Has the time come to phase out codeine?

Thank you for bringing this important issue to the attention of the readership. As clinicians, we all wish to deliver evidence-based and effective pain treatment to our patients by considering (a) efficacy, (b) safety and (c) practicality. While this editorial focused on safety, we would like to highlight the limitations of codeine in the other areas.

Clinical trials have repeatedly demonstrated that codeine is no more effective than ibuprofen in providing pain relief for mild/moderate pain.[1-6] In many trials, the side effects reported by patients receiving codeine were significantly higher than ibuprofen.[1,2,5,6] These adverse effects, reported by 50-71% of patients, likely affect compliance. Additionally, the poor palatability of codeine suspension is an issue in pediatrics. Children rated this aspect of their codeine experience as highly unsatisfactory.[2] Given the well-recognized negative side effect profile for codeine, can we justify choosing a drug that will likely be avoided by the patient in clinical scenarios where ibuprofen has a comparable clinical effect with a more favorable side effect profile?

We cannot ignore the real safety concern associated with genetic differences in metabolism of codeine for a subsection of the population. But, clinical trials also suggest that codeine is no more effective than ibuprofen and there are a number of drawbacks that likely affect compliance and effectiveness. Since there are alternative analgesics (i.e. ibuprofen) and opioids (i.e. hydrocodone and oxycodone) available with efficacy and safety profiles that are superior to codeine, we advocate for their thoughtful/judicious use over codeine.

Dr. Amy L. Drendel DO MS, Assistant Professor, Medical College of Wisconsin, Milwaukee, Wisconsin

Dr. Samina Ali MDCM, FRCPC, Associate Professor, University of Alberta, Edmonton, Alberta.

1.Chen T, Adamson PA. Comparison of ibuprofen and acetaminophen with codeine following cosmetic facial surgery. J Otolaryngol Head Neck Surg. 2009 Oct;38(5):580-6.

2.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. Ann Emerg Med. 2009 Oct;54(4):553- 60.

3.Friday JH, Kanegaye JT, McCaslin I, Zheng A, Harley JR. Ibuprofen provides analgesia equivalent to acetaminophen-codeine in the treatment of acute pain in children with extremity injuries: a randomized clinical trial. Acad Emerg Med. 2009 Aug;16(8):711-6.

4.Clark E, Plint AC, Correll R, Gaboury I, Passi B. A randomized, controlled trial of acetaminophen, ibuprofen, and codeine for acute pain relief in children with musculoskeletal trauma. Pediatrics. 2007 Mar;119(3):460-7.

5.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 Oct 30;165(9):1203- 9.

6.Raeder JC, Steine S, Vatsgar TT. Oral ibuprofen versus paracetamol plus codeine for analgesia after ambulatory surgery. Anesth Analg. 2001 Jun;92(6):1470-2.

Conflict of Interest:

None declared

In this editorial by MacDonald and Macleod we hear a request for the elimination of codeine from practice. The primary reason cited is apparently the death of 1 infant at Sick Children’s Hospital. The authors rightfully write “life-threatening or fatal consequences of genetic variation in codeine metabolism have been few”. The authors should have worded this minimal risk by placing into it s appropriate context. Codeine has been available since 1832, when first isolated by Pierre Robiquet. Since that time people have consumed billions of doses of codeine. It has been available as an over-the-counter analgesic for decades in Canada. Its track record of safety over the past 180 years is undeniable. While many may feel that its efficacy as an analgesic is questionable, it does provide very good relief for moderate pain for many patients. Its long acting format is invaluable for some chronic pain patients. Given its safety record as well as its role in mild to moderate pain relief, it would seem that the call for its withdrawal from the market is inappropriate and almost paranoid in nature. A more reasoned approach would be to provide balanced recommendations using our (improved) current knowledge. Based on the one case mentioned above, incredibly, many downtown Toronto hospitals have removed codeine from their formularies. Given that there have been deaths from every opioid – and almost every prescription medication for that matter - on the market, should we not then ban all prescription medications if we follow the authors' logic?

Conflict of Interest:

None declared

Thank you for identifying the real risks associated with codeine’s wide use in Canada as a perceived safe and effective analgesic. As a family physician, may I respectfully suggest that the use of morphine in place of codeine for pain relief in children might lead to another serious side-effect: unrelieved pediatric pain. Given the lack of chronic pain education in most Canadian undergraduate medical curricula, as well as recent concerns about overuse of opiates leading to addiction and diversion, 1,2 I suspect that many non-specialist physicians will be loathe to use morphine when needed. Parents may also raise concerns about using what they perceive to be a very potent opiate for their children. Given that tramadol has been tested in the pediatric population and shown to be safe and effective3, this drug may be more acceptable to both physicians and families for moderate non cancer pain, provided, of course, that drug plans cover it. Our pediatrician colleagues can support those of us in primary care by commenting on the safety and efficacy of this drug which has been widely used for decades in other countries. In the meantime, if we rashly discard codeine, let’s be sure we have a workable back-up plan in place, otherwise we might end up truly throwing the baby out with the bath-water.

Sincerely, Ruth E. Dubin, MD,PhD,FCFP Kingston Family Health Team and Assistant professor, Dept of Family Medicine Queen’s University

1. Pain Res Manag. 2009 Nov-Dec;14(6):439-44. A survey of prelicensure pain curricula in health science faculties in Canadian universities. Watt-Watson J, McGillion M, Hunter J, Choiniere M, Clark AJ, Dewar A, Johnston C, Lynch M, Morley-Forster P, Moulin D, Thie N, von Baeyer CL, Webber K. 2.CMAJ. 2010 Jun 15;182(9):923-30. Epub 2010 May 3. Opioids for chronic noncancer pain: a new Canadian practice guideline. Furlan AD, Reardon R, Weppler C; National Opioid Use Guideline Group. Institute for Work and Health, Toronto Rehabilitation Institute, Toronto, Ont. 3. Pain Res Manag. 2004 Winter;9(4):209-11. Treatment of pediatric chronic pain with tramadol hydrochloride: siblings with Ehlers-Danlos syndrome - Hypermobility type. Brown SC, Stinson J.

Conflict of Interest:

None declared

While I whole-heartedly agree with the review and recommendations given in this very thorough editorial, I would suggest one very minor correction for the sake of historical obsessives such as myself: change "over" 200 years to "almost" 200 years. While morphine was indeed isolated 205 years ago by Seturner, it was not until 1832 that Pierre-Jean Robiquet isolated codeine. It was manufactured commercially that same year by E. Merck.

Reference:

Pierre-Jean Robiquet. (2010). In Encyclopædia Britannica. Retrieved November 24, 2010, from Encyclopædia Britannica Online:http://www.britannica.com/EBchecked/topic/505806/Pierre-Jean- Robiquet

Conflict of Interest:

None declared

The editorial references to the genetic variability in metabolizing codeine and warns of potential serious harm for newborns and children. What about the elderly population? Their change in physiology certainly would result in similar responses to the change of codeine metabolism. Are the authors aware of any literature that paves the way to more in-depth understanding in this population?

Conflict of Interest:

None declared

Noni MacDonald and Stuart M. MacLeod have found a tiny number of cases where Codeine has caused serious problems in very young children. They also claim has 'poor analgesic properties' despite the fact that most Canadians consider Codeine the best painkiller available over the counter and have since before the Country came into existence. How can their fears based on a few examples and some extrapolations be more significant than nearly 200 years of actual use by millions of people around the world? And, just as important, how can they live with themselves proposing to deprive millions of their fellow citizens of pain relief?

I say shame on them both for playing at being God with one of the very few effective and available pain killers.

Conflict of Interest:

None declared