Opiates in the Past, Present and Future:

Blessing or Menace?

Intro

For centuries, opiates have had a profound influence on the societies of our world.
Early writings by Homer, Hippocrates, Virgil, and Ovid describe the use of opium for a
variety of reasons, including gastrointestinal distress and insomnia as well as recreational
abuse. Success in treating these ailments led to increasing medicinal use throughout
Greek and Roman civilization. Early in the16th century, Paracelsus created an elixir
combining alcohol and opium, two of the most potent substances known at the time. This
concoction, known as Laudanum (Latin for “something to be praised”), was used to treat
the full spectrum of known diseases.
Opium use was not just documented in the European civilizations. The Opium
Wars in China during the early 1800’s have been described by many historians as one of
the most demoralizing conflicts ever experienced. The British smuggled massive
quantities of opium from India into China where people quickly became dependent on it.
By 1835, most of the Chinese population found itself seeking opium to the feed their
addiction in illegal opium parlors in spite of tremendous efforts by the government to
stamp out drug use. Over time, the prevalence of opium dependence among the Chinese
was strategically exploited by Europeans, forcing the Chinese to open their ports to
unwanted foreign trading.
As laboratory techniques grew more sophisticated, morphine (named after
“Morpheus”, the Greek god of dreams) was successfully extracted from opium juice and
widely used to treat pain. During the American Civil War, this potent opiate was used for
even minimal pain relief, resulting in widespread addiction known as “soldier’s disease”.
But the most serious consequences of opiate misuse became apparent with the advent of
the hypodermic needle in 1856. IV drug abuse spread rampantly and resulted in many
accidental overdoses from respiratory failure by inexperienced users. To combat this
epidemic, laws were passed to prohibit illegitimate drug use, but the fight to eliminate
abuse continued to modern day.
Today, as in the 1800s, the addictive properties of opium and its derivatives are
still taken advantage of for financial gain. In areas such as Afghanistan, home to 75% of
the world poppy crop, opium and opiates are not only one of the primary sources of
income, but also a determinant of socioeconomic status. Possession of plentiful opium
crop conveys wealth and power to the owner. This power, in turn, is used to coerce
impoverished parts of the country to grow even more opium, continuing the downward
spiral.
While opium can cause considerable suffering if misused, its opioid derivatives
remain irreplaceable as the most powerful medicinal weapon against severe pain
throughout the world today. For this reason, a clear line must be drawn between
legitimate and illegitimate use, highlighting the mechanism of opiate action and
addiction.
Relevance

But first, how prevalent is drug abuse in today’s population? In 2003, 52.8% of
17 year old students in the United States admitted to illicit drug use. Although most of
these data relate to marijuana use, this alarming number demonstrates how common
substance abuse is in a community of young people. The consequences, of course, are
devastating. In England, more than 2300 people died in 1998 due to drug-related habits,
illustrating the negative impact of drug use. These deaths are not only a direct result of
drug effect on nervous and immune systems, but also through indirect means such as road
accidents. Additionally, many IV drug abusers die from HIV, Hepatitis B, and other
blood infecting pathogens. These infectious diseases are usually acquired from syringes
used to inject drugs, which are frequently shared between groups of people, and unsafe
sexual practices. Only one diseased person is required to contaminate the whole group.
But how common is opiate abuse? The prevalence of alcohol and marijuana
abuse is still much higher in comparison to opiate abuse. In fact, alcohol abuse has a
lifetime prevalence of 13-23% percent of the population. Among young adults, 90%
admit to alcohol use and 53% admit to marijuana use. In contrast, only 9% have used
opiates. Nevertheless, alcohol and marijuana are not used intravenously, and the serious
consequences of intravascular abuse such as accidental overdose and infectious diseases
do not readily apply. Moreover, high doses of opiates quickly result in respiratory
depression, which can cause fatalities. On another note, opiate abuse may also pose a
serious problem in the clinical setting. High tolerance to opiate effects in abusers may
present difficulty in providing analgesia to chronic pain and surgical settings.

Etiology

Where do opium and its derivates come from? Opium, Greek for “juice”, is
derived from the opium poppy Papaver somniformum. This plant is found extensively
throughout southeast Europe and western Asia. Incising the wall of immature seeds
yields a milky exudate, which is dried to produce opium. A variety of compounds are
extracted from opium, including its most potent component, morphine. Morphine makes
up approximately 10% of opium, while codeine, a less potent opiate, makes up 0.5%.
Both morphine and codeine have widespread medicinal application for pain relief and
cough suppression, respectively. These two naturally occurring compounds are referred
to as “opiates”, whereas all others acting on opiate receptors are more commonly known
as “opioids”.
While morphine and codeine are extremely useful in medicine, other opioids have
been synthetically created for use in anesthesia, gastrointestinal distress, and substance
abuse treatment programs. These differ widely in properties and formulation and will be
discussed later.

Mechanism of Action

Opioids act widely throughout the body, including not only the central, but also
the peripheral nervous system. Specifically, they act on small proteins located on the
surface of some neurons which are appropriately named “opiate receptors”. When
classifying opiates, a clear distinction is made between drugs that bind to these receptors
and cause an effect (known as “agonists”) and drugs that bind, but have no visible effect
(known as “antagonists”). Although antagonists do not have intrinsic activity, they may
precipitate withdrawal symptoms in chronic opiate use, because they completely block
receptors and prevent agonists from binding to the active site.
Opiate ligands act on four different types of opiate receptors - mu1, mu2, kappa
and delta (see Table 1). The distinction is important, because different opiate receptor
subtypes are found in separate locations in the nervous system and are responsible for
different effects (and side effects!).

Table 1: Responses mediated by opioid receptors

Receptor Response on activation

Mu Analgesia, respiratory depression, miosis, euphoria,
reduced gastrointestinal motility
Kapp Analgesia, dysphoria, psychotomimetic effects, miosis,
a respiratory depression
From Cherny, p. 715

It has been known for some time that these receptors ordinarily respond to
naturally occurring human substances. These substances, referred to as endogenous
morphine (or more commonly, “endorphin”), regulate pain and hunger and are involved
in the production of sex hormones. In vivo, endorphins cause mild analgesia and a
general sense of well-being. They are released in response to laughter, exercise,
acupuncture and chili peppers. Binding of these natural endorphins is very specific.
Beta-endorphin, dynorphin and enkephalin bind most tightly to mu, kappa, and delta
receptors, respectively. Similarly, the binding of opioids is also very specific, leading to
distinct drug profiles (see Table 2).

Table 2: Classification of opioid analgesics by actions at opioid receptors

Receptor types
Compound Mu Kappa Delta
Morphine +++ + +
Naloxone - - -
Pentazocine +/0 + unknown
Butorphanol +/0 + unknown
Nalbuphine - + unknown
Buprenorphine ++ + +
Fentanyl +++ + +
Dezocine + + +
 From Julien, p. 262

The cascade of events following drug-receptor binding is complex. It is known

that all three opiate receptor subtypes are G-protein linked receptors. The three subtypes
are very similar in sequence, sharing approximately 60% of their amino acid sequence.
To date, no ion channel opiate receptors have been identified, indicating that opiates
affect the nervous system by modulating intrinsic activity and may have longer lasting
effects. It has become apparent through molecular studies that opioids exert their effects
presynaptically and inhibit the amount of transmitter released from the neurons. For
example, opioids reaching the spinal cord attach themselves presynaptically to a sensory
neuron. The bound drug inhibits the release of transmitters, such as substance P which is
released during injury, from the postsynaptic neuron. This effectively reduces the
perception of pain. In other areas of the nervous system, a similar mechanism involving
the inhibition of other transmitters results in different drug effects.
Opiate receptor subtypes are differentially distributed throughout the nervous
system, giving an insight to their unique contributions. Mu receptors are the most
prevalent, occurring in many structures of the brain including the thalamus,
periaqueductal gray, spinal trigeminal nucleus and nucleus accumbens as well as in the
brain stem, the dorsal horn of the spinal cord and the intestine. Sites such as the
periaqueductal gray, spinal trigeminal nucleus, and dorsal horn of the spinal cord have
established roles in sensory perception including pain. Not surprisingly, opiate agonists
acting on the mu receptors inhibit the release of substance P and produce considerable
analgesia. Other important locations of mu receptors are the “chemo-trigger zone” and
the respiratory center in the brain stem. Activation of receptors in the chemo-trigger zone
is responsible for opiate-induced nausea and vomiting. Activation in the respiratory
center, however, results in decreased and sometimes absent respiratory drive, which is
frequently the cause of death in overdose. Clinically, this area is also targeted for cough
suppression with less potent opiates, such as codeine. Unfortunately, mu receptors are
also prominent in the nucleus accumbens, a crucial component of the reward circuit in the
brain. Drug action at this site triggers a cascade of events that ends in dopamine release
and resulting euphoria, which puts opiate users at risk for addiction. Lastly, mu receptors
feature prominently in the gastrointestinal tract, where they decrease motility and
increase tone, sometimes causing severe constipation.
Kappa receptors also occur in the spinal cord and periaqueductal gray where they
produce modest analgesia. They are also present in the nucleus accumbens, but in
contrast to mu receptors, these receptors produce dysphoria. Activation of kappa
receptors can actually counter some of the effects of mu receptors in other areas of the
nervous system as well in spite of their similarity in structure. Additionally, kappa
receptor activation results in feelings of depersonalization and disorientation, but
respiratory depression is only mild. While the modest analgesia and low risk of
respiratory depression appear promising for medicinal use, opiate agonists specific to the
kappa receptor have had limited success in the past, because patients were unable to
tolerate the resulting dysphoria.
 So far, delta receptor function has remained largely unknown. The receptors are
prominently dispersed throughout the limbic system, suggesting that they may be
responsible for emotional reactions to opioids including euphoria.

Opioid Classification

As mentioned earlier, morphine and codeine are no longer the only opiate
receptor ligands available. Many additional opioids have been synthesized to specifically
target opiate receptor subtypes. These opioids may be characterized in a variety of ways;
some more useful in certain settings than others. They may be classified by receptor
subtype, potency of analgesia, and half-life in the body. In the clinical setting, opioids
are frequently prescribed for conditions causing chronic pain. The appropriate
medication is selected based on the severity of the pain. For pain of minor degree, less
potent opioids are selected to minimize the risk of side effects. More potent formulations
are only used when these fail. In this case, analgesic potency is a useful means for
classification. In the surgical setting, on the other hand, half-life becomes very
important. For anesthetic induction, a powerful but short-acting opioid is selected. As
anesthesia deepens, the short-acting drug is exchanged for a longer-acting maintenance
opioid. Again, this is done to minimize side effects as well as decrease the frequency of
drug administration.
In order to understand how these drugs exert their effects, it is more useful to
classify opioids by their receptor interaction. As discussed previously, agonists activate
receptors while antagonists inactivate them. In addition to these two categories, there are
also partial agonists and mixed agonist-antagonists. Partial agonists are opioids which
cause only minimal activation upon binding. For a person unaccustomed to opioids, this
results in mild analgesia and is very useful for moderate pain unresponsive to over-the-
counter medications. When administered to an opioid-dependent person, on the other
hand, partial agonists effectively act as antagonists, because the resulting receptor
activation is minimal compared to accustomed doses of opioid. In fact, withdrawal may
result.
Mixed agonist-antagonists activate one receptor subtype while antagonizing
another. These opioids are classically kappa agonists and mu antagonists, which results
in appreciable analgesia with much less risk of addiction than traditional agonists. As
with partial agonists, however, withdrawal may be precipitated in opioid-dependent
individuals. All opioids can easily be classified by receptor interaction (see Table 3),
which makes it possible to predict drug effects and side effects.

Table 3: Classification of opioid analgesics by analgesic properties

 Pure agonists Mixed agonist/antagonists Pure antagonists Partial agonists
From Julien, p. 261
Morphine Nalbuphine (Nubain) Naloxone (Narcan) Buprenorphene (Buprene)
Codeine Butorphanol (Stadol) Naltrexone (Trexan) Tramadol (Ultram)
Heroin Pentazocine (Talwin) Nalmefene (Revex)
Meperidine (Demerol) Dezocine (Dalgan)
Methadone (Dolophine)
Oxymorphone (Numorphan)
Hydromorphone (Dilaudid)
Fentanyl (Sublimaze)

Many consider the most dangerous effect of opium the element of dependency on the
drug. Not only is there a psychological feeling of a requirement of the drug but also a
physic dependency arises. Serious symptoms may result if an individual, who formerly
incorporated opium into his body frequently, suddenly discontinued his use of it. During
heavy use of opium, nerve cells become accustomed to the high concentrations of opiates
present and therefore may begin to rely on them to function properly. The cells strive to
function at a certain rate despite a given opiate concentration. However a dosage greater
than approximately 2g overwhelms them giving the characteristic light-headed feeling. If
the opium presence is then reduced immediately, “withdrawal symptoms” occur. This is
the period in which the nerve cells, unfamiliar with the change in conditions, become
overactive causing these symptoms. Luckily these symptoms are only temporary as the
nerve cells are restored to their original state.
An opium addict, who has used opium over an extensive time period, will often
struggle to rehabilitate. The nerve cells will find it more difficult to return to their healthy
state and their “withdrawal symptoms” will be much more excruciating. Due to these
powerful symptoms the person must be occasionally treated with a substitute, which has
similar effects to that of the actual drug. Methodone is an opioid which is often
administered to heroine addicts to avoid such symptoms as insomnia, fever and vomiting.
It is an oral pill making assimilation much more controlled as it can be vomited. The
dosage is steadily decreased until the patient no longer requires any whatsoever.

Bibliography
-Bucholz, K.K. “Nosology and Epidemiology of Addictive Disorders and Their Comorbidity”.
Psychiatric Clinics of North America 22 (1999): 221-240.

-Czerny, N.I. “Opioid Analgesics: Comparative Features and Prescribing Guidelines”. Drugs 51
(1996): 713-737.
-Feldman, R.S. et al. Principals of Neuropsychopharmacology. (Sunderland: Sinauer, 1997).

-Goldberg, J. Anatomy of a Scientific Discovery. (Bantam Books, 1988).

-Goldsmith, R.J. “Overview of Psychiatric Comorbidity: Practical and Theoretical

Considerations”. Psychiatric Clinics of North America 22 (1999): 331-349.

-Julien, R.M. A Primer of Drug Action, 9th ed. (New York: Worth Publishers, 2001).

-Rang, H.P. et al. Pharmacology, 5th ed. (Edinburgh: Churchill Livingstone, 2003).

-Spielman, F.J. “God’s Own Medicine”. American Journal of Anesthesiology 25 (1998): 273-
275.