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1. Introduction
Despite that Webster’s Dictionary devotes a full column of exceedingly fine print
to definitions of the word pain, it is all too easy to recognize that discomfiting sen-
sation. Pain, which plays an important role in relations with the environment,
commonly comprises the first and most immediate response to a new or poten-
tially injurious circumstance. Almost every explanation of the term invokes
the reaction to touching a finger to a hot stove. The sensation that results
from that contact leads to quick withdrawal of the finger and, thus, avoidance
of a burn. Pain-causing stimuli are not only restricted to the exterior environ-
ment but can as well originate at an organ or other structure within the body
as an alert that something within is amiss. The immediate signal from an
event that will be manifested as pain travels up the autonomic nervous system
to the cerebral medulla. The signal for the required response, pulling back the
finger, is then sent back via the autonomic nervous system. The signal is also
communicated to the central nervous system (CNS) where it elicits conscious
recognition of pain. Although pain plays a vital role in day-to-day function, a pro-
blem often originates when the pain-causing stimulus persists as in the chronic
pain from an inflamed appendix, or in cases where the sensation persists long
after the stimulus has been withdrawn. Drugs used to treat pain fall into
three categories based on their mode of action. The local anesthetics block
nerve transmission from the site of the injury, effectively numbing the area.
These agents are relatively short acting and of little use in treating pain of
any duration. The so-called peripheral analgesics that comprise the corticoster-
oids and the nonsteroidal antiinflammatory drug agents (NSAIDs) act at the site
of the pain stimulus by inhibiting the synthesis of thromoxanes and prostaglan-
dins. The opiates, sometimes, classed as central analgesics, act at the level of the
CNS, where they alter the conscious perception of the pain. Although opiate, or
central analgesics, are sometimes referred to as narcotics, that term will not be
used in what follows.
The origin of the discovery of the opiates, drugs that have proven useful for treat-
ing deep and persistent pain, is as the cliche has it, lost in the mists of time.
There is thus no record of the person who first ingested the sap exuded on the
seedpods of the poppy papaver somniferum and noted that doing so made him
sleepy. That dried sap, or opium, became an article of commerce as early as
the second millennium B.C. as a consequence of its soporific and narcotic activity
(1). The drug constituted one of the few items that had true physiological activity
in pharmacopeias well into the nineteenth century. Abuse of the drug because of
its narcotic activity led to recognition of its propensity to cause addiction. Modern
research has revealed that the crude drug may contain as many as 20 compounds
with very closely related chemical structures. The most active of those com-
pounds, morphine, was first isolated from the mixture in crystalline form in
1803 by Friedrich Sertuner. The name, morphine, after the Greek god of sleep
Kirk-Othmer Encyclopedia of Chemical Technology. Copyright John Wiley & Sons, Inc. All rights reserved.
2 OPIATE ANALGESICS
Morpheus, derives from what was considered, at the time, the principal activity
of the drug. This purified compound replaced opium in many applications such as
analgesia because doses could be more easily and reliably gauged with the pure
crystalline substance. One of the minor constituents that accompanied morphine
in opium later became a drug in its own right. This compound, codeine, although
somewhat less potent than its parent, is more readily absorbed on oral adminis-
tration. It can be prepared in a single step from morphine as it is simply the
methyl ether of the latter. From that point until about 1930, chemists in various
laboratories carried out a variety of experiments to modify the structure of mor-
phine to try to find drugs with superior activity and lower addiction potential.
The chemical structure of the compound was, however, unknown at the time,
beyond its relative empirical formula. The very concept of molecular structure
was in fact not fully recognized until the end of the nineteenth century (2).
These transformations thus involved largely treating morphine with selected
reagents and isolating the products, if any. The structures of these derivatives
were thus not assigned until the structure of morphine itself was announced
in 1927 by Robert Robison (later Sir) and J. M. Gulland in 1925 and indepen-
dently by Sch€opf (3). A relatively small number of opiates derived from morphine
was then synthesized in the pharmaceutical and academic laboratories. The
development by Grewe of a total synthesis of a compound that incorporated a
major portion of the morphine carbon skeleton, a so-called morphinan, from
ordinary laboratory chemicals, opened the door for a large number of opiates,
many of which found uses in treating pain.
The signal elicited by a painful event, as noted, travels to both the autonomic and
the central nervous system, the latter encompassing the brain. Several regions in
the brain, richly endowed with endorphin receptors, are involved in recognizing
pain messages. Activation of those areas by the pain-elicited signal leads to the
conscious recognition of pain. Binding of an opiate to endorphin receptors does
not actually block the perception of pain; that binding instead modulates the per-
ception of pain as an unpleasant and in the extreme case, unbearable sensation.
The individual treated with an opiate usually recognizes that the pain is still pre-
sent but no longer interprets that as an unpleasant sensation.
3.1. Opiate Receptors. Scientists who studied the chemistry of opiates
had for some time considered the likelihood that these molecules acted via a
receptor. This hunch was confirmed in 1973 when Pert and Snyder demonstrated
the existence of a site in nervous tissue that stereospecifically bound a tritiaded
sample of the opiate antagonist naloxone (4). These receptors are widely distrib-
uted in nervous tissues particularly those in the brain and the gastrointestinal
(GI) tract. The presence of such structures was something of a puzzle because
they had obviously evolved in the absence of opiates. This apparent paradox
was laid to rest in 1976 with the discovery of endogenous five amino acid peptides
dubbed enkephalins that bound to the receptor (5). This peptide was found to be
but one of a group of small peptides, which also includes dynorphins, known
collectively as endorphins.
OPIATE ANALGESICS 3
The m (mu) receptor accounts for most of the activity of classic opiates. It is
found mainly in the brain, spinal cord, and GI tract. Binding to this struc-
ture results in analgesia. The classic opiate side effects that include
respiratory depression, constipation, and physical dependence are attribu-
ted to binding to this receptor.
The k (kappa) receptor is found mainly in the brain and spinal cord.
Binding results in analgesia and sedation. It does not apparently lead to
physical dependence.
The d (delta) receptor is found mainly in the brain. Binding leads to analge-
sia but also to dependence.
available indicates that these assays or modified versions are still used to screen
for new analgesics.
1. In the hot plate test, the animal is either placed on a hot plate heated to
50 C or on a cold plate that gradually reaches that temperature. An
untreated rodent will respond by jumping to try to avoid the painful
stimulus or under certain conditions liking the sole of its hind paw.
2. The tail flick assay involves focusing a hot beam onto the tail of the rodent.
An untreated animal will respond by flicking that tail.
3. The writhing assay involves injecting an irritating substance, typically
hydrochloric or acetic acid into the rodent’s peritoneum. Untreated rodents
will respond by writhing.
4. Follow-up tests to exclude analgesics that act by other mechanisms such as
NSAIDs will involve opiate receptor binding assays as well as reversal of
the analgesic action by naloxone.
H3C
H3C
N
N
O OH
O OH OH
HO
Conventional Stereochemical
Morphine
(1)
Fig. 1. Morphine.
OPIATE ANALGESICS 5
H3C H3C
N N
Despite the problem posed by its propensity to cause drug dependence, mor-
phine, was and is still an indispensable drug for treating severe acute or chronic
pain. This dilemma has led to continuing research aimed at providing derivatives
or totally synthetic compounds that act on the same receptor but do not cause the
dependence that typify morphine itself. Virtually all of the analogues obtained by
modifying that opiate were prepared decades before the isolation of opiate recep-
tors. It was found much more recently that the analgesics in this class bound to
the m (named after morphine) receptors. Most analogues were prepared by rela-
tively simple chemical manipulations. Simple reduction of the double bond in
morphine and subsequent oxidation of the hydroxyl group in the same ring
leads to hydromorphone (4) (7). The same sequence starting with codeine leads
to hydrocodone (5) (8,9). Both compounds are more potent than the parent
molecules; the latter is often prescribed as a cough suppressant.
H3C H3C
N N
HO O O H3CO O O
Hydromorphone Hydrocodone
(4) (5)
H3C H3C
H3C N
N
N
H3CO O
O H3CO OH O CH3 O
H3CO O
Metopon
Hydrocodone
(6)
five-membered ring is then reestablished. The fact that the final product,
metopon (10) (6) (Fig. 2), shows much the same analgesic activity as hydrocodone
showed that biological activity was retained in the face of substantial structural
changes. All these compounds interact largely with m receptors and show the
same addicting properties as morphine.
H
N
N
HO O OH
HO O OH
Norhydromorphine Nalorphine
(7) (8)
H3C
H3C N
H3C H3C HO
N
N N OH
OH
O OCH3 H2O 2 O OCH3
H3CO O O
H3CO O OCH3 OCH3 OCH3
H3C
H3C
N
N
OH
OH
HO O O
H3CO O O
Oxycodone Oxymorphone
(11) (12)
N N N
OH OH OH
HO O O HO O O O OH
HO
Variants on this theme in which other alkyl groups replace the methyl
group on nitrogen exhibit differing mixtures of agonist/antagonist activities.
Naltrexone (14) (12), in which a cyclopropyl group replaces the methyl group
on nitrogen, binds to both m and k receptors and is used largely to help addicts
overcome their dependence. The drug is also used to treat alcohol dependence
although it does so by some unknown mechanism. The closely related drug nal-
bufine (15) (13) in which the double bond is replaced by a cyclobutyl ring is also a
mixed agonist-antagonist in laboratory models. Analgesia, however, predomi-
nates in humans. This drug interestingly does not appear on the FDA list of con-
trolled substances.
Replacing the ring carbonyl by a hydrazone affords naloxazone (16) (14).
Like its precursor, this compound is an opiate antagonist. The drug is however
strictly a laboratory tool because it forms a permanent covalent bond with the
opiate receptors and more or less permanently inactivates those structures.
The compound, here named ‘‘aminocodone,’’ (17) in which an amino group
replaces the hydroxyl group in oxycodone can be prepared from thebaine by a
somewhat more involved scheme than that used for introducing oxygen at that
position (see Fig. 3). Adding a five-carbon side chain to the primary amino group
produces pentamorphone (18) (15). This product is a potent analgesic in humans.
It has not been introduced in the market because it offers no advantages over
currently available drugs.
OPIATE ANALGESICS 9
CH3 CH3
CH4
N N N
OH NH2 NH
O H3CO O O O
HO N HO O
H2N “Aminocodone”
Naloxazone Pentamorphone
(16) (17) (18)
H3C
N
OH CH3
CH3
HO O OCH3
Etorphine
(19)
The double-bond array in thebaine (diene), which reacts with hydrogen per-
oxide, will also accept an intermediate that features an activated double bond.
This results in the formation of two new carbon-to-carbon covalent bonds and
thus a new ring that spans the ends of the reactive diene. Further transforma-
tion of that condensation product affords etorphine (19). This product shows clas-
sic opiate activity; the potency of etorphine ranges between 1,000 and 10,000 that
of morphine in animals including humans. The drug is used mainly to knock
down large animals to permit physiological studies.
The development of a scheme for preparing opiate analogues lacking the fused
five-membered, oxygen-containing ring from so-called coal-tar intermediates
led to the synthesis of a host of analogues, some of which are still used in the
clinic. This also led to the synthesis of opiates with yet further simplified struc-
tures some of which hardly resemble morphine. Lest this narrative leaves the
impression of a smooth progression toward ever simpler molecules, it should
be noted that discovery of some of the abbreviated molecules, such as methadone
and meperidine, occurred out of order chronologically.
6.1. Morphinans. Opiates lacking the fused oxygen-containing, five-
membered ring named morphinans are prepared in approximately six steps
from readily available so-called coal tar starting materials. The key step in
this sequence involves formation of the morphine carbon nucleus. The product
10 OPIATE ANALGESICS
HO H3CO H3CO
R = CH3, Cyclizaton Product Dextromethorphan
Levomethorphan
R = H, Racemorphan (20) (21)
H3C
N N
HO H3CO
Levorphanol Levallorphan
(22) (23)
CH3
CH3
N
N
OH
CH3
HO HO
Ring Contracted Ring Opened
N
OH
HO
Butorphanol
(24)
CH3
N N N
O N N
NH2
CH3 CH3
CH3 CH3
CH3
HO HO
HO Cyclazocine
Dezocine Ketazocine
(28) (29) (30)
Fig. 6. Benzomorphans.
morphine itself. The much simpler structure compared with morphine led to
intensive work on the preparation of related compounds in many other labora-
tories. It has been estimated that more than 5,000 analogues had been prepared
by 2005 (25). The preponderance of drugs related to meperidine bind almost
exclusively to m receptors. Although this research failed to produce the long
sought after nonaddicting analgesic, it did eventually yield a series of extremely
potent analogues that will be touched on later in this account.
OCH3
N CH3 N CH3
H5C2O 2C
O
Meperidine Ketobemidone
(31) (32)
NH2
N N
H5C2O 2C H5C2O 2C
Pheniridine Anileridine
(33) (34)
N N
H5C2O 2C H5C2O 2C
Fig. 7. Analogues.
H5C2O 2C N
CH3
CH3
N CH3
H5C2O 2C
H3C Cis Isomer
N
CH3
N CH3 CH3
H5C2O 2C H5C2O 2C
H3C Trans Isomer
H5C2OCO N
CH3
N
CH3 CH3
CH3
H5C2OCO
Betaprodine Alphaprodine
(35) (36)
HO HO
HO N CH3
H3C N H3C N
CH3
Nitrogen isomer Allyl Derivative
Picenadol
(37)
because of steric crowding in the alternative configuration. This mimics the con-
figuration of the benzene ring in morphine in which this fragment is locked in
place. The corresponding ring in the trans isomer occupies the expected position
parallel to the plane of the piperidine (30). Much the same is obtained in analge-
sics in which the ester group on the benzene-substituted carbon is reversed so
that oxygen is connected to that atom. Betaprodine (35) in which the methyl
group is on the same side of the cyclohexane ring is some five times more potent
than its isomer alphaprodine (36).
Analgesic activity is retained in the analogue in which the carbethoxy
group is replaced by a three-carbon aliphatic side chain (Fig. 9). That isomer
in which the ring methyl group are on opposite sides of the ring, picenadol
(37), shows approximately the same potency as meperidine or one sixth that of
morphine (31). Although this drug shows good activity in trials in humans, it has
not been commercialized. The analogue in which nitrogen has been moved closer
to the quaternary carbon by one atom retains analgesic activity in animal tests
(32). The N-allyl derivative in this series exhibits no analgesic at all; the com-
pound acts as a pure opiate antagonist again in animal and in vitro assays.
Analgesic activity is retained in ethoheptazine (38), the analogue in which
the size of the heterocyclic ring is enlarged by the insertion of a methylene group
(33) (Fig. 10). The analgesic potency of that congener is approximately one half
that of meperidine. The analogue in which the ring is contracted to a pyrrolidine
shows little if any analgesic activity.
The large intestine ranks second only to the brain as a target organ for
opiates. There, these drugs slow peristaltic contraction to the point where consti-
pation sets in. The aryl-piperidine diphenoxilate (34), with a complex side chain
on nitrogen, was prepared in the course of search for novel opiates diphenoxilate
(39). The compound was at first rated as a failure because it was devoid of
CH3
CH3 N
N
H5C2O 2C H5C2O 2C
NC
N
H5C2O 2C
Diphenoxilate
(39)
analgesic activity; the drug did, however, it was noted, retain activity on the gut,
slowing contractions. This agent, under the trade name Lomotil (Pfizer, New
York), was at one time the principal drug for treating traveler’s diarrhea.
6.4. Fentanyl and its Derivatives. The wealth of structure/activity
data available by the end of the 1950s led to the formulation of the so-called
Beckett Casey rule for the chemical structure requirement for central analgesics
(35) (Fig. 11). In brief, that postulate posited that analgesic opiates need to incor-
porate a benzene ring attached to a carbon atom bearing four substituents none
of which is hydrogen, and a tertiary amino group removed at a distance equiva-
lent of a two-carbon chain that originated from the quaternary center. The dis-
covery of the extremely potent synthetic opiate fentanyl (36) raises questions
about that rule because neither of the two benzene rings is attached to a quatern-
ary center. That drug, which is 50 times more potent than morphine in humans
as an analgetic, is still widely used.
The shortcomings of this drug, especially its relatively short duration of
action, spurred further work on analgesics with structures based on the fentanil
motif (Fig. 12). At least five congeners from this program have been evaluated in
clinical trials. Two of these products alfentanyl and sulfentanyl (37) are potent
opiate analgesics currently approved for use in the clinic. Another, carfentanyl
(38), is so potent that its use, like etoprphine, is restricted to knocking down
large animals. The dose required to knock down a moose for example ranges
from 6 to 14 micrograms per kilo. This amounts to about 6 milligrams total
per average moose. It is of note that the benzene ring in these later analogues
of fentanyl is one atom removed from the quaternary center that forms part of
the Becket and Casey postulate.
R
N N N
[ ]
O
R"
Fentanil
(40)
O O
N N
N N S
O
O O
H3C
Carfentanil Sufentanil
(41) (42)
O O
O
N N CO2CH3
N N N
N O
N N
H O
H3C
O
Alfentanil Remifentanil
(43) (44)
H3C CO2CH3
N
H3C
Tilidine
(45)
18 OPIATE ANALGESICS
H3C Cl H3C Cl
N CH3 N CH3
Cl Cl
NH O NH
O O O
Cl
N N
Cl
O
NH NH
O O O O
Spiradoline Enadoline
(48) (49)
R X
OH
OH
H3C N H3C N
CH3 CH3
Aminoalcohols Bromadol
(50)
O O O
CH3
N N N
CH3 O
congener, doxpicomine (52) (50), in which the benzene ring is replaced by pyri-
dine and the other ring comprises an oxygen-containing cyclic acetal, displays
about the same potency of codeine. This drug has been characterized as a mild
analgesic that binds to m opiate receptors; it has been used mostly for treating
postoperative pain.
N O
N OH N
H3C CH3 H3C CH3
Ciramandol Doxpicomine
(51) (52)
H3C CH3
N H3C N
N
H3C N S
H3C
CH3
HO
H3C HO CH3
N
N
CH3 CH3 CH3
Tramadol Tapentadol
(55) (56)
One principal activity of the U.S. Drug Enforcement Administration (DEA) com-
prises enforcement of regulation for potentially addictive drugs. One first step in
controlling what they call narcotic drugs involves assignment of the substances
to one of five Schedules. At one extreme of these categories is Schedule I for drugs
such as heroin that have no recognized medical use. Schedule V at the other end
in terms of severity lists such items as cough suppressants that contain a small
amount of codeine. Most opioid analgesics, and the subjects of this review are
consigned to Schedule II drugs. Most constraints are aimed to prevent diversion
of the drugs to nonmedical users or purveyors. Inclusion in Schedule II means
among other things that pharmacies are enjoined to provide the drug only on
presentation of an original prescription signed by a physician who also lists his
DEA registration number; and permits refills only on presentation of a new
valid prescription. Regulations become progressively less stringent for drugs in
Schedules III to V. Those regulations deal in large part with conditions for refills
and record keeping. Some mixed agonist-antagonists are listed in Schedule IV.
It is of interest in this connection that tramdol is not scheduled by the DEA.
The structurally related analgesic tapentadol, however, is listed in Schedule II,
the same group that includes morphine.
CITED PUBLICATIONS
1. For a more detailed account, see A. G. Gibson, Plants and Civilization, http://
www.botgard.ucla.edu/html/botanytextbooks/economicbotany/Papaver/.
2. J. Buckingham, Chasing the Molecule, Sutton, Gloucestshire, U.K., 2004.
opf, Annals 452, 211 (1927).
3. C. Sch€
22 OPIATE ANALGESICS
DANIEL LEDNICER
Bethesda, MD