Worldwide, opioids are the most common cause of drug related deaths.
The number of individuals abusing them has quadrupled in the last 20 years, with an uptick
in heroin use, an even bigger uptick in prescription opioid use, and a large group of folks abusing
both.
Because of their potential for addiction and overdose, opioids are regulated substances
in a lot of countries.
As a class, opioids share one thing in common—they bind to opioid receptors in the brain, spinal
cord, and gastrointestinal tract.
Some are endogenous, meaning that they are produced naturally by the body, like endorphin,
short for endogenous morphine.
But others are exogenous, meaning that they come from the environment, like heroin and
morphine because they come from the opium poppy—a flowering plant that oozes out a
milky white liquid, while others like fentanyl are synthesized in the laboratory.
To understand how opioids work, let's zoom into a region of the brain tissue that has
opioid receptors.
Normally, in the absence of endorphins, inhibitory neurons secrete a neurotransmitter that prevents
nearby neurons from releasing the neurotransmitter dopamine.
Now, let's say someone goes to play a rigorous game of badminton.
Exercise releases endorphins which activate the three major opioid receptors located on
the inhibitory neurons, called the mu, kappa, and delta receptors.
As endorphins binds to these receptors, they block the inhibitory neuron from releasing
neurotransmitters, allowing the dopamine secreting neurons to freely unload dopamine.
The dopamine then gets picked up by a third neuron in the same area.
When dopamine release takes place in pain processing regions of the brain like the thalamus,
brainstem, and spinal cord, the result is feeling less pain.
When dopamine release takes place in reward pathway regions like the ventral tegmental
area, nucleus accumbens, and prefrontal cortex, the result is a calming effect that feels
good.
So that's how it works normally.
But when a powerful exogenous opioid binds to the opioid receptors, the result is a massive
flood of dopamine.
This helps with pain control, but it can also cause an incredible state of euphoria within
the regions of the brain involved in the reward pathway, which is an emotional "high".
Now remember, the purpose of the reward pathway is to train the brain to repeat activities
that cause dopamine-mediated pleasure, so when opioids stimulate this reward pathway,
the brain learns to do that behavior again and again.
With exogenous opioids there are multiple routes to get the drug to the brain.
One way is by ingesting it, but that route is the slowest.
A faster route would be inhalation, because the drug is rapidly absorbed through the lungs.
The fastest route, though, is direct injection of the substance into the blood.
Typically, the faster the exogenous opioid reaches the brain the stronger the relationship
between the behavior and the reward.
Now over time, people that are consistently using a drug, even when taking them as exactly
as prescribed, can develop tolerance which means that with repeated use, they have a
reduced response, and therefore an increased dose is needed to achieve the original response.
At a cellular level, there are two theories that explain why this might happen.
One theory is that opioid receptors might become less sensitive to a drug, and the other
theory is that the neurons may remove opioid receptors from the cell wall in a process
called down-regulation, leaving less receptors available for binding.
In either scenario, tolerance leads to the need for higher and higher doses of a drug,
and often times that tolerance remains for a long time even after tapering from the drug.
Alright, so now let's say that you're at rest, there aren't any drugs or anything
stimulating your reward pathway.
In this situation, your brain keeps your heart rate, blood pressure, and wakefulness in a
normal state, called homeostasis.
Now, let's say that your secret crush sends you a text.
All of a sudden you may feel sweaty and flushed, your heart rate may jump a bit.
You're now above your normal level of homeostasis, because something has changed, right?
But it doesn't stay that way for long, and after the text message, your brain brings
things back down to this baseline.
With repeated drug use, a few things start to happen.
Let's say you take the drug at a specific time and setting, like 3pm in the bedroom,
and, being a depressant, it makes everything go lower, heart rate, blood pressure, and
wakefulness.
Your brain being the smart brain that it is, will pick up on the pattern.
Now, next time, at 3pm in the bedroom, the brain preemptively increases each one, since
it knows that when you take the drug, everything's going to decrease again.
Now, let's say 3pm in the bedroom rolls around, but there's no drug...In that situation,
the brain still increases everything..but the changes aren't countered with the effects
of the drug, and so the person can feel awful, and these are called withdrawal symptoms.
These symptoms can persist to the point where a person may need drugs just to feel normal,
and if that's the case, they are considered to be dependent on that drug.
Now, on the flip side, let's say that you use the drug in an unfamiliar setting, like
at 11pm at a party.
Well in that situation, your body's not ready for the drug and there's no physiologic
"counterbalance" to help offset the effect of the drug.
When that's the case, it can lead to overdose, even on a dose that the person's been normally
taking, and that's often times what happens.
The symptoms of opioid withdrawal include anxiety, shivering, tremors, yawning, body
aches, vomiting, diarrhea, abdominal cramps, runny nose, sneezing, sweating, and an increased
heart rate and blood pressure.
These symptoms can feel really awful, and often prompts people to use opioids again;
a process called negative reinforcement, since you're removing the drug, which causes withdrawal
symptoms which reinforces more drug use to avoid those symptoms.
There is also positive reinforcement from the dopamine-induced euphoria, again leading
to more drug use.
Together this positive and negative reinforcement leads to opioid addiction also known as opioid
use disorder.
The DSM-5 or Diagnostic and Statistical Manual, the 5th edition, defines opioid use disorder
as causing at least two of the following behavior patterns within a year: 1.
Using more opioids or using them for longer than intended.
2.
Being unable to cut down on the use of opioids.
3.
Having opioid use take up a significant amount of time 4.
Having cravings to use opioids.
5.
Having opioid use affect responsibilities at work, school, or home.
6.
Using opioids even if they cause recurrent interpersonal problems 7.
Giving up important activities in order to use opioids.
8.
Using opioids in physically dangerous situations.
9.
Using opioids even if its worsening a physical or psychological problem 10.
Becoming tolerant to the opioids.
And finally 11.
Feeling withdrawal symptoms from opioids.
Having 2 or 3 of these symptoms is considered mild, having 4 or 5 is considered moderate,
and having 6 or more is considered severe.
In addition to ruining a person's life, opioid addiction can also end it in an overdose.
Most often, an opioid overdose causes severe cardiac and respiratory depression, to the
point where a person may have pinpoint pupils and simply stop breathing.
In that situation, the most important thing is to performing rescue breathing, giving
supplemental oxygen, and administering naloxone.
Naloxone is an opioid antagonist that powerfully binds to opioid receptors, and rather than
having a direct effect, it blocks other opioids from binding and activating the receptor.
This works because at any given moment, opioids are binding and unbinding to receptors which
means once an opioid releases its hold on a receptor, the naloxone can simply sneak
in and bind more strongly.
When naloxone given intravenously it can reverse the effects of opioids within minutes, potentially
saving a person's life.
Generally speaking, high doses of strong opioids carry the greatest risk of addiction and death,
and when paired with other substances that can cause respiratory depression, like benzodiazepines,
they're more likely to cause overdose because they can act synergistically to cause respiratory
depression.
It's clear that opioids have strong addictive potential, so their use should be limited
and well defined.
They have a role in controlling acute pain, for example, but the goal should be to use
short-acting opioids at the lowest effective dose for just a few days, and slowly increase
their dose only as needed.
When opioids are used for chronic pain, they should be weaned off as soon as possible,
ideally at a wean rate of 10% of the dose per week.
In general though, chronic pain should be treated with non-opioid approaches.
These include exercise and biofeedback as well as other types of medications such as
acetaminophen and NSAIDs like ibuprofen.
There are also disease-specific treatments, like for migraines use triptans, or for neuropathic
pain use gabapentin, or for joint pain topical pain treatments like capsaicin.
For people with opioid dependence, the most effective treatment is a combination of therapy
with medications.
Specific therapies that work include motivational interviewing, which can be used to understand
why an individual wants to stop using opioids and identify specific barriers to treatment.
Also cognitive-behavioral therapy can help an individual learn about withdrawal, discuss
the thoughts, feelings, and behaviors that lead to opioid usage, and create a plan to
navigate triggers for usage.
Another form of therapy are peer-support programs which use group discussions to help individuals
commit to ending the use of opioids and by holding one another accountable.
In addition, the evidence strongly supports the use of medications, which reliably decrease
cravings and reduce withdrawal symptoms.
Methadone is a full opioid agonist with a long half-life that slowly builds up in the
tissues over time, allowing it to reach a steady-state level within a week.
Steady-state refers to the situation where the overall intake of the drug is more or
less in balance with its elimination, so that the body is exposed to a stable level.
In contrast, buprenorphine is a partial agonist that is sometimes given in combination with
naloxone, forming an agonist/antagonist combination.
Buprenorphine has a ceiling effect, meaning that above a certain dose it does not have
any more of an effect, which reduces the chance of an overdose.
These medications can competitively bind to the opioid receptor without producing the
same euphoria as the opioids they take the place of.
Since they have opioid effects, though, they can cause side effects like constipation,
insomnia, weight gain, hormonal changes, and cardiac arrhythmias.
The good news is that over time, an individual can safely taper their use of opioid treatments
altogether, and this approach is more likely to succeed than simply stopping opioids without
these treatments.
Another medication called naltrexone, can be used for people who are already abstaining
from active opioid use.
Naltrexone is a mu-opioid receptor antagonist that blocks the effects of opioids and helps
maintain abstinence.
Finally, all of these approaches work best when an individual has a strong network of
family and friends offering support.
Opioid use still carries heavy stigma because usage is still tied to a notion of individual
choice and moral failure, even though we now know that opioid use is a consequence of biological,
psychological, and social factors—all of which need to be addressed to maximize the
chances of recovery.
Alright, as a quick recap, opioids stop inhibitory neurons from releasing inhibitory neurotransmitters,
which allows dopamine to flood the ventral tegmental area, nucleus accumbens, and prefrontal
cortex, and causing euphoria.
Long-term use can cause tolerance which is the need for increasing doses to achieve the
same effect, as well as dependence which is the reliance on the opioid to function normally.
The most effective treatment is a combination of therapy and medications, with a lot of
love and support from family and friends.
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