Codeine is an opioid found naturally in Papaver somniferum, the opium poppy.
Its name comes from "kodeia," a Greek word for "poppy head."
It's somewhat misleading to call it an opioid, however.
The drug almost exclusively functions as a prodrug for morphine and other active substances.
Codeine is typically a controlled substance, but it may be available over-the-counter in
certain preparations.
Often it's combined with paracetamol or NSAIDs like ibuprofen.
These combinations can provide additional pain relief, but they come with additional
safety risks.
Among the positive effects are analgesia, sedation, euphoria, anxiolysis, physical euphoria,
and dreaminess.
The negatives include respiratory depression, drowsiness, depression, nausea, vomiting,
constipation, bradycardia, and dysphoria.
In medical settings, codeine is mainly an analgesic, antitussive, and anti-diarrheal.
Rarely does it actually make sense as a medication.
For cough, codeine does nothing in a large portion of cases, despite its alleged antitussive
properties being utilized for many decades.
Neither codeine nor other opioids are recommended for cough associated with the common cold.
And multiple controlled trials have found it's no better than placebo.
The support for its antitussive properties primarily comes from animal models and from
experiments with induced and chronic cough, NOT from cough associated with upper respiratory
infection.
There's reason to believe different kinds of cough are controlled through different
pathways in the body.
Codeine may be practically ineffective at the pathway relevant to most acute coughs.
Even some research with COPD shows codeine may have little to no efficacy in other kinds
of cough.
Therefore, taking it as a cough medicine, usually doesn't make sense.
In the case of children suffering from cough, an FDA advisory panel overwhelmingly recommended
it be contraindicated for everyone under 18 years old.
When it comes to pain, codeine does have some efficacy, but it's not what you'd expect.
Primarily due to non-efficacy factors like widespread accessibility and its unjustifiably
good reputation, codeine is a popular analgesic for minor and moderate pain.
It can dull the sensation of pain to the extent that it becomes bearable or almost unnoticeable.
As I noted in the beginning, codeine is essentially nothing more than a prodrug.
Though there's some debate about this, it's most important metabolite appears to be morphine.
As such, why give someone codeine when you can just give them morphine?
Well, there really isn't a good answer to that question.
Codeine rarely makes sense from an efficacy perspective.
The evidence strongly suggests patients are better off receiving NSAIDs, paracetamol,
and other opioids like oxycodone or morphine.
NSAIDs and paracetamol can be fairly effective on their own and when used in combination.
Adding codeine to the mix can somewhat improve their efficacy, but it can often be avoided.
And since codeine is a hit-and-miss way of giving someone an opioid, it's best to avoid
whenever possible.
An interesting application of codeine is in narcolepsy, where it may reduce daytime sleepiness.
This area hasn't been heavily explored, yet some evidence suggests it could be useful.
In medical settings, constipation is one of the most problematic negatives and it necessitate
the use of laxatives.
Other negatives include drowsiness, dizziness, cognitive impairment, depression, nausea,
and vomiting.
Changes in respiration can sometimes be observed at doses near the medical range, but they
don't typically become a problem until someone overdoses or if they have a co-occurring respiratory
issue.
The drug is also used, typically at higher doses, for recreational purposes.
Like other opioids, it offers relaxation, reduced care for physical or emotional problems,
euphoria, and a dreamy state that facilitates easily shifting into semi-awake dreams.
The contentment, relaxation, and general sense of well-being offered by codeine has the potential
to be quite addictive depending on the user.
Physical euphoria is a common effect at higher doses, presenting as waves of pleasurable,
warm sensations around the body.
Your limbs may also feel heavy and a sense of floatiness can be present when moving around.
The drug doesn't cause overwhelming sedation at common doses.
As the dose increases, people can become significantly impaired and drowsy.
Higher amounts are also connected with a somewhat dissociative state, where people feel disconnected
from their surroundings, their problems, and even their body.
People may experience memories and see dream-like scenarios in this state.
Users report being still and laying down are ideal for experiencing the effects.
The negatives include an unpleasant taste in the mouth, sweating, severe nausea, stomach
cramps, vomiting, respiratory depression, facial flushing and swelling, and itchiness
around the body.
Itchiness is considered an especially notable and annoying effect at higher doses.
Codeine may be combined with antihistamines like promethazine and diphenhydramine.
This can increase the depressant activity, which could raise the chance of unconsciousness,
but it may also reduce itching.
It's very important to remember codeine products often have other drugs in them.
Paracetamol is one example and is also one of the most important to avoid using high
doses of.
Though you also shouldn't take high doses of ibuprofen or aspirin.
Unless you're using them for medical reasons, combination products should be avoided.
It hasn't been fully investigated, but there seems to be a ceiling dose with codeine.
For the average user, a single-dose ceiling is somewhere around 300 to 500 mg.
The analgesic and recreational properties don't significantly increase beyond this point,
yet the negative effects might.
This could stem from a high occupancy of mu-opioid receptors by codeine, which limits the ability
of morphine and other metabolites to provide the desired effects.
Codeine is a naturally occurring methylated morphine derivative, specifically 3-methylmorphine.
It's an alkaloid in the morphinan class and is found in opium at a concentration of .2
to .8%.
Though it can be collected from opium, it is now synthesized from morphine.
On its own, codeine is basically inactive.
It's best viewed as a prodrug, with metabolism to morphine and codeine-6-glucuronide controlling
its efficacy.
Much of its activity is ultimately tied to the mu-opioid site, a G protein-coupled receptor
located along ascending and descending pain transmission pathways.
These receptors are found in the PAG, locus ceruleus, rostral ventromedial medulla, and
substantia gelatinosa, among other areas, like the cerebral cortex, thalamus, and limbic
system.
Mu-opioid agonism provides analgesia, euphoria, respiratory depression, and sedation.
Agonsim in the midbrain is thought to be the core mechanism behind analgesia and the activity
of drugs like morphine ultimately leads to the activation of descending inhibitory neurons.
Opioids can also directly inhibit pain transmission from the periphery.
Codeine's Tmax is 60 minutes and it's half-life is 2 to 3 hours.
A specific enzyme, CYP2D6, is very important in the pharmacology of codeine.
It controls the metabolism of codeine to morphine.
This process, though perhaps not accounting for all of codeine's activity, is important.
CYP2D6 is highly polymorphic.
Some people are poor metabolizers, so they get little to no morphine, while others are
ultrarapid metabolizers, capable of more easily generating dangerous levels of morphine.
Only a small portion, 5 to 10%, actually becomes morphine.
The primary metabolite is codeine-6-glucuronide, which does seem to have its own analgesic
effects.
Yet codeine's minor metabolite, morphine, plays a crucial role in the overall activity
of the drug.
If you're a poor metabolizer, like 7 to 10% of Caucasians are, codeine may do almost nothing
for you.
And if you're an ultrarapid metabolizer, like 20 to 30% of those with African or Middle
Eastern heritage, you could be at a greater risk of severe negative effects.
If you have a normal CYP2D6 genotype, your phenotype can also change if you're taking
other drugs.
People on antidepressants like fluoxetine and paroxetine can become worse metabolizers
of codeine, reducing its efficacy.
Some drugs, like rifampicin and dexamethasone, will do the opposite, thereby leading to more
morphine per dose.
Outside of directly using codeine, you can be exposed to the drug in a couple ways.
Poppy seeds do contain some morphine and codeine.
So a few poppy seed bagels can lead to detectable opioid levels in your body, though not enough
to provide effects.
The other source is your own body.
There are signs pointing to a mammalian biosynthetic pathway for codeine and morphine that's similar
to the one in P. somniferum.
It appears the biosynthesis could begin with L-tyrosine and codeine ends up functioning
as a precursor to morphine.
Studies have found codeine and morphine in the brains of rats and nonhuman primates.
Whether or not endogenous codeine and morphine do anything in humans isn't known, but morphine
could be another endogenous opioid.
Codeine is taken orally at 15 to 60 mg every 4 to 6 hours in medical settings.
Nonmedically, a light dose is 50 to 100 mg, a common dose is 100 to 150 mg, and a strong
dose is 150 to 200 mg.
Due to genetic factors, you should evaluate your response to a light dose before attempting
larger amounts and it's wise to avoid using more than a common dose.
Codeine technically has a very long history because of its presence in opium.
P. somniferum may have been cultivated for opium around 3000 BC by the Sumerians living
in today's Iraq.
The referred to opium as "gil," meaning joy.
And the poppy was called the "plant of joy."
The Ebers Papyrus from 1500 BC Egypt included a "remedy to prevent [the] excessive crying
of children."
This remedy involved a poppy-sourced substance and would be given for 4 days, after which
the crying would "stop at once."
Remedies of this kind were considered dangerous due to the unreliable potency of opium preparations.
Arab traders likely brought the drug to India and China in the 700s.
And the Arabian system of medicine, including opium use, certainly spread to India by the
900s.
From the 900s to 1200s, opium made its way from Asia Minor to all parts of Europe.
Within a few centuries, manuscripts began to discuss the nonmedical use of opium and
physical dependence in Turkey, Egypt, Germany, and England.
After another few centuries, codeine was finally isolated from opium in 1832 by a French chemist.
Throughout its history codeine has been a popular antitussive and it's also been treated
as significantly safer than morphine.
Neither of these reputations makes a lot of sense, so the history of codeine is that of
a drug being used without much justification.
Around 1900, codeine was thought to have a very low chance of fatal overdose.
A report in JAMA said there were no fatalities in the literature.
Though some reports of fatalities associated with the drug began to show up in the coming
decades.
This led a publication in 1937 to estimate codeine's lethal dose as 300 to 500 mg, though
that paper eluded to people surviving larger amounts.
A death was reported in 1932 and another was reported in 1943, involving a patient with
acute asthma.
There were also claims suggesting the drug was nonaddictive and had no real potential
for physical dependence.
Unsurprisingly, a test in 1934 confirmed codeine had morphine-like dependence potential.
From the 1960s onward, it's continued to be used as an analgesic and antitussive in the
West and around the world.
Its recreational use started to receive more attention in the 60s and 70s.
Publications like The Wall Street Journal described teenagers using codeine-containing
cough syrups.
A similar kind of use started in the 1990s, though this time it involved a combination
of codeine, promethazine, soda, and candy.
That combination, known as "purple drank" and "lean," spread outward from the Houston,
Texas region in the early 1990s.
Throughout its existence, purple drank has been associated with hip-hop and the African
American community, with musicians like Lil Wayne bringing the drug into the spotlight.
People seem to frequently underestimate the harm potential of codeine and codeine-centric
combinations.
At least two key figures in the Houston hip-hop community, Robert Davis Jr and Chad Butler,
died from causes associated, in part, with purple drank.
Reports from the early 2000s found up to 25% of at-risk youth in Houston had used codeine
cough syrups, with 10% reporting use in the past 30 days.
Other surveys near Houston and in other parts of the US suggest codeine and purple drank
are fairly common drugs among young people.
Interest in codeine has been driven by the media and by the music community.
Some high-profile codeine-related arrests also increased interest.
A former Green Bay Packer, Johnny Jolly, was arrested in 2008 for possessing 200 grams
of codeine.
Two years later, former Oakland Raiders Quarterback JaMarcus Russell was arrested for possession
of codeine.
And in 2011, ESPN did a special on purple drank and codeine, partly focusing on the
the drug's apparent popularity among athletes.
The use of codeine for nonmedical purposes exists well beyond the United States.
Reports from India, South Africa, Ireland, and other countries have indicated codeine-containing
products are at least a minor source of recreational drug use and addiction.
Since the 1990s there's been a pushback against codeine in the medical community.
For example, the American Academy of Pediatrics said in 1997 that there's no good evidence
supporting codeine as an antitussive in children.
That didn't actually prevent it from being used as such, unfortunately.
Many papers have called for codeine to no longer be treated as a first-line analgesic,
to rarely be used in children, and to not be recommended as an antitussive.
But changing prescribing practices isn't easy.
There has been some traction at least when it comes to minimizing its use in young children.
Due to a lack of clear efficacy and the existence of accidental deaths, the World Health Organization,
the FDA, The European Medicines Agency, and Health Canada have all taken a stricter stance
towards codeine.
Some hospitals have largely moved away from codeine products, particularly in children,
instead choosing to administer NSAIDs, paracetamol, and alternative opioids.
Despite all this, codeine prescribing to children barely changed in the US from 2001 to 2010.
And in 2011, the FDA reported 1.7 million children ha d a codeine prescription filled
at a pharmacy.
Some of the most frequent prescribing comes from otorhinolaryngologists.
Yet, the American Academy of Otolaryngology-Head and Neck Surgery determined the negatives
of codeine outweighed its utility for adenotonsillectomy patients.
As you can see, the modern history of codeine often involves physicians prescribing codeine
even though the leaders in the field recommend against its use.
Other frequent prescribers are dentists, pediatricians, emergency department physicians, and general
physicians.
US poison control centers reported over 900 codeine-associated poisonings in children
12 and older in 2011.
An additional 1400 poisonings were reported with analgesics or cough and cold preparations
containing codeine.
Codeine was the most frequently prescribed opioid in children in 2013.
When physicians have been pushed to use morphine in place of codeine, they've sometimes been
hesitant.
A 2013 survey in the UK found doctors appeared to view the switch to morphine negatively,
yet not necessarily with good justification.
As we move forward, the push to largely abandon codeine will continue, but it's unlikely we
will see the end of codeine any time soon.
In the US, codeine is a Schedule 2 drug.
Certain polysubstance formulations are Schedule 3 or 5.
And there are some over-the-counter products containing codeine with other drugs.
A similar regulatory framework is seen around the world.
Australia, Canada, and the UK all treat codeine as a controlled drug.
Yet low-concentration preparations featuring multiple substances can be purchased over-the-counter
or without a physician's prescription.
There have been calls in those countries to change this framework, so we could see more
restrictive policies in the coming years.
Australia has already decided to eliminate non-prescription codeine beginning in 2018.
Codeine is relatively safe at common and medical doses.
An overdose can come with respiratory depression, coma, and vomit aspiration.
It may also be somewhat more likely to produce seizure activity, delirium, mania, and other
psychological symptoms than other opioids.
Though the seizure activity could just be coming from hypoxia.
Death, while rare, occurs via respiratory depression.
Ultrarapid metabolizers are at a much higher risk of fatal overdose and severe respiratory
depression, along with every other overdose symptom.
This issue has received a lot of attention in the context of breastfeeding women and
young children.
There have been instances of severe respiratory depression and death from medical doses in
children.
Outside of breastfeeding exposure, which has sometimes caused problems, issues seem to
be more common after adenoidectomy or adenotonsillectomy.
Kids undergoing those procedures may also have obstructive sleep apnea, raising the
chance of hypoxia when they're given codeine.
It's best to avoid codeine in those cases.
Physical dependence to codeine is entirely possible and its severity is determined by
dose and how long you've been using.
Withdrawal can range from moderate flu-like symptoms to a significantly more uncomfortable
state.
Insomnia, restlessness, runny nose, stomach pain, diarrhea, and chills are common.
Craving for the drug is also much higher.
Acute psychiatric problems beyond depression and low mood are rare, but they have occurred.
Some people appear susceptible, especially in overdose, to psychotic states, mania, and
other issues.
Morphine isn't the only opioid associated with these psychiatric changes, so there appears
to be some connection between the opioid system and problematic psychiatric conditions.
Chronic use might raise the risk of depression, sometimes mediated by androgen deficiency,
which occurs in a large portion of chronic users.
Some of the risky combinations include other depressants, like ethanol, other opioids,
dissociatives, benzodiazepines, pregabalin, and GHB.
If you have any questions, feel free to put them in the comments.
You can also email me.
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