Don’t prescribe codeine

Don't prescribe codeine

Last week, I discussed the reasons that I believe that tramadol is a bad drug that shouldn’t be prescribed. This week, I will tackle a similarly bad drug: codeine.

The argument is essentially the same. Tramadol may be moderately worse, because of the added SNRI effects, but the variable effects of codeine make it a bad choice when compared to a more reliable agent like morphine.

Pharmacology

Once again, the main reason not to use codeine is simple pharmacology. Codeine is a pro-drug that only very weakly binds to the opioid receptor. It’s analgesic properties are primarily the result of its metabolites codeine-6-glucuronide, norcodeine, and morphine. (Drendel 2007; Fortenberry 2019) Unfortunately, much like tramadol, codeine is metabolized in the liver by CYP2D6, meaning that a significant portion of the population will get no analgesia, while rare individuals (“ultra-metabolizers”) will get unusually high doses of morphine. The result is as much as a 17 fold difference in the serum concentration of the morphine. (Drendel 2007) The pharmacologic effects are further compounded by interactions with other medications. For example, SSRIs will decrease the efficacy of codeine, whereas dexamethasone and clarithromycin will increase conversion to morphine. (Niesters 2013; Kress 2017)

Overall, ultra-metabolizers are estimated to make up between 1 and 4% of the population, while 7-21% of the population is a poor metabolizer. (Tobias 2016; Fortenberry 2019) We have no idea who these patients are, so every time you write a prescription for codeine, you are gambling. You are giving an unpredictable dose of morphine. It isn’t clear why you would ever use codeine, when we have perfectly good alternatives that don’t require the gamble.

Efficacy

Although codeine is metabolized to morphine, it consistently provides underwhelming pain relief when studied.

In children with fractures in the emergency department, 1 mg/kg of codeine plus acetaminophen provided no better pain relief (and perhaps worse) than 10 mg/kg of ibuprofen, but had significantly more adverse events. (Drendel 2009) In another pediatric RCT, 10 mg/kg of ibuprofen was better than 1 mg/kg of codeine at 1 hour. (Clark 2007) In a systematic review looking at patients after dental surgery, in order to achieve a 50% reduction in pain, codeine had a number needed to treat of 21. In comparison, ibuprofen had an NNT of 2 and paracetamol had an NNT of 4. (Barden 2004) Multiple other studies support the idea that codeine, at doses normally prescribed, is no better than ibuprofen, or potentially worse, but has more side effects. (Peter 2001; Chen 2009; Friday 2009; Nauta 2009; Mitchell 2012)

As far as I can find, there are no studies directly comparing oral codeine to oral morphine. We know that oral morphine is effective for pain control. (Wiffen 2016) One RCT in post-operative patients compared codeine 60 mg IM to morphine 10 mg IM, and the morphine provided better pain relief, required less redosing, and there was no difference in adverse events in the small trial. (Goldsack 1996) This makes sense, considering older research concluded that 10 mg of morphine IM is equivalent to 120-130 mg of codeine IM. (Shanahan 1983 referencing older data I can’t access)

Overall, codeine in the doses usually prescribed doesn’t seem to provide any better pain relief than ibuprofen (and maybe worse in some settings), but has more adverse events. Standard doses of morphine are at least as good as standard doses of codeine, but will provide a more reliable serum concentration of the active drug.

Harms

Codeine has been around for a long time. For the most part, I like older drugs, because there has been more time to develop experience and identify rare side effects. However, one has to be careful, because older medications were not introduced with the same evidence and safety standards we use today. In the case of codeine, I think time has provided us plenty of evidence of rare but serious harms, but unfortunately we have been ignoring them.

Death

There are multiple case reports of death following codeine use in ultra-metabolizers, both when prescribed directly to children, and when given to breastfeeding mothers. (Madadi 2008; Ciszkowski 2009; Kelly 2012; Niesters 2013; Racoosin 2013; Tobias 2016)

Codeine is a widely prescribed drug, and the total number of case reports is relatively small. However, in comparison to other opioids, such as morphine or fentanyl, codeine has many more reported deaths. With the known pharmacological variability, we have a plausible mechanism for why. Furthermore, many of the children ultimately had genetic testing proving they were ultra-metabolizers. The risk, although small, seems to be real. Why take the risk?

Warnings

Multiple agencies have warned against the use of codeine in pediatrics. The US FDA states that codeine is contraindicated for patients under 12 years of age, and should not be used in patients between 12 and 18 years of age if there is any respiratory compromise. (Food and Drug administration 2018) The European Medicines Agency and Health Canada both have similar bans on codeine, and also recommend against using it in breastfeeding women. (EMA 2013; Health Canada 2016) The World Health Organization has removed codeine from its list of essential medications for children, because of questions about its safety and efficacy. (Tobias 2016)

Although these warnings are all pediatric specific, the underlying pharmacologic problems are present in adults as well, which makes codeine a generally poor choice.

Despite all these warnings in pediatrics, my experience is that codeine is still the most commonly used opioid in children. Whenever I have tried to prescribe a child morphine, at multiple hospitals both in Canada and New Zealand, it has been suggested to me by the well meaning nursing staff that morphine is unsafe, and that I should use codeine instead. My experience is supported the results of a brief survey of physicians and nurses, in which 100% identified morphine as potentially causing respiratory depression, whereas only 42% felt codeine could cause respiratory depression, despite being metabolized to morphine. Furthermore, 92% ranked codeine as safer than morphine and 15% even ranked it as safer than ibuprofen. (Wynn-Jones 2013) Those opinions are not supported by the evidence.

An added complication: combination medications

In New Zealand, codeine seems to be primarily prescribed as a solo agent. However, in Canada the problems with codeine are further complicated by the fact that it is usually combined with acetaminophen (or paracetamol) in a single tablet.

For acute processes, combination medications are almost always a bad idea. They don’t allow you to change the dose of each medications individually, and the result is that one medication is frequently either under or over dosed.

In the case of “Tylenol #3” or the various other combinations of codeine and acetaminophen, overdose is my bigger concern. We know that codeine is not a very effective medication. In fact, for a significant minority of the population, it will have no analgesic effect at all. As a result, we can expect some of our patients will take more than the recommended dose in an attempt to manage their pain. The result is a risk of a deadly acetaminophen overdose.

On the other hand, if taken correctly, the combination products almost certainly underdose acetaminophen. For most patients with acutely painful conditions, I recommend 1 gram of acetaminophen 4 times daily. The combination products usually contain only 300 mg. So the patient may be required to take more codeine than is necessary in order to get the appropriate dose of acetaminophen, or they have to add additional acetaminophen, which is a recipe for medical error. Furthermore, as the patient’s pain improves, I want them to titrate off their opioid medication. After a few days of treatment, acetaminophen may be enough on its own. However, if you have prescribed a combination product, your patient will not be able to try acetaminophen on its own, so may end up using their opioid longer than necessary,

Cost

Drug costs vary widely around the world, but in general, not only is codeine inferior to morphine for the various reasons described above, it also tends to be more expensive ($55 vs $30 for 100 tabs on drugs.com). (MacDonald 2010)

Summary

When you prescribe codeine, you are really prescribing morphine. You are just prescribing in erratic doses. Why add the complication? Why gamble? Just prescribe morphine instead.

Other FOAMed

Pediatric Pain Management

Codeine is a terrible choice for treating children’s pain and cough. Here’s why.

EM Cases: Best Case Ever 37 Neonatal Lazy Feeder

EM Cases: Episode 67 Pediatric Pain Management

PEM Playbook: Just Say No To (These) Drugs

I’ve also bashed codeine in multiple prior Articles of the Month (Jan 2016 and Nov 2016), as well as in the corresponding BroomeDocs podcasts.


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References

Barden J, Edwards JE, McQuay HJ, Wiffen PJ, Moore RA. Relative efficacy of oral analgesics after third molar extraction. British dental journal. 2004; 197(7):407-11; discussion 397. [pubmed]

Chen T, Adamson PA. Comparison of ibuprofen and acetaminophen with codeine following cosmetic facial surgery. J Otolaryngol Head Neck Surg 2009;38:580-6

Ciszkowski C, Madadi P, Phillips MS, Lauwers AE, Koren G. Codeine, Ultrarapid-Metabolism Genotype, and Postoperative Death N Engl J Med. 2009; 361(8):827-828.

Clark E, Plint AC, Correll R, et al. A randomized, controlled trial of acetaminophen, ibuprofen, and c0deine for acute pain relief in children with musculoskeletal trauma. Pediatrics 2007;119:460–7

Drendel A. Pharmacogenomics of Analgesic Agents Clinical Pediatric Emergency Medicine. 2007; 8(4):262-267.

Drendel AL, Gorelick MH, Weisman SJ, Lyon R, Brousseau DC, Kim MK. A randomized clinical trial of ibuprofen versus acetaminophen with codeine for acute pediatric arm fracture pain. Annals of emergency medicine. 2009; 54(4):553-60. [pubmed]

Friday JH, Kanegaye JT, McCaslin I, et al. Ibuprofen provides analgesia equivalent to acetaminophen–c0deine in the treatment of acute pain in children with extremity injuries: a randomized clinical trial. Acad Emerg Med 2009;16:711-6.

Food and Drug Administration. FDA Drug Safety Communication: FDA requires labeling changes for prescription opioid cough and cold medicines to limit their use to adults 18 years and older. 2018.

EMA: European Medicines Agency. Codeine containing medicines. 2013. Available at: https://www.ema.europa.eu/en/medicines/human/referrals/codeine-containing-medicines

Fortenberry M, Crowder J, So TY. The Use of Codeine and Tramadol in the Pediatric Population-What is the Verdict Now? Journal of pediatric health care : official publication of National Association of Pediatric Nurse Associates & Practitioners. 2019; 33(1):117-123. [pubmed]

Goldsack C, Scuplak SM, Smith M. A double-blind comparison of codeine and morphine for postoperative analgesia following intracranial surgery. Anaesthesia. 1996; 51(11):1029-32. [pubmed]

Health Canada. Health Canada’s review recommends codeine only be used in patients aged 12 and over. Ottawa, Canada: Health Canada; 2013. Available at: http://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2013/33915a-eng.php

Kelly LE, Rieder M, van den Anker J, et al. More Codeine Fatalities After Tonsillectomy in North American Children PEDIATRICS. 2012; 129(5):e1343-e1347.

Kress HG, Untersteiner G. Clinical update on benefit versus risks of oral paracetamol alone or with c0deine: still a good option? Current medical research and opinion. 2017; 33(2):289-304. [pubmed]

MacDonald N, MacLeod SM. Has the time come to phase out codeine? CMAJ. 2010; 182(17):1825. [pubmed]

Madadi P, Koren G. Pharmacogenetic insights into codeine analgesia: implications to pediatric codeine use. Pharmacogenomics. 2008; 9(9):1267-84. [pubmed]

Mitchell A, McCrea P, Inglis K, Porter G. A randomized, controlled trial comparing acetaminophen plus ibuprofen versus acetaminophen plus c0deine plus caffeine (Tylenol 3) after outpatient breast surgery. Annals of surgical oncology. 2012; 19(12):3792-800. [pubmed]

Nauta M, Landsmeer ML, Koren G. Codeine-acetaminophen versus nonsteroidal anti-inflammatory drugs in the treatment of post–abdominal surgery pain: a systematic review of randomized trials The American Journal of Surgery. 2009; 198(2):256-261.

Niesters M, Overdyk F, Smith T, Aarts L, Dahan A. Opioid-induced respiratory depression in paediatrics: a review of case reports. British journal of anaesthesia. 2013; 110(2):175-82. [pubmed]

Peter EA, Janssen PA, Grange CS, Douglas MJ. Ibuprofen versus acetaminophen with codeine for the relief of perineal pain after childbirth: a randomized controlled trial. CMAJ. 2001; 165(9):1203-9. [pubmed]

Racoosin JA, Roberson DW, Pacanowski MA, Nielsen DR. New evidence about an old drug–risk with codeine after adenotonsillectomy. The New England journal of medicine. 2013; 368(23):2155-7. [pubmed]

Shanahan EC, Marshall AG, Garrett CP. Adverse reactions to intravenous c0deine phosphate in children. A report of three cases. Anaesthesia. 1983; 38(1):40-3. [pubmed]

Tobias JD, Green TP, Coté CJ, et al. Codeine: Time to Say “No”. Pediatrics. 2016; 138(4):. [pubmed]

Wiffen  PJ, Wee B, Moore  RA. Oral morphine for cancer pain. Cochrane Database of Systematic Reviews 2016, Issue 4. Art. No.: CD003868. DOI: 10.1002/14651858.CD003868.pub4

Wynn-Jones W, Casely E, Laycock H, Bantel C. Codeine: the ‘safe’ analgesic? British Journal of Anaesthesia. 2013; 110(5):843-844.

Cite this article as: Justin Morgenstern, "Don’t prescribe codeine", First10EM blog, May 20, 2019. Available at: https://first10em.com/codeine/.

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