In the last days before the codeine upschedule, it’s time to look at how we manage acute pain, writes Ben Basger

What do you think about codeine? Are we going to be disadvantaged by its restriction?

I don’t think so. Codeine is a poor analgesic. It is a prodrug whose analgesic effects are almost entirely due to its principal metabolite, morphine.

However, the way in which individuals metabolise codeine is unpredictable. This is because genetic factors can substantially influence the rate of metabolism of codeine to morphine and therefore its effectiveness (CMAJ 2010. DOI:10.1503/cmaj.101411).

For example, up to 10% of the Caucasian population may have insufficient or even absent CYP2D6, resulting in incomplete or total ineffectiveness of analgesia. (Drugs Aging 2013. DOI 10.1007/s40266-012-0047-7).

Some medications frequently prescribed to elderly patients (like amiodarone, celecoxib, fluoxetine, duloxetine and paroxetine) can inhibit CYP2D6, thereby reducing codeine’s analgesic effects. Codeine’s active/toxic metabolites also accumulate in (age-related) renal impairment and have a longer half-life than morphine. This may interfere with respiration and cause delirium.

What about tramadol? Like venlafaxine, tramadol augments serotonergic and noradrenergic neurotransmission, although its main active metabolite (O-desmethyltramadol) is an opioid. Both mechanisms of action are thought to contribute to tramadol’s analgesic effects.

But guess what? Conversion of tramadol to 0-desmethyltramadol is catalyzed by CYP2D6, the very same enzyme subject to the same variability as described above. Further, generalised seizures and serotonin syndrome can occur with tramadol use, sometimes with modest doses, and particularly when the drug is combined with other serotonergic or proconvulsant agents such as antidepressants (CMAJ 2013. DOI:10.1503/cmaj.121592).

It has been stated that giving a known dose of tramadol is tantamount to giving an unknown dose of opioid!

Guess it’s the same for morphine. Interesting way to use drugs, especially if you are in pain.

What about oxycodone? Did you know that the relative risk (the number of times more likely) that nausea occurs compared to taking a placebo is 2.7? Constipation 3.6? Dizziness 2.8? Sedation 3.3?

No wonder there is more chance of crashing your car when taking it! (JAMA Intern Med DOI:10.1001/2013.jamainternmed.733).

Did you know that except for treatment of acute post-operative pain and the use of zolmitriptan in migraine, it has been found that for all other drugs and in all other conditions examined, fewer than half of patient achieved at least a 50% reduction in pain intensity? (BMJ 2013 doi: 10.1136/bmj.f2690).

So what does all this mean?

  1. No single drug will successfully treat more than a minority of patients, so a wide range (choice) is needed.
  2. Successful pain relief is also likely to improve sleep, depression, fatigue, quality of life, function, and ability to work.
  3. Failure with one drug does not necessarily mean failure with others, even within a class.
  4. Success or failure can be determined within two to four weeks, and success, when achieved, tends to be long lasting.

Dr Ben Basger PhD MSc BPharm DipHPharm FPS AACPA is a clinical pharmacist and educator at Wolper Jewish Hospital and The University of Sydney, NSW.