or centuries upon centuries, people
have used opium or its components—morphine and other similar narcotics—to get “high”
or feel mellow.1,2 Opium is tied to ancient civilizations in Egypt,
Persia, and China, and such figures as Alexander the Great, Hippocrates, John
Keats, and John Jacob Astor. Paintings portray old Chinese men relaxing and
apparently deep in thought in rocking chairs, smoking pipes filled with opium, dried
latex that comes from poppies grown in many regions in Asia. In countries such
as Afghanistan3 and Myanmar, opium production and exportation is the
basis of their economies.
While raw opium products historically have been highly prized
mood-altering drugs, one of their main active components, morphine, converts
very easily, with a simple chemical step, to heroin. Users appreciate that heroin
travels to the brain much more quickly and effectively than morphine. Although
once in the brain heroin breaks down to morphine, heroin is the drug of choice
because its high is much quicker and more intense.
In the last 200 years, opium and its derivative, heroin, have also enjoyed enormous popularity for its potent pain-relieving (analgesic)
effects. The unfortunate, often unrecognized, downside of opium and heroin is
that both drugs are powerfully addictive, partially because they are snorted,
smoked, or injected, which produce very intense and immediate effects. Of
course, our concern today is not only for opium and its derivatives but also
for the myriad of structurally related narcotic analgesics that have been
developed in laboratories. Few would argue that opiate abuse is now a national
How Narcotics Work
All derivatives of the opium poppy
are classified as narcotics and share common properties in the brain. All
narcotics enter through the central nervous system (brain and spinal cord) to
exert their effects. In the brain they bind to specific opioid “receptors”
(so-called G-protein coupled receptors) on brain cells that use the
electrochemical messenger GABA (gamma-aminobutyric acid) to communicate with
There are at least three major
subtypes of opioid receptors: mu,
delta, and kappa. Each of these, particularly the mu receptor, have multiple
subtypes (some estimates put the total number of opioid receptors at 25 to
30). Furthermore, while there is considerable overlap of receptor networks in
the brain, each receptor is localized in a distinct brain region and has its
own communication pathway. Why this diversity and extensive network in the
brain? This is not totally known, but probably relates to the fact that
“endogenous” opioids are produced by cells in the brain (as opposed to
exogenous narcotic drug opioids) that regulate pleasure, pain, appetite, sexual
behavior, hormonal balance, gastrointestinal activity, respiration, and other
bodily functions, via effects on discrete brain areas. So, while endogenous
opioids play a fundamental role in many bodily functions, narcotic drugs
similarly interfere with these same systems.
Pain relief produced by opioids is
facilitated primarily by mu-opioid receptors and, to a lesser extent, by delta
receptors. While endogenous opioids bind to these receptors to alleviate pain,
such as that arising from stress, it is primarily narcotic drugs that bind to
these receptors to relieve pain. All narcotic analgesics, arising internally or
from narcotic drugs, have a high affinity for the mu-opioid receptor: the
higher the affinity, the greater the response.
Narcotic analgesics work at the
spinal cord level to overexcite nerve fibers so that they are poor conveyers of
pain signals to the brain. These drugs also exert powerful effects in the
brainstem to both transmit signals to the spinal cord to dull the transmission
of pain and to lessen the conscious perception of pain.
Unfortunately, the very property of
certain narcotics that makes them excellent painkillers also makes them the
most rewarding and addictive drugs known to humans. Indeed, all effective
opioid analgesics produce euphoria and this effect is mediated almost
exclusively by mu-opioid receptors, just like pain. Thus, the correlation
between the potency of analgesia and euphoria is nearly perfect. This explains
why it has been literally impossible to develop a narcotic drug that is useful
for pain but devoid of addictive properties—despite efforts over the last
The ways in which opioids produce
rewarding effects is complicated, but it appears that the neurotransmitter
dopamine is intrinsically involved in the rewarding properties of all drugs,
especially opioids. Moreover, it has been possible to trace the reward pathway
in some detail. The pathway involves perhaps a dozen or so different brain
areas, several different neurotransmitters, and some stress-related factors.
It is important to note that
euphoria, or rewarding pleasurable effects, are complex emotions, undoubtedly
mediated by many regions in the brain. What we are trying to do is determine
the molecular basis of a very elusive target: a thought or a feeling.
Neuroscience has not yet reached the point where emotions can be reduced to
While it is clear that many people
who use opioids for pain management or to feel better handle their consumption
well, others develop addictive patterns of use characterized by rapid
tolerance, physical dependence, and, most importantly, craving. What happens in
the brain to produce these effects? The brain adapts (develops tolerance) to
the presence of high concentrations of drugs. The entire purpose of tolerance
is to restore homeostasis, even in the presence of high levels of an
environmental toxin, such as a drug. The downside, of course, is that more drug
is required to produce the same effect, thus initiating further neuroadaptive
changes. The mechanisms underlying tolerance are fairly well understood: It
takes more drug to elicit a response from receptors, but the end result is that
the brain is under constant assault and keeps adapting in ultimately
non-productive ways to keep up with the insult produced by ever-increasing drug
What happens, then, when the brain’s
neuroadaptations are confronted by abrupt cessation of drug use? A withdrawal
response ensues, a hyperactive reaction that is generally the opposite of the
effects produced by heavy use of the narcotic: Instead of drug-related
constipation and elation, diarrhea and depression occur. While it was once
thought that the mechanisms underlying withdrawal were confined to
hyper-excitability after the neuroadaptations were disrupted, it now appears that other brain areas that were
recruited during the development of dependence are affected as well, and
responses by these areas may be just as—or even more--important than the direct
result of the neuroadaptive responses. One thing we know for sure is that the
withdrawal response is profound and often contributes to relapse.
While obtaining relief from
withdrawal probably plays an important role in addictive processes, physical
dependence and drug withdrawal occur with many drugs, yet most people do not
develop the craving that is associated with addiction. Craving distinguishes
physical dependence from addiction. So while clearly craving must be present
for a diagnosis of substance-use disorder (SUD), some other mechanism beyond
physical dependence also must be involved in craving. The nature of these other mechanisms is only
now being examined.
From a neurobiological perspective,
the answer to why some withdrawals are worse than others is largely unknown.
But we do know that the perception of the depth of withdrawal symptoms and
their unpleasantness is unique to certain drugs. With opiates, the difficulty
of the withdrawal response is among the worst.
Government Steps In
In 1914, the Harrison Narcotics Tax Act made opium and opium
products illegal unless prescribed by a physician.6 Before that,
many artists and intelligentsia used freely available opium to enhance their
artistic experience, while others—such as Abraham Lincoln’s wife, Mary Todd
Lincoln—famously used it to escape depression and feel better about themselves.7
Additionally, many elixirs were sold over-the-counter or by “snake oil”
salesmen at carnivals and fairs, and their use was condoned. Instead of
eliminating narcotics abuse, though, the Harrison Act perpetuated an extensive
black market, an underground network that still exists.
Shortly before World War II, all the way through the Reagan
era, narcotics steadily gained momentum for pain relief, but abuse rates stayed
relatively low.9 When abuse occurred, heroin was mainly the drug of
choice, particularly among inner-city male minorities seeking to feel better
and escape their poverty and hopelessness. Despite drug wars and drug-related
murders, mainstream society mostly ignored the heroin problem because the
problem occurred in a marginalized segment of the population.
In the year 2000, a huge momentum shift came about when a nationally
recognized non-profit health standards-setting and accrediting body, the Joint Commission on the
Accreditation of Healthcare Organizations (JCAHO),10 released a
scathing report on the undertreatment of pain. It concluded that effective
narcotic analgesics were available but seldom used, and that doctors were
ignoring pain management because of an irrational fear of addiction. They
argued that narcotics should be more widely used, since an anecdotal report in
a prestigious medical journal found that few patients abused their narcotic
medications.11 As referenced in an Institute of Medicine Committee
report in 2011, the JCAHO report reasoned that pain should be the fifth vital
sign, meaning that doctors should routinely ask about pain as part of any
physical exam, not wait until the patient volunteers this information, and
treat it accordingly. This report made headlines nationwide; Time magazine featured it on its cover.
The report and subsequent campaign became successful to the
point that doctors began prescribing narcotics in record numbers, some probably
inappropriately.12 Inevitably, with that many new prescription drugs
now in medicine cabinets and on nightstands, quantities were diverted by people
who sought not pain relief but a high (or a profit on selling the drugs for
such purposes). Prescription narcotic abuse quickly reached epidemic levels,
fueled by drug companies that rushed to meet the new demand.
New products began arriving on a fairly regular basis in the
1990s, but the most impactful of these was a novel type of product: a sustained-release
drug, oxycodone, that would provide pain relief for eight to 12 hours.13
Oxycodone is an opioid agonist with very high affinity for the mu opioid, making
it an excellent pain reliever but also a powerful euphorogenic agent. The
drug—marketed as OxyContin—was attractive because it needed to be taken only
once or twice a day, instead of every two to four hours. The long-lasting
relief was particularly beneficial for older patients who suffered from memory
loss and for people with limited mobility.
The extended-release capsules work by containing copious
amounts of drug that a built-in delivery device would release slowly over time.
Given its slow-release properties, the Food and Drug Administration (FDA)
concluded that the delay in reinforcement would dissuade abuse because addicts
typically seek an immediate reward. Thus the FDA, now infamously, allowed the
sponsoring company to state in the package insert or label that abuse was
expected to be low.
This was an ill-informed blunder of epic proportions. What
the manufacturer claimed it did not recognize, nor apparently did the FDA, was
that addicts cleverly and quickly realized that they could defeat the slow-release
devise by crushing pills and making large amounts of oxycodone immediately
available in a form suitable for snorting or intravenous injection—an immediate
rush akin to that of intravenous heroin.
The ease with which addicts could breach the slow-delivery
device—with Internet “how-to” tips posted within days—makes it somewhat
difficult to believe that the manufacturer and the FDA were not quickly aware
of their collective blunder and did not take aggressive action to rectify a
very bad design. The pharmaceutical company’s lethargic response to the revised
FDA mandates may explain the $635 million in fines they received for marketing
strategies that failed to recognize or mention the potential for abuse.14
The quality of the rush or high that addicts seek,
particularly after the intravenous injection of narcotics, is characterized in
many ways—including, graphically, as a whole-body orgasm. This very powerful
sensation is a huge part of what keeps people dependent. Why these drugs are so
rewarding is elusive. What is probable is that some individuals are genetically
predisposed to have a much more pleasurable response than others. Still, the
precise nature of this predisposition is unknown. Several quotes from patients
in our clinical research program illustrate the powerful sensation these drugs elicit
and the constant yearning that ensues:15-17
“I found a bottle of 5mg hydrocodone tablets my dad had after knee surgery, and I took 1½ tablets. I was 18
old and had just started smoking pot and experimenting with drugs. I went to bed, and after about an hour I felt an intense warm, fuzzy, pulsating euphoria come over my entire body. It was pure bliss and felt extremely good. I immediately always sought out opiates before any other drugs after that.”
“The high or reaction to it was the first of its kind, tingly body and feeling of being in a cloud. It lasted longer than I expected. I never achieved the same feeling from them again however I continuously searched for it.”
The most logical question about the surge in the abuse of
prescription narcotics is why it took off in such dramatic fashion, given that
narcotic analgesics and heroin had been available for years. For starters, there
was a seemingly endless supply of narcotic drugs, given their widespread
therapeutic use and the proliferation of “pill mills” (pain clinics that
carelessly dispensed huge amounts of narcotics for profit) and disreputable
“script” doctors who would write prescriptions, whether they were needed or not,
for quick cash.
Second, what makes prescription narcotics acceptable in many
users’ minds is that they produce a good, dependable, “safe” high. Unlike
heroin, the dose is known with certainty, the pill labeled clearly, and they are
legal (the latter often is not true, depending on extenuating factors). To
justify their use and assuage any guilt, patients also may tell themselves, “At
least it’s not heroin; I’m not a heroin addict.”
Regarding heroin, at least, they may have a point: Heroin bought
on the street is usually sold in nonsterile powder form and is rarely more than
a few percent pure, and some of the powder additives (talcum powder, quinine,
sugar, and sometimes other drugs, including powerful opiates such as fentanyl)
that make up the rest can be very dangerous, particularly in those in whom the
IV route is employed. Of course, the IV route also introduces the possibility of
blood-borne pathogen transmission and, given the uncertainty of the purity of
street-purchased heroin, there is a distinct possibility of overdose. Thus, for
most narcotic drug users who administer their drugs orally, the use of heroin,
at least in the beginning stages of abuse, was considered to be a degenerate,
However, the climate for heroin and prescription drug abuse
has changed. Most new users are not impoverished minorities from inner cities,
but middle-class men and women living in suburban and rural areas who find it easy
to justify their use. Thus, a perfect storm has developed: legal narcotics readily
available with little or no social stigma attached to their use.18
The Great Escape
Other than the obvious high, what
purpose do these drugs serve that accounts for their popularity? It turns out
that the initial potent high is not really what most users seek. Rather,
narcotics relieve anxiety or depression by providing a short-lived escape from
difficult circumstances. For those who become addicted, the initial high is
pure bliss and something they continue to seek, often for years. But pure bliss
becomes an elusive goal and does not repair emotional dysfunction and
unpleasant circumstances. More often than not, the user’s life gradually disintegrates
Several quotes from our clinical study participants are
excellent representations of the utility users often find with narcotics, beyond
their initial reaction:15,16
“I didn’t know who I was anymore, I didn’t like who I was and didn’t want to be in my own skin. I would use to feel good about myself, feel comfortable, confident, beautiful. Also, just life things in general, the unknown, life is scary and using was my escape to not deal with responsibilities.”
I used drugs to hide the pain of not loving/accepting myself in the beginning. Then my father passed away and I used drugs to mask the pain of grieving for many years. My life quickly spiraled out of control and I used drugs to hide how bad things really were.”
“It numbs pain, emotional and physical. It makes everything temporarily seem amazing, even when everything around you sucks.”
Beginning in 2010, prescription narcotic abuse began to level
off,19,20 and heroin began to resurface.21-23 The primary
difference with this current surge is that it migrated from primarily an inner-city
problem to the same type of users who became the norm for prescription narcotic
abuse.21-23 The reasons—as comments from our clinical research
program indicate21-23—are surprisingly straightforward. For example:
“It [heroin] was most cost effective in terms of the high established over the more expensive and less effective [O]xy[C]ontin, Percocet, [V]icod[i]n, etc.”
“You could get more for the price. Around my area ‘Southern Oregon’ one [OxyContin] 80 mg (bluish green pill) goes for 70-80 bucks nowadays; used to be 50 but they are hard to find now because of changes made by the pill companies to make the [Oxy] unshootable, unsnortable and unsmokable. Heroin is always coming up from Cali … and is in high demand around here.”
In addition, and perhaps as or more important, the social
stigma associated with heroin use began to dissipate:
“I knew I liked it [heroin] above all else, and once I had a drug dealer it became almost too easy to get, I had access to money because I am an upper middle class family and I also became close to my dealers, driving them around so I could get paid in drugs and just becoming super close, even if it meant sexually, so I could get the drug. The two dealers and the people around them that I developed that relationship with are also middle class white kids, not even kids we were all in the age range of 25-41. It just became easy, and we weren’t really looked at as being addicts because everyone thinks heroin addicts are all homeless, shady looking, dirty junkies.”
What’s next? Where do we go from here? It seems obvious that
while we could and should do all that we can to reduce the supplies of heroin
and its legal counterparts, we must also reduce the demand. The evidence shows,
as outlined in part above, that narcotics satisfy—in a very harmful way—a
variety of “needs” in individuals who use them. We need to find better ways to persuade
users that narcotics are not the answer. There have to be, and are, better ways
than entering the vicious cycle of abuse to meet those needs.
Until we make a serious effort as a society to implement
those alternatives, expect to read and hear more about the devastating impact,
including overdose deaths, of the continued use of legal and illegal narcotic
compounds. What factors, if any, will break our centuries-old love affair with
opium and other narcotics? The drug formulations may change over time, but the
appetite for narcotics has persisted for a very long time, with no obvious end
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