inposition 4 of the piperidine ring (R=OCO,COO or COCH,), consisting of a straightchain of 4 carbon atoms or of 3' carbon- andone oxygen-atom (figs. 9 and 11).

(c) The presence of a phenolic OH-group is notrequired for high potency (fig. 12). Othersubstituents on the phenyl-nucleus generallydecrease activity.

(d) A suitably selected and stereochemicallyarranged substituent X in position 3 of thepiperidine ring (e.g. methyl or lower alkyl)may have a potency-increasing effect. The

conformation of X is probably equatorial andthe most active optical isomers are probablystereochemically related to (—)-betaprodine(fig. 8).

(e) All attempts to increase the analgesic potencyof pethidine-like compounds by isomericreplacement of its typical substituents fromposition 4 to position 3 or 2, or by increasingor decreasing the size or further substitutionof the piperidine-ring have only produced lessactive or inactive narcotics (e.g. ethoheptazineor zactirin®, trimeperidine, promedol andisopethidine).

The well-known 3 : 3-diphenylpropylaminesrelated to methadone (structure 3 in table III)constitute another, chemically somewhat relatedclass of narcotics. Table III illustrates how thepiperidine ring of pethidine-like drugs can be"opened" to produce the analgesically very weakderivatives of 3-phenyl-butylamines (2 in tableIII; e.g. propoxyphene). Replacement of the lastcarbon atom in 2 by a phenyl ring, however,produces 3 : 3-diphenylpropylamines. Inspectionof table III gives a rough idea of the chemicalfeatures (R, a, p, NAA') associated with highanalgesic activity in this series.<1J) Branching of

TABLE HI

Illustration of the chemical relationship between the pethidine-(l) and the methadone series (2), and analgesicnan (morphine=l) of a representative series of 3 : 3-diphenylpropyl-amines related to methadone (3).(1JIpotency in man

—- N-C-C-C-C — i.J -CH-CH-C

R

COCH.CH,COCH.CH,COCH.CH,COCH.CH,COCH.CH,COOC,H5

CON

OCOCH,CH CH.CH,CH CH.CH,CONH,CNOHH

(0

NAA'

N(CH,),N(CH,),N(CH,).PiperidineMorpholineMorpholine

Morpholine

N (CH,),N (CH,),PiperidinePiperidinePiperidinePiperidine

a

HCH,HHHH

CH,

HHHHHH

(2)

P

CH,HH

CH,CH,H

H

CH,CH,HHHH

d,l

dldl

dldl—

d

a—dlp-di

—

—

Potency

21122

low

4

—0000

(3)

Name

Methadone, amidone (Polamidone*;IsomethadoneNormethadone (Ticarda*)Dipipanone (Pipadone*)Phenadoxone (Heptazone*)

Dextromoramide (Palfium* R875)

AlphacetylmethadolBetacetylmethadolVery potent atropine-like drugPotent atropine-like drugWeak atropine-like drugAspasan*



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o

L—C-OCH.CH,

L=CH, : pethidine : 25-150 mg.OH

L = / VcH-CH,CH,- :

O

phenoperidine (R 1406):0.25-2 mg.

j - : R 951 : 0.50-3 mg.

L = f ~>CH,CH,- : pheneridine : 10-50 mg.

L = H , N - / VcH.CH,- : anileridine (Lerituie®):N = / 10-50 mg.

L=^f \NH-CH,CH,CH,- : piminodine (Alvodine®)\=/ 10-40 mg.

L=HO-CH,CH,-O-CH,CH,- : ctoxeridine (Atenos®):~ 75 mg.

FIG. 10Structure and usual clinical dose range (in mg per 70 kgbody weight) of some analgesically active 4-phenyl-piperidines derived from norpethidine (i=H). ( t ' "• ">

,—v /R-alkCH^N "X

alk

HCH,

CH.CH.

CH,CH|CH|CH!

(•) pethidine(••) bemidone

R

O

t"reversed"

ester

O

0

+

"straight"ester

O

0

ketone

_^_

0

ether

nihil

00

alkyl

OH

—CH—

oo

oo

o

s.alcohol

FIG. 11Replacement of the carbethoxy-group (COOC,H,) in pethidine by other moieties of the type R-alkyl has the

following effects on analgesic potency.11'1"

CH3—N\ X = H

RRR

OCO.C.H,COO.QH,CO.CH,

R = CH.QH,

OH

i : hydroxypethidineketobemidone

(Cliradon ®)

Fro. 12Introduction of a phenolic OH-group in meta-position has the following irregular effects on analgesic potency

of pethidine-like narcotics."•••1"



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the side chain in a or p with a methyl-groupproduces a pair of optical isomers of which one,as a rule, is twice as active as the racemate, theother virtually devoid of analgesic activity. Themost active narcotic of this series is Dextro-moramide (Palfium*, R 875). Substitution of thephenyl-rings, shortening or lengthening theethylene side chain as well as the substituents Rof table III results in great loss in activity.

An interesting recent development shows thathigh morphine-like potency may be associatedwith the presence of a secondary amine group,monomethylamines related to the acetylmethadols(table III) being highly active narcotics. Thehighly active narcotics considered thus far are all

I3-phenylpropylamines of the type CgHg-C-CH-

I ICH-N-CHj-. The carbon atom attached to theI

phenyl-group can, however, be replaced bynitrogen to yield 2-anilinoethylamines of the

Igeneral type QHu-N-CH-CH-N-CHj-. Figures

I I I13 and 14 illustrate the possibilities of obtaininghighly active narcotics of this general structure.

H C H 3A \ ) N

—/ f-FIG. 13

Two derivatives of 2-anilinoethylamine: phenampromidand diampromid, respectively as active as pethidine

and as morphine.1"

OC2H5

FIG. 14Another derivative of 2-anilinoethylamine, the prototypeof a series of benzimidazol derivatives with very high

potency (up to 1,000 times morphine)."1

Noticeable features:the nitro-group, enhancing activity considerably;the diethylamino-group, a rare moiety among potentnarcotics.

Much less is known about the relationshipbetween chemical structure and morphine-likepotency of ethylenediamine derivatives related tothe structures of figures 13 and 14, than about thecompounds derived from 3-phenyl-propylamine,discussed above.

Recent findings in this laboratory revealed theextremely high narcotic potency of certain4-anilino-piperidines (fig. 15).

In these surprisingly active compounds, thephenyl ring, attached to the piperidine nucleusthrough a nitrogen atom, is separated by a chainof 4 atoms from the basic nitrogen, whereas in allthe other potent narcotics, previously discussed,this chain consists of only three atoms.

N-C-CH2CH3

FIG. 15Compound JR. 4263, the extremely potent (up to 5,000times morphine) prototype of a new series of 4-anilino-

piperidines.'"

There are a few more prototypes that should bebriefly discussed before making an attempt todraw general conclusions.

The first is Pirinitramide or R 3365 (fig. 16),a potent analgesic with relatively little physicaldependence producing capacity, in which thephenyl-ring attached to the piperidine-nucleus in4-phenyl-piperidine-derivatives, is replaced by asecond piperidine-ring.(11)

FIG. 16Piritramide (R 3365; 1 to 4 times morphine), theprototype of a series of 4-amino-4-carbanimayl-

piperidines."1'

Another type of narcotics that is produced byisosteric replacement is the thiambutine-series(fig. 17). These dithienylbutenylamines are ob-viously related to the 3 : 3-diphenylpropylaminesof which methadone is the prototype (table III).



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iA ' - '

FIG. 17The thiambutene series

(potency: up to 2 times morphine).

The spiro-compounds of figure 18 were recentlyprepared in this laboratory and found to beextraordinarily potent and much longer acting(several days) than any other narcotic describedthus far. These compounds are obviously relatedto the methadone-type as well as to the pethidine-

-CH2CH2-

FIG. 18Spiro-compounds related to diphenoxylate. High mor-phine-like potency. Very long duration of action.11

L m phenyl or bonenc ring (Lt connected to N ts follows'L- CH, CH,. V CH, CH, CH,. I-tCCH, CH_ LtHOHCH, CH_L-NHCH, CH,. LOCH, CH.. LCH-CHCH,. L"C. H. CX CH.CH. (X-CO ilk. CN.HI or L .H.

-•?¥ nog: morpboline or ppendinc.

- -baitc nitrogen

-Drlng piperidlnc

NO," -

OH. OAc

ring- cydobeure.

X • "central ire*'C. N or MT-fiR

\ E rio|. furyl, unidazoM orcjrdobcuue.

FIG. 19Tridimensional structure representing the commonchemical features associated with morphine-like activity

at low dose levels.a, (3, a, b, z. 1 to 6 are carbon atoms,a', b', b" are carbon or hydrogen atoms.The small black circles are hydrogen atoms.R represents lower alkyl, OCOC,H,, COOC,H,,CHOCOCHjQH,, COC.H,, COC,H7, CONMe,,CONC4H8) or CCH,C,H4pOC,Hi.

type of narcotic drugs (table III and figure 9).(1)

In recent years a large number of relativelyweak morphine-like narcotics have been describedand studied. These data, however, are of verylimited usefulness in connection with the structure-activity problem discussed in this paper and can'therefore not be discussed in this short review.

Figure 19, summarizing the relevant datadiscussed in this paper, represents the commonstereochemical features found among the com-pounds that are known to display typical morphine-like properties at low dose levels.

Because these molecules look alike chemically,it appears reasonable to assume that there mightbe something like a common receptor for mor-phine-like drugs.

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14. May, E. L., Kugita, H., and Ager, H. (1961). Struc-tures related to morphine. XVII: Furtherstereochemical studies with 9-oxobenzomor-phans. J. Org. Chem., 26, 1621.

15. Schaumann, O. (1957). Handbuch der Experimentell.Pharmakol. Springer Verlag.

16. Winter, C , Orahovats, D., and Lehman, E. G(1957). Analgesic activity and morphine anta-gonism of compounds related to nalorphine.Arch. Int. Pharmacodyn., 110, 186.

BOOK REVIEW

Halothane. By C Ronald Stephen, M.D., and DavidM. Little, jr., M.D. Published by the Williams andWilkins Co., Baltimore (1961). Price 4Ss.

At so early a stage as the Preface the authors makeit quite clear that they are aware of the intenseemotional disturbance which the advent of halothanehas caused among anaesthetists the world over. Theyassume that the truth lies somewhere between thosewho regard it as the universal anaesthetic and thosewho think it should be avoided like poison. Accord-ingly they attempt to separate fact from fiction, thewheat from the chaff, and present to their readersboth sides of the question. They have been very suc-cessful in their self-imposed task, but it must beobvious that they would not have taken the troubleof writing a book about halothane unless they hadhad a favourable experience of its use.

They point out that halothane is unique amonganaesthetics in that it is the outcome of a deliberateattempt to find a body that was nontoxic, non-inflammable and yet had anaesthetic properties. Ashort re'sume of this research of Dr. Suckling'sintroduces the first chapter which is concluded by

Dr. Raventos's work on the absorption, distributionand elimination of halothane. The question ofvaporizers is adequately dealt with. "Is your vapor-izer really necessary?" is one of the questions sotreated. Separate chapters are allotted to the con-sideration of the action of halothane on the respira-tory, cardiovascular and central nervous systems aswell as to its effect on the liver, kidney and otherorgans. Two chapters are devoted to methods ofadministration. The danger of putting the vaporizerin the closed circuit, especially if respiration isartificially aided, is stressed; the table on page 100,of cases of cardiac arrest, gives a number of examplesillustrating this point. The book concludes with achapter on the use of halothane in Great Britain byDr. J. P. Payne, who expresses the opinion thathalothane is a safe and reliable anaesthetic for opera-tions outside the chest and abdomen, and with betterunderstanding of its administration is likely soon toconquer these fields of activity. There are no lessthan 338 papers referred to in the list at the end.

The print and paper are good and its size, 140 pages,makes it easy to handle.

E. Falkner Hill



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A Review of the Chemical Features Associated With Strong Morphine-Like Activity - Paul a. J. Janssen - Br J Anaesth, Apr 1962, 34(4), 260-268