FDA warns about codeine! What about hydrocodone?

Codeine is a prodrug.  It gets broken down to other drugs to provide pain relief.  10% of codeine gets broken down to morphine in a “normal” individual.  The enzyme that does this is located in the liver, cytochrome P450 2D6 (CYP2D6).  This has been known since the 1980s.

Well, so what?

5-10% of Caucasians lack this enzyme, and therefore achieve little pain relief when given codeine.  This varies from 1-20% depending on your racial background.

A smaller percentage of Caucasians (1-2%) are “ultrametabolizers,” that is they break down the codeine very quickly and may either have a varying analgesic response or increased risk of toxicity.

In children, there is almost no CYP2D6 present at birth, and by the age of 5, levels in most children have only reached 25% of the adult level.

This information is so important that the “WHO guidelines on the pharmacological treatment of persisting pain in children with medical illness” dropped Codeine from their recommendations. This created a two step ladder for children: mild pain to be treated with Tylenol (Paracetamol) and ibuprofen; moderate to severe pain, to be treated with opioids such as morphine.

In now in an FDA press release, Bob Rappaport, director of the Division of Anesthesia, Analgesia and Addiction Products in FDA’s Center for Drug Evaluation and Research, is quoted; “The FDA is currently conducting a review of adverse event reports and other information to determine if there are additional cases of inadvertent overdose or death in children taking codeine, and if these adverse events occur during treatment of other kinds of pain, such as post-operative pain following other types of surgery or procedures.  The FDA will update the public when more information is available.”

So what could this mean to the FDA (and the rest of the medical community)?

  • The WHO has endorsed a 2-step ladder for children with the two steps being “mild” and “moderate-severe” pain.  Perhaps another reason to restrict US labeling for opioids to severe pain.
  • Codeine is not widely used drug in the US.  In Australia, one could buy lower doses of Panadeine (Codeine and paracetamol) over the counter but it now requires a discussion with a pharmacist. Stronger formulations still require a prescription. (ABC Health report Interview with Dr Janette Randall, chair of the National Prescribing Service).
  • Hydrocodone, very similar in structure to codeine, is extensively used in the USA, in fact the US is the major user of hydrocodone in the world.  It should not be surprising to learn that hydrocodone is a prodrug that is broken down to form hydromorphone (the opioid in Dilaudid). And the enzyme? CYP2D6 (0tton et al, 1993)
  • The activity of CYP2D6 can be either blocked or induced (increased) by other very common drugs used daily by many (e.g. antidepressants, and beta-blockers).
  • Oxycodone’s metabolism is influenced by CYP2D6 but is stated to not be a factor in pain relief.

Maybe we need more evidence not just on codeine but on hydrocodone.  WHat questions would I ask?

  • Are there deaths from hydrocodone that are related to the levels of CYP2D6?
  • Are there people who get no analgesia from hydrocodone so they stop using it: and it sits in their “medicine cabinet?”
  • Is there an association with one’s CYP2D6 level and abuse?  If one doesn’t get pain relief and takes more drug (again with no relief), is one placing oneself at increased risk of dependency syndrome (the new term for addiction)?

So many questions? But another illustration of the need to understand the facts and not to make decisions without understanding the complexity of the problems.   Yes decisions regarding clinical practice were made in the past at a time that science did not have the level of understanding we have today.

But responsible clinicians would be looking at all of the evidence!

What questions does it raise for you?

About Pain policy & palliative care

Improving global pain relief by achieving balanced access to opioids worldwide


3 thoughts on “FDA warns about codeine! What about hydrocodone?

  1. On the occasions that I have been prescribed medicine containing codeine, or a prescription for hydrocodone, I have not experienced any pain relief. Tylenol doesn’t work on me either. I thought it was just in my head, but now I realize that my body may not respond to it like everyone else’s. My mom and my aunt both have the same issue. Thanks for the information, now I can mention this possibility to my doctor without the fear of sounding ridiculous.

    Posted by Monica Clark | August 28, 2012, 8:54 AM
  2. OMG… I cannot speak for the hydrocodone (or any other powerful painkillers like Oxy, Vic, Tramadol and many others more related to the morpihine derivates)… But codeine? I fully understand the fact that when someone is taking high dosages of this opiate (and especiall for a long time), it definitely does its work and the person will start to be addicted to it. But don’t be funny when you’re writin’ ’bout codeine and low dosages. It is a well-know thing that codeine in itselft is really the weakest one alcaloid of the opium (from the poppy seeds). In opium are the three main alcaloids… codeine, morhpine and thebaine (and, of course, some others but really in the very small amounts). Yup, morphine is the strongest one, that’s a real fact and I can’t nothing to say against that. Thebaine? Nahhh… nothing interesting at all. And our third candidate: codeine. Every person which had sometimes prescribed codeine knows, that in the world of the painkillers (those for the Rx or those which are in the OTC drugs) especially the codeine is very well functioning (without a lot of side effects which the stronger painkillers can have) and what’s the best… It is also common fact that the dependence on codeine is a waaaay lower than on any other (stronger) painkillers. In other word, if somenone isn’t taking codeine for a really long time, the risk of being addicted to it is really very low. On the other hand, codeine isn’t a strong painkiller at all… Nope. It is prescribed especially only for the moderate pain, Only higher amounts of this substance can (what a surprise) relief the stronger pain. But because of this, there are stronger painkillers on the (really f*cking pharmaceutical corporations) market. Just like mentioned it before… some Oxys, Hydromorphone, Vic and a bunch of others really strong sh*its.
    Btw, it’s not a surprise that especially the codeine is in the most cases one of the part of many, many, MANY painkillers, which are selling like the OTC drugs. Yup, that’s a fact but the amount of codeine in those meds are, in the most cases, very low For example, in my country which is in the EU zone, there are only 2!!! OTC drugs which contains codeine… in one of them is only 8 mg/pill, the second one contains 30mg but that’s a cought syrup and its price isn’t low, so the risk of abusing it is pathetical. Of course, there are countries (and I’m a little bit surprised about that) when the dose of codeine in the OTC drugs are in the double amount than those in my country. As I know that this is the case of the USA market (really great… the country which is banning almost everything!!!) and… which is funny… the Great Britain. There’s the third one, but I don’t know if it’s there like in those 2 countries… I mean Canada. Anyway, in the US and the Britain are OTC painkillers, which are selling as a normal the OTC painkillers containing (among with the paracetamol in the most cases) 13.5 – 15 mg of codeine in the single pill!!! And if I’m not wrong, that’s not the lowest amount but 15 mg in the OTC??? I’m not surprised that especially in the USA are many ppl addicted to the painkillers (of course, those more powerful, ’cause in that country are painkillers something like the candies or what…). I’ve read the study HOW MANY ppl in the US are taking strong painkillers every year… It’s a really horrible number but as I see… It’s normal for the docs in that “wonderful country” to prescribe them.
    Ppl like you (and other “experts” which are blabbering about the danger of the opioid substances… which are in the most cases really weak, like this “so bad” codeine) are prescribing a way dangerous opiates but yaeah… when you don’t have to write about anything else, you start to blame one of the weakest opiate, which the coideine definitely is. But keep in mind that especially codeine (when it’s using like it means to be using!) can really help many ppl out there from the moderate pain, it has definitely an anti-cough effect and (but it’s not the last good effect of this substance) it can very well helps with the diarrhea (well, like all the opiates does).
    I can say you are really stupid, like all the so-called docs and scientist in our “all-meds” era. All the good drugs are controlled by the hypocrites organizations. It’s not like in the (for example) 18th and 19th century (till the start of the 20th centh and starting of the controll process)… In those years ppl instintively know what is good for them. That was the fact why the opium tinctures, hashish oils and a lot of other drugs which are completely banned today, were helping them. Ppl are not dumb!!! They have their instincts still alive but nowaday culture is trying to eliminate it. And that’s why the so well known Big Brother is slowly bigger and bigger. My opinion is, that all the drugs may be legal, ’cause ppl still know what is worth and what is not. Yeah, if everything will be legal, there always be humans which cross the line and the drugs will destroy them. But… and THAT’S VERY IMPORTANT!!! What else is doing the “MODERN” pharma-mafia in this (ooooh) “modern society”??? They are producing a thousands of meds, most of them have a really serious side effects and that’s what??? Is it normal??? Who gave the ppl standing behind those pharma corps. to decide what is good for us and what is not??? The pharma-mafia is gaining a huge profit from the meds which ppl don’t need but it’s okay (and everyone knows it’s billions of dollars every f*cking year!!!).
    So, stop moralizing, stop spreading sh*t about the “whoo-hooo… “dangerous codeine” and wake up! Sorry for the long post, but when I (accidentally) found THIS article I’ve think that I have to write some completely other opinion, ’cause your article is really full of a typicall propaganda sh*t.
    So, stop saying a shit about a “dangers of codeine”, especially when it can (and it does) help a lot of ppl to treat a lot of diseases. Of course, in the therapeutical doses, not when it’s overtaking.

    Posted by Strasny Bubak | January 20, 2016, 12:35 PM


  1. Pingback: Codeine and Kids | painpolicy - April 25, 2014

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