CHAPTER 13
OPIOIDS
A. History of Opioids
It is widely believed that the origin of opium can be traced back to a hot and arid
country in the Middle East, dating back several millennia. It is hypothesized that an
individual discovered that Papaver somniferum, during a brief period of 7 to 10 days in
its annual life cycle, secretes a substance that induces euphoria and alleviates pain and
suffering when ingested. The opium poppy is an ephemeral botanical species that attains
a height of 3 to 4 feet and bears expansive flowers measuring 4 to 5 inches in diameter.
The floral specimens exhibit a range of hues including white, pink, red, purple, and
violet. Opium can be obtained during a limited period of the plant's life cycle, specifically
between the time when the petals have fallen and the seedpod has reached maturity.
Presently, akin to the past, the opium cultivators traverse the fields during the early hours
of the evening and employ a pointed, serrated instrument to create superficial incisions on
the immature seed capsules without penetrating them. Over the course of the nocturnal
period, a pale substance emanates from the lacerations, undergoes oxidation resulting in a
reddish-brown hue, and subsequently acquires a viscous texture. During the morning, the
resinous material is meticulously removed from the pod and gathered into diminutive
spheres.
The unprocessed opium serves as the foundation for opium-based medications
that have been utilized over the course of time. It is the primary constituent from which
morphine is obtained, and subsequently, heroin is synthesized. The significance and
prevalence of the opium poppy in the ancient Egyptian and Greek societies remain a topic
of scholarly discussion. However, the Ebers papyrus (circa 1500 BC) references a
medicinal solution aimed at curbing the excessive weeping of infants. Numerous authors
assert that the initial explicit medicinal application of opium can be traced back to the
Ebers papyrus, given that a subsequent Egyptian treatment with analogous objectives
evidently comprised opium (alongside fly excrement).
Despite the fact that opium and the opium poppy had been introduced to China
prior to the year AD 1000, its usage was limited to a privileged and exclusive group. The
introduction of tobacco smoking resulted in a rapid spread of its usage. The exact
timeline of tobacco's introduction to the Chinese population remains unclear. However,
its widespread usage had reached a level of offensiveness that prompted the emperor to
issue a prohibition on tobacco smoking in China in 1644. The decree's duration was
short-lived, as anticipated, however, it played a role in the rise of opium consumption.
Until this juncture, the act of smoking tobacco and consuming opium had
coexisted simultaneously. The prohibition of tobacco usage and the populace's affinity
for smoking gratification resulted in the amalgamation of opium and tobacco for
inhalation. It can be inferred that the combined impact of the stimulant properties of
nicotine and the calming properties of opium resulted in a desired overall effect that
differed from the effects of each substance in isolation. With the passage of time, the
quantity of tobacco consumption underwent a gradual reduction and eventually was
eliminated. Despite the fact that opium consumption did not appeal to a significant
portion of the Chinese population, the practice of opium smoking proliferated swiftly. It
is hypothesized that this phenomenon may have arisen due to the fact that the
consumption of opium through smoking necessitates lower dosages and produces
consistent and expeditious effects, in contrast to oral ingestion which demands larger
quantities and may exhibit a wide range of delayed onset effects.
The year 1806 marked the publication of a report by Frederich Sertürner, a
German pharmacist's assistant, detailing over 50 experiments that conclusively
demonstrated his successful isolation of the principal active component of opium. The
potency of the active agent was found to be tenfold higher than that of opium. Morphine
was christened by Sertürner in honor of Morpheus, the deity associated with dreams in
Greek mythology. The adoption of the recently developed agent was gradual, however,
by 1831 the ramifications of his chemical research and the medicinal significance of
morphine had become so compelling that he was bestowed with the French equivalent of
the Nobel Prize. Subsequent research on the enigmatic properties of opium has revealed
the existence of over 30 distinct alkaloids, among which the second most significant
compound was extracted in 1832 and christened codeine, derived from the Greek term for
"poppy head." In the field of medicine, the utilization of a pure chemical with a known
potency that has clinical utility is frequently leveraged. The significant surge in the
utilization of morphine can be attributed to two non-pharmacological advancements,
namely a technological and a political one. Dr. Alexander Wood's invention of the
hypodermic syringe in 1853 marked a significant milestone in technological
advancement. The aforementioned advancement facilitated the administration of
morphine via direct injection into the bloodstream or tissue, as opposed to the
comparatively protracted method of ingesting opium or morphine and awaiting
absorption via the gastrointestinal tract. An additional benefit associated with the
administration of morphine was believed to be present. Initially, there was a belief that
the administration of morphine via injection would not elicit a comparable level of drug
dependence as its oral consumption. Subsequent investigation revealed the
aforementioned assertion to be erroneous.
In the latter part of the 1800s, a significant chemical modification was performed
on the morphine compound, which proved to be of great significance. The process of
attaching two acetyl groups to morphine resulted in the formation of diacetylmorphine,
which was subsequently marketed under the brand name Heroin by Bayer Laboratories in
1898. This event occurred in 1874. The significance of the chemical alteration lies in the
fact that heroin possesses approximately three times the potency of morphine. The
pharmacological properties of heroin and morphine are indistinguishable, with the
exception of the presence of two acetyl groups in the heroin molecule, which enhance its
lipid solubility and consequently facilitate its faster penetration into the brain. Subsequent
to detachment, the supplementary groups are separated, resulting in the production of
morphine. Consequently, the impacts of morphine and heroin are almost
indistinguishable, with the exception that heroin is reputed to possess greater potency and
a more rapid onset of action. Heroin was initially introduced as a cough suppressant that
was non-addictive and intended to serve as a substitute for morphine and codeine. The
drug appeared to possess ideal characteristics, exhibiting heightened efficacy while
simultaneously exhibiting reduced toxicity. Despite its commercial introduction taking
place in 1898, heroin had already undergone extensive study, with numerous reports
detailing its pharmacological properties dating back to 1890.
During the latter half of the 19th century, the United States witnessed the
emergence of three distinct types of opioid addiction. The practice of orally consuming
opium and morphine gained significant popularity with the advent of patent medicines,
which emerged as a prevalent mode of self-medication. Following 1850, a substantial
influx of Chinese laborers was brought over to the West Coast, subsequently introducing
the practice of opium smoking to the United States. The administration of morphine via
injection represents the final and most perilous form of medical intervention. During the
early 1900s, it is likely that the proportion of individuals in the United States who
regularly consumed opioids was higher than any other period prior or subsequent.
According to various sources, including historical and contemporary authorities, it is
widely acknowledged that a minimum of 1 percent of the populace was afflicted with
opioid addiction, although precise statistical data is not readily accessible. Despite the
fact that approximately one-fourth of the opium imported at the beginning of the 20th
century was in the form of smoking opium, it did not attain widespread popularity in the
United States, as it was introduced by the Chinese.
One possible explanation for the limited duration of opium smoking sessions
could be attributed to the manual skill required for manipulating the opium pipe, which
may not be sustainable for prolonged and frequent dosing. As opium consumption
increases during a given period of use, the individual's manual dexterity may be impaired
as a result of the increasingly sedative effects induced by higher doses of the substance.
The primary factor that hindered the proliferation of opium smoking was the prevalence
of American racism. The origin of opium smoking can be traced back to the Chinese
community, who were subjected to disdain by a significant number of white Americans.
As a result, the prevailing societal norms deemed this practice as unacceptable and
stigmatized individuals who partook in it.
The data presented in this paper provides evidence to suggest that the medical use
of opioids, when initiated by a physician, was a primary contributor to addiction in the
United States during the period under investigation. According to a government report
from 1918, individuals of "good social standing" who were addicted to drugs were
primarily influenced by physicians. The widespread use of opioid medications by
physicians can be comprehended in view of the literature available at the time, including
a publication in 1889 entitled "Advantages of Substituting the Morphia Habit for the
Incurably Alcoholic." The author has claimed that their approach has successfully
restored tranquility and order to numerous homes that were previously troubled and
disordered. Additionally, they have prevented the head of households from engaging in
scandalous misconduct and neglecting their responsibilities, as well as avoiding the
dangers and consequences of delirium tremens. Most notably, the author asserts that their
intervention has prevented the individual from committing a heinous offense, which they
firmly believe would have occurred otherwise.
The enactment of the Harrison Act in 1914 resulted in a highly ambiguous status
of the addict. The legislation in question did not criminalize addiction nor did it explicitly
grant or prohibit physicians from routinely administering drugs to individuals struggling
with addiction. The only requirement that was unambiguously stated was that individuals
who are addicted to drugs must obtain their medication from physicians who are
registered under the aforementioned act. Additionally, it was mandated that the act of
obtaining drugs must be documented. Prior to 1914, certain drug users had acquired their
drug supplies through medical practitioners, however, this was not a prerequisite as drugs
were readily accessible for purchase through pharmacies and even via mail-order
establishments. In 1915, the U.S. Supreme Court rendered a decision that classified the
possession of smuggled opioids as a criminal offense. Consequently, individuals who
obtained the drug without a prescription from a licensed physician were deemed to have
committed a criminal act by virtue of this judicial ruling. Prior to 1919 and 1922 Supreme
Court rulings, individuals with addiction were able to procure their drug supply through a
medical prescription from a licensed physician.
As a result of these pressures, there was a decrease in the population of
individuals who consumed oral opioids, leaving behind a predominant group of
individuals who administered morphine or heroin intravenously. As of 1922, the sole
means of accessing opioids for a non-institutionalized individual with substance abuse
tendencies was through illicit channels. Due to its high potency, heroin emerged as the
preferred option for illicit drug dealers, owing to its ease of concealment. The expense
incurred through this particular channel was found to be 30-50 times higher than the cost
of the identical medication obtained from authorized sources, which were no longer
accessible to individuals grappling with opioid addiction. Due to the expenses incurred,
users sought to maximize their investment and thus, intravenous injection gained
popularity. Sustaining a consistent provision of the medication through this method
incurred significant costs. A subset of individuals engaged in illicit behavior,
predominantly theft and other forms of property-related offenses, as a means of funding
their substance dependency.
During the latter part of the 20th century, it was observed that approximately 50%
of the heroin supply in the United States was believed to have originated from Southwest
Asia, specifically from countries such as Afghanistan, Pakistan, and Iran. The Golden
Triangle region of Southeast Asia, encompassing Myanmar, Laos, and Thailand, was
responsible for approximately 15 to 20 percent of the overall production, while Mexico
emerged as the second largest contributor. Presently, there has been a significant shift in
the global supply of heroin, whereby over 90 percent of the substance is traced back to
Afghanistan. It is noteworthy that the primary source of heroin in Europe, Russia, the
Middle East, and Asia is Afghanistan, whereas the majority of heroin consumption in the
United States is attributed to poppies cultivated in Mexico. Colombia is also a source of
heroin production in the United States, albeit to a significantly lesser degree.
Hydrocodone and oxycodone are the most commonly prescribed opioids,
marketed under different brand names such as Vicodin, Lortab, OxyContin, and Percocet.
The administration of these substances is primarily oral, although in recreational
contexts, alternative routes of administration such as intranasal or intravenous injection
may be employed. According to data from 2018, a mere 1% of individuals aged 12 years
and above in the United States reported engaging in nonmedical utilization of
prescription pain relievers within the preceding month. In contemporary times, it is
plausible that you have been exposed to various media outlets or literary sources
asserting that the consumption of prescription analgesics has escalated to epidemic
proportions. In the absence of contextual information, it may pose a challenge to
ascertain the significance of the usage of these drugs in the preceding month. When
formulating this assessment, it is important to note that the incidence of non-medical
usage of prescription opioids has been consistently low and stable over the course of
recent years. In the year 2002, a reported 2 percent of the American population engaged
in nonmedical use within the past month, a statistic that exhibits a marginal increase
compared to present-day figures.
It is important to consider that the usage of the previous month may vary from
infrequent use to frequent use. An additional inquiry that warrants consideration is the
comparative analysis of rates of unlawful utilization of prescription opioids vis-à-vis
other illicit substances. According to data from 2018, 10.1 percent and 0.7 percent of
individuals residing in the United States reported using marijuana and cocaine within the
past month, respectively. The prevalence of nonmedical prescription opioid use is slightly
higher than that of cocaine use, but significantly lower than that of marijuana use.
B. Pharmacology of Opioids
Raw opium typically comprises approximately 10% morphine by mass and a
lesser quantity of codeine. Diacetylmorphine, commonly known as heroin, is produced by
the incorporation of two acetyl groups into the morphine molecule. The presence of
acetyl groups facilitates the permeation of heroin through the blood-brain barrier,
resulting in a slightly higher potency of heroin compared to morphine. Over the course of
several decades, medicinal chemists have exerted considerable effort in developing
compounds that exhibit potent analgesic properties while minimizing the potential for
dependence associated with opioids. Despite the inseparability of the two effects, the
study has yielded a diverse range of opioids that are marketed as analgesics.
The discovery of opioid receptors in the neuronal membrane prompted an inquiry
into the role of these receptors in brain synapses. It is unclear whether these receptors are
present solely for the purpose of extracting opiate compounds from the poppy plant.
Researchers worldwide conducted investigations to identify a substance within the brain
that could potentially function as the endogenous activator of the opioid receptors. In
1974, certain groups in England and Sweden achieved success by isolating a pair of
molecules, namely leu-enkephalin and met-enkephalin, from brain extracts. The
enkephalins exhibited morphine-like properties and demonstrated significantly greater
potency. Subsequently, a cluster of endogenous morphinelike substances, known as
endorphins, were identified in brain tissue, exhibiting robust opioid properties. Apart
from the two primary categories of endogenous opioids, dynorphins and other
compounds exhibit certain effects that are akin to those of morphine. The aforementioned
compounds, in addition to both naturally occurring and artificially produced opioid
medications, elicit effects on no fewer than three distinct subtypes of opioid receptors,
whose molecular architectures were first identified during the 1990s.
Apart from the existence of these endogenous opioids within the cerebral region,
substantial quantities of endorphins are discharged from the pituitary gland as a reaction
to stress. Enkephalins are secreted from the adrenal gland. The physiological roles of
these peptides, which are present in the bloodstream in the form of hormones, remain
unclear at present. It is plausible that these agents may elicit analgesic effects via spinal
cord modulation; however, their ability to exert direct effects on the brain is improbable
due to their limited ability to traverse the blood-brain barrier. There has been speculation
regarding the occurrence of a phenomenon known as the "runner's high" among long-
distance runners, which may be attributed to the release of endorphins. Regrettably, the
sole substantiation for this concept was the assessment of endorphin levels in the
bloodstream, which appeared to be heightened in certain runners, albeit not universally. It
is hypothesized that these endorphins originate from the pituitary gland and may not
possess the ability to induce euphoria. The impact of physical exercise on the levels of
aforementioned substances in the brain remains unclear.
C. Beneficial Uses
The primary therapeutic application of morphine and other opioids is the
mitigation of pain. Following the administration of a therapeutic dose of morphine,
certain patients have reported experiencing residual pain perception, albeit without the
negative affective component. Opioids appear to exert their impact, at least in part, by
reducing the patient's perception and reaction to the unpleasant stimulus. The principal
effect of morphine is the mitigation of the affective component of pain, namely the
experience of suffering, and to a certain degree the perception of the nociceptive
stimulus. The analgesic properties of opioids are relatively targeted towards pain
management. The analgesic doses of these agents exhibit a lower impact on mental and
motor ability in comparison to other analgesic and depressant drugs that have equivalent
doses. Whilst these medications possess the attribute of mitigating pain without eliciting
somnolence, it is not infrequent to experience lethargy following an appropriate
therapeutic dosage. The individual exhibits prompt responsiveness upon being roused
from slumber, and experiences a high frequency of dream occurrences throughout the
duration of the sleep cycle.
Opioid analgesics have been observed to reduce the frequency of peristaltic
contractions, a form of muscular contraction that facilitates the movement of ingested
food through the gastrointestinal tract. The absorption of a significant amount of water
from the intestinal material, coupled with the reduction in peristaltic contractions,
frequently leads to constipation in individuals who are administered pain relief
medication. This particular adverse reaction has been instrumental in preserving the lives
of numerous individuals suffering from dysentery. Contemporary synthetic opioids have
been commercialized for this intention; however, traditional paregoric, which is an
opium-based solution, is still accessible for the alleviation of diarrhea symptoms.
The opioids exhibit the property of reducing the activity in the cough control
center located in the medulla, as described by the advertisers. While coughing can serve
as an effective means of expelling undesirable substances from the respiratory system,
unproductive coughing can occasionally present as a concern. Codeine has been
extensively utilized for its antitussive effects since its initial isolation from opium and is
presently obtainable in various prescription cough medications. Over-the-counter cough
remedies are comprised of dextromethorphan, an opioid analogue that exhibits a degree
of selectivity in its antitussive properties. At elevated dosages, dextromethorphan elicits
psychedelic outcomes via an alternative mechanism, which involves the inhibition of the
N-methyl-D-aspartate (NMDA) glutamate receptor.
D. Causes for Concern
Tolerance typically arises in response to the effects of opioids, albeit at varying
rates depending on the specific effects in question. In cases where the drug is utilized as a
chronic pain management strategy, it is likely that a dosage escalation will be required to
sustain a consistent analgesic outcome. The aforementioned assertion holds valid for the
elation pursued by individuals engaging in recreational drug use. Frequent utilization
leads to a reduction in efficacy, which can be remedied by either augmenting the dosage
or refraining from usage for a few days. Cross-tolerance is present across all opioid
substances. The phenomenon of developing tolerance to the effects of opioids is
commonly regarded as an adverse outcome of drug consumption. Tolerance is included
as a diagnostic criterion in the DSM-5 for assessing the presence of a substance use
disorder. Nonetheless, the development of tolerance to opioids may present a potential
advantage. Individuals who frequently use opioids and have developed a tolerance are
comparatively less susceptible to opioid-induced respiratory depression, even at dosages
that could potentially pose a risk to those who use opioids infrequently. In other words,
individuals who have developed tolerance to opioids exhibit a lower susceptibility to
experiencing a lethal overdose in comparison to those who lack such tolerance.
The establishment of physical dependence occurs simultaneously with the
development of tolerance. Individuals who have engaged in chronic and high-dose drug
use may experience the onset of withdrawal symptoms as each dose gradually diminishes
in effect. The confluence of symptoms such as nausea, vomiting, diarrhea, aches, pains,
and a general sense of discomfort can provide an accurate depiction of a moderate
instance of opioid withdrawal. While such an occurrence is seldom fatal, it is certainly
unpleasant. In cases where an individual has ingested a substantial quantity of the drug,
the resulting symptoms may exceed the severity of those associated with a 24-hour flu
and persist for a duration of time that is at least twice as long. It should be noted that
methadone, a synthetic opioid with a prolonged duration of action, elicits withdrawal
symptoms that are typically less intense and delayed in onset compared to those of
heroin, yet may persist for a more protracted period. Interdependence is observed among
various types of opioids. Regardless of the individual responsible for inducing the
primary addiction, the manifestation of withdrawal symptoms can be averted through the
administration of an adequate dosage of any opioid agonist. The utilization of methadone
in the treatment of heroin addiction is founded on the principle of substitution therapy,
whereby the administration of legal methadone serves to mitigate the onset of withdrawal
symptoms for a duration of up to 24 hours.
In recent times, the mass media has been saturated with reports cautioning the
general populace about the uncontrolled hazards associated with opioid usage. The
predominant focus of media attention has been on the topics of addiction and fatal
overdose. A distinct consequence of opioids is the depression of respiratory centers
located in the brain, leading to a reduction in the rate and depth of respiration.
Respiratory depression is a prominent adverse effect of opioids and is considered to be
one of the most perilous, owing to the potential fatality that may ensue from an overdose
of these substances. The underlying mechanism for this phenomenon is that the
respiratory centers exhibit reduced sensitivity towards the levels of carbon dioxide
present in the bloodstream. The aforementioned effect is the reason why opioids remain
prominently featured among the drugs implicated in cases of fatal drug overdose. The
majority of opioid overdose incidents entail the involvement of multiple substances. A
considerable proportion of individuals who succumb to heroin overdose exhibit
heightened levels of blood alcohol and could be more accurately characterized as having
passed away due to a blend of heroin (or a different opioid) and alcohol. This
circumstance poses a challenge in assigning the cause of death to a specific opioid. The
diagnosis of opioid overdose can be established through the identification of the opioid
triad, which includes symptoms such as coma, depressed respiration, and pinpoint pupils.
The administration of naloxone (Narcan) is a crucial aspect of emergency medical
treatment as it effectively counteracts the opioid effects within a brief timeframe.
The majority of individuals possess firmly entrenched convictions regarding
heroin, which are primarily informed by various media outlets such as television,
magazines, films, and interpersonal dialogues. Numerous individuals, including a
significant number of professionals, harbor significant misunderstandings regarding the
nonmedical utilization and abuse of opioids. One of the prevalent fallacies pertains to the
notion that the administration of heroin or morphine elicits an unparalleled sensation of
intense pleasure in all individuals. Frequently, it is characterized as akin to a
comprehensive bodily climax that endures for a duration of 5 or more minutes. Certain
users have reported attempting to replicate the intense euphoric sensation experienced
during their initial injection with subsequent injections, yet consistently observe a
diminished effect. Numerous studies, along with clinical and anecdotal evidence, indicate
that a significant number of individuals encounter feelings of nausea and physical
discomfort subsequent to the administration of morphine or heroin, particularly in cases
where substantial dosages are administered. Nevertheless, certain users continue to
persist despite this phenomenon, whereby the level of discomfort diminishes at a faster
rate than the euphoric effects, indicating a greater degree of tolerance. Under such
circumstances, the administration of opioids promptly leads to predominantly pleasurable
outcomes. In order to sustain the desirable sensations, it is necessary to incrementally
augment the dosage when the substance is consumed habitually.
One additional misapprehension pertains to the emergence of withdrawal
symptoms. The depiction of a heroin user experiencing withdrawal symptoms in the
absence of medication is commonly characterized as a state of intense agony and genuine
distress. The answer is contingent upon various factors. Withdrawal from a significant
habit can prove to be exceedingly challenging in the absence of pharmacological
intervention. The dynamic nature of the illicit opioid use landscape renders it difficult to
definitively characterize the contemporary user; however, a significant proportion of
users tend to consume a modest daily dosage of the substance. Several users experience
withdrawal symptoms that bear resemblance to a mild form of intestinal flu, including
cramps, diarrhea, headache, and lethargy.
One of the most prevalent misconceptions surrounding heroin pertains to the
notion that a single injection is sufficient to cause addiction for the remainder of an
individual's life. None of the opioids, or any other pharmacological substance, can be
classified under the aforementioned idealized category. The process of developing
dependence is a gradual one, often spanning several weeks, and requires consistent effort
and dedication from the novice individual. The frequency of drug consumption appears to
play a more significant role in the development of physical dependence than the quantity
of the drug administered. The possibility of developing physical dependence can manifest
within a weekend, however, it is commonly observed to necessitate a more prolonged
duration, involving the administration of three to four injections on a daily basis.
