Research Review Paper on Opiates

Running Head: RESEARCH REVIEW ON OPIATES 1

Research Review Paper on Opiates

Casey Anderson

State University of New York at Geneseo

RESEARCH REVIEW ON OPIATES 2

Abstract

This research paper takes a look at the history of opiates,

starting with raw opium, thousands of years ago. It looks at the

beginning of the opium poppy in the Middle East and how as it

traveled west, it changed from a clay-like freebase to a tincture

of alcohol and opium, to the pills that exist today. The way

opiates work through inhibiting pain signals from traveling from

the spine to brain and vice-versa. Also, the ventral tegmental

area (VTA) and nucleus accumbens (NA) are examined in how

disinhibitng opioids of GABAergic neurons increase the firing

rate of mesolimbic dopaminergic cells, increasing dopamine, and

making opiates addictive. Future outlooks are analyzed and the

discussion of partial agonist/antagonist, like suboxone, is

discussed as well as the treatment of ibogaine, a wild

hallucinogenic plant. Ibogaine has claimed to get completely

hooked opiate addicts off opiates, without withdrawals, within 2

days.


Research Review Paper on Opiates

Opiates began with opium, the dried milky sap from the seed

of the opium poppy plant, called Papaver somniferum. It was smoked

by the Muslims and Chinese and drank in an alcoholic preparation

called laudanum in Europe. During these times people did not

think twice about giving some opium to their child for a cough or

diarrhea, despite how addicting and powerful it is. This was not

first recognized until Serturner was able to isolate the alkaloid


morphine, from opium, and people began seeing others focusing

their daily routines on a substance (Reisine & Bell, 1993).

Researchers spent nearly a century trying to separate the pain

relieving and addictive properties, resulting in chemist Heinrich

Dreser’s discovery of heroin. Heroin was introduced as the ideal

nonaddictive substitute for morphine, but around 10 years later

it became clear that heroin has a higher addictive potential than

morphine, and was banned in the United States in 1905 (Gerrits,

et al., 2003). During the 20th century, a number of semi-

synthetic and completely synthetic opiates were synthesized from

morphine, codeine, and thebaine, all alkaloids of opium.

Numerous opioid drugs began appearing on pharmacist’s

shelves and has continued to this day. Now there are full

agonists with a variety of strengths that increase pain relief as

the dose increases. There are partial agonists, which have a

“ceiling effect” meaning that above a certain dose there is no

more gain in pain relief (Gordon, et al., 1999). There are also

mixed partial agonist/antagonist, which can be used to treat

opiate addiction, like buprenorphine. The abuse potential is

certainly the main focus and concern with opiates. Opiates have


been abused for thousands of years and known to have a high

addictive potential. In 1999, approximately 4 million people in

the United States were using prescription painkillers non-

medically, about double the 2.1 million people who use heroin and

cocaine (Miller & Lyon, 2003).

A future possible treatment for opiate addiction is looking

at the drug ibogaine. It is a natural plant, that causes

hallucinations for nearly a day, but cases have shown opiate

addicts using the drug and within two days being off opiates,

experiencing no withdrawals, and somewhat in awe at how quick

their life changed. Research like this and studies geared towards

finding analgesics that do not have the addictive properties are

what chemists are interested in.

Brief History of Opiates

Opiates began with opium, the dried milky sap from the seed

of the opium poppy plant, called Papaver somniferum. Research has

found remnants of Papaver somniferum dating back to 8000 B.C., but

the first known cultivation of opium poppy plants was in

Mesopotamia, around 3000 B.C., by Sumerians (Gerrits, Lesscher, &

Ree, 2003). Around 600 A.D. the territory became Persia, where


the opium poppy was cultivated then exported by Arabic traders

from the Middle East to India, China, and later to Europe

(Gerrits, et al., 2003). The Muslim prohibition of alcohol and

Chinese ban against tobacco smoking may have favored the spread

of opium. The Muslims and Chinese were known to mainly smoke

opium, but as it moved west the manner in which it was consumed

changed.

The ancient Greeks and Romans were aware of opium and at the

end of the middle ages the physician Paracelsus invented the

opium tincture, laudanum, which was a liquid preparation of

alcohol and opium (Gerrits, et al., 2003). It was commonly used

as an ailment for pain relief, diarrhea, and cough suppression.

The problem with laudanum was its addicting nature due to the

opium, which contains the alkaloids morphine, codeine, and

thebaine. These are natural opiates found in opium that induce

analgesia (pain relief) and euphoria, enhancing their risk of

addictiveness (Miller & Lyon, 2003). In 1806 German pharmacist

Friedrich Serturner was able to isolate an active component of

opium, the alkaloid morphine (Reisine & Bell, 1993). Morphine was

a very effective painkiller, but it appeared as addictive as


opium. This sparked an interest in researchers to find a

painkiller that did not have addictive properties.

Researchers spent nearly a century trying to separate the

pain relieving and addictive properties, resulting in chemist

Heinrich Dreser’s discovery of heroin (Gerrits, et al., 2003).

Heroin was introduced as the ideal nonaddictive substitute for

morphine, but around 10 years later it became clear that heroin

has a higher addictive potential than morphine, and was banned in

the United States in 1905 (Gerrits, et al., 2003). During the

20th century, a number of semi-synthetic and completely synthetic

opiates were synthesized from morphine, codeine, and thebaine.

Examples include semi-synthetic opiates like hydromorphone,

oxycodone, heroin, and completely synthetic opiates like

meperidine, fentanyl, methadone, buprenorphine, and many others.

These are all regulated by the Federal Drug Administration (FDA)

and controlled by doctors and pharmacists under the Controlled

Substances Act.

Pharmacological Properties

In the beginning of the 1970s, the first opiate binding

sites were discovered and labeled using radioligand binding (Pert


& Snyder, 1973). Pert and Snyder (1973) showed that as the amount

of radioactive naloxone, an opiate antagonist, is increased the

binding also increased in a linear fashion, until the receptors

were fully occupied. The receptors showed a high affinity, or

strong bond, for opiates and each affinity was different, seen

and located on autoradiography (Pert & Snyder, 1973). The three

most important opioid receptor subtypes identified have been the

-receptor (for morphine), -receptor (for ketocyclazocine), -

receptor (for vas deferens), which all have distinct locations in

the brain and spinal cord (Lord, Waterfield, Hughes, &

Kosterlitz, 1977).

The discoveries of opioid receptors lead researchers to look

for endogenous neurochemicals that must interact with these

receptors. The first indication of endogenous opioids came from

studies showing that brain extracts contain opioid-like activity,

which with further research led to the determination of

enkephalin, formed by enzymatic processing of the precursor

peptide, pro-enkephalin (Gerrits, et al., 2003). Biologists

accordingly found the enzymatic processing of the precursor

peptides, pro-opiomelanocortin (POMC) for -endorphin and pro-


dynorphin for dynorphin (Gerrits, et al., 2003). A preference for

the endogenous opioid ligands appeared for the different opioid

receptor subtypes: -endorphin for , enkephalins for ,

dynorphins for , and endomorphins for the -receptor (Gerrits,

et al., 2003). Endomorphins, have no identified precursor

peptide, but selectively bind to the -receptor and are as potent

as morphine for pain relief (Gerrits, et al., 2003).

The -receptors have a high affinity for morphine and this

is where all opiates primarily act on, inducing analgesia and

euphoria in the medial thalamus, periaqueductal gray (PAG),

median raphe, and clusters within the spinal cord (Miller & Lyon,

2003). Miller and Lyon (2003) stated these receptors are located

in the peripheral nervous system (PNS) and gastrointestinal

tract, upon activation of the receptors in the PNS, miosis

(constricting pupils), decreased breathing rate and muscle tone,

cough control and nausea occur in the brain stem region, while

constipation is due to decreased motility in the digestive tract.

This receptor is directly linked to addiction, because it is

responsible for positive reinforcement due to activation of the


ventral tegmental area (VTA) and nucleus accumbens (NA), which

transmits dopamine (Miller & Lyon, 2003).

The -receptors have a similar distribution to the -

receptor but are more restricted, in that they are located

primarily in the forebrain structures such as the neocortex,

olfactory areas, substantia nigra, striatum, and nucleus

accumbens (Gerrits, et al., 2003). Due to a concentration of

receptors in the forebrain there is a focus on modulating

olfaction, motor impairment, cognitive function, and the overlap

with -receptors, in the spinal cord, results in analgesia and

reinforcement. Wise and Rompre (1989) discovered that opioid

agonists produce respiratory depression at very high doses, but

at low to moderate doses of the opioid agonists it actually

stimulated respiratory function. The ability to relieve pain and

stimulate respiration, simultaneously, is certainly an advantage.

The -receptors have a high concentration in the pituitary,

hypothalamus, amygdala, striatum, and nucleus accumbens (Miller &

Lyon, 2003). The opioid agonists for these receptors have shown

to cause dysphoria, stress, dissociative, and hallucinating

effects but these receptors have an integral role as a


neurochemical component of addiction (Miller & Lyon, 2003). These

receptors are also involved in temperature control, water

balance, and analgesia (Miller & Lyon, 2003).

These opioid receptors and endogenous opioids work together,

when an opioid agonist enters the body, to produce numerous

effects on the central and peripheral nervous systems. When the

opioid enters the body via oral consumption, mucous membranes,

bloodstream, or whatever manner, it binds to opioid receptors and

mimics the inhibitory action of the endogenous opioids (Gerrits,

Wiegant, & Van Ree, 1999). Pain signals are carried by afferent

neurons, from the body into the spinal cord, where these afferent

neurons end on projection neurons, or short excitatory

interneurons, that transmit pain signals to the brain (Gerrits,

et al., 1999). Opioids can release endorphins that inhibit the

projection neurons, inhibit the excitatory interneurons, or

excite the inhibitory opioid neuron (Gerrits, et al., 1999).

Those are all ways that opioids can properly block the

transmission of pain signals.

The model of the opposing effects of opioids, however, works

by opioids binding to opioid receptors, in the ventral tegmental


area (VTA), located on the terminals of GABAergic interneurons

and of long GABAergic neurons that project back from the nucleus

accumbens (Gerrits, et al., 1999). This is the projection region

of the dopamine neurons, in the VTA, and through GABAergic

disinhibition opioids, like the -endorphin, the firing rate of

the mesolimbic dopaminergic cells increases and release more

dopamine in the nucleus accumbens (Gerrits, et al., 1999). The

release or rush of dopamine creates feelings of euphoria and a

“reinforcement pathway”. This is the other pharmacological manner

that opioids effect the body and in this model it displays how

opiates create their reinforcing effects, or desire, to use

again.

Therapeutic & Abuse Potential

There are certainly therapeutic effects of opiates that go

beyond just relieving pain, but that clearly is one of the most

beneficial uses for them. The therapeutic ability for opiates to

be able to relieve mild, moderate, or severe pain can be life

changing for many people. Now there are full agonists with a

variety of strengths that increase pain relief as the dose

increases. There are partial agonist, which also very in


strength, but have a “ceiling effect” meaning that above a

certain dose there is no more gain in pain relief (Gordon, et

al., 1999). There are also mixed partial agonist/antagonist,

which can be used to treat opiate addiction, like buprenorphine

(Suboxone). Methadone is another partial agonist that helps

treating previous opiate addicts. Both work by filling the opioid

receptors with a tight ‘grip’, or affinity, but having just

enough of an effect to erase cravings to use opiates. These are

all medicines that can improve your living or allow you to not

have to live your life in pain. Pain medication can be a great

help to those suffering from Crohn’s, fibromyalgia, arthritis,

degenerative discs, and other diseases that involve pain. Opiates

help with diarrhea, suppressing coughs, and small issues like

these but their addictive potential outweighs their helpfulness.

The abuse potential is certainly the main focus and concern

with opiates. Opiates have been abused for thousands of years and

known to have a high addictive potential. In 1999, approximately

4 million people in the United States were using prescription

painkillers non-medically, about double the 2.1 million people

who use heroin and cocaine (Miller & Lyon, 2003). Miller and Lyon


(2003) reported that between 1996 and 2000, there was a 239%

increase in oxycodone prescriptions written. This pattern has

continued in the United States, which faces an epidemic in

painkiller addiction. These painkillers, being over-prescribed,

are in 12 hour time-release coatings that are pealed off,

instantly making the pill as strong or stronger than heroin.

Opiates are dangerous due to the side effects like respiratory

depression and the tolerance increases 20 to 100-fold in dosage,

versus alcohol, which increases 2 to 4-fold in dosage (Okie,

2010). The VTA to NA pathway that was described in the

pharmacological properties section explains how opiates can be so

addicting by building a “reinforcement pathway”. People born with

predisposition toward addiction and exposure to opiates tend to

naturally continue the cycle of using once they start using,

because opiates can become addicting within one week (Okie,

2010). It takes constant training throughout an opiate addict’s

life to ensure they do not relapse, since triggers, which are

things that remind an addict of using, are constantly in the

world. The use of MAOIs or SSRIs has shown to help recovering

addicts build their levels of catecholamines back up and slowly


improve their mood (Clouet & Iwatsubo, 1975). Overall, opioids

have a very high addictive potential and are very dangerous.

Developments, Innovation, and Future Perspectives

Research has been done and will continue, looking at new

ways to treat pain without a high addictive or dependency

potential. After about a decade of skyrocketing abuse of opioids,

in particular Oxycontin, the United States sued the

pharmaceutical company Purdue Pharma and made them create a new,

non-crushable, version of Oxycontin due to an epidemic in

painkiller addiction across the United States. Treatment for

opiates has been methadone for decades and still is, but the

success rate of people getting off methadone and staying clean

from opiates is not high.

This has resulted in new medicines, like suboxone, which is

more efficient in that weekly prescriptions can be given, instead

of day-to-day trips to get medicine. It also is a weaker agonist,

allowing the brain to heal and has a “ceiling effect”, where

methadone doses can increase to the point where a person is


nodding off and getting a buzz. Suboxone also contains small

amounts of the antagonist, naloxene, to block opiate receptors.

This further prevents opioid abuse, since any agonist taken would

be blocked by the suboxone.

A future possible treatment for opiate addiction is looking

at the drug ibogaine. It is a natural plant, that causes

hallucinations for nearly a day, but cases have shown opiate

addicts using the drug and within two days being off opiates,

experiencing no withdrawals, and somewhat in awe at how quick

their life changed. Research has found mixing a -agonist with a

-agonist can allow for safer opiate medications, since -agonist

have shown in low doses to increase the rate of respiration, the

opposite of opiates that bind to the -receptor. Until the time

comes when researchers find a possible way to separate pain

relief from the addictive properties of euphoria that come with

opiates, it will be hard to make significant progress.

Summary

Opium, the dried sap of the opium poppy plant, Papaver

somniferum has been around since Neolithic ages. It was used


medicinally and recreationally across China, the Middle East, and

in Europe. Throughout time the composition has changed from a

clay-like material that was smoked to a liquid, opium tincture,

to powders and pills of the synthesized derivatives of opium.

Morphine was isolated, then heroin was made to be “nonaddictive”

and throughout the 20th century numerous semi-synthetic and

completely synthetic opiates have been created. All of these

forms share certain traits of analgesia, euphoria, drowsiness,

and addictiveness.

There are three main opioid receptor subtypes, the (mu),

(delta), and (kappa). The -receptor is the receptor morphine

and nearly all opioids bind to, with very high affinity. It is

also the receptor that is associated with the highest levels of

analgesia, euphoria, and addictiveness. It’s important to

consider all three, although -receptors and -receptors are the

main two receptors that opioids interact with most. Opioids work

by binding to opioid receptors and mimicking the inhibition of

endogenous opioids by blocking pain signals at various areas,

especially where nerves of the spinal cord and brain meet. The

VTA to NA loop shows how reinforcing opiate use can be, with the


constant inhibiting of -endorphins on GABAergic neurons,

increasing the firing rate of the mesolimbic dopaminergic cells

and amount of dopamine in the nucleus accumbens.

The increase in various opioids has come with outrageous

increases in the number of prescriptions getting written for

painkillers. This has caused an epidemic of painkiller addiction

the United States is just starting to realize. Methods of

treatment are slowly getting updated with methadone, LAAM, and

buprenorphine. Future treatments are slowly developing and the

use of ibogaine is fairly promising in treating opiate addicts,

because they can skip the withdrawals, but counseling is key to

staying sober from any addiction. Opiates are a very beneficial

medicine to have since it helps those in chronic pain live a life

without being in agonizing pain. However, all opioid medications

are addictive and even when taken as prescribed can be very easy

to become dependent on. The day a painkiller is discovered that

has the analgesic effects without the addictive properties will

be the mark of a new point in science.


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