WHO Analgesic Ladder: which opioid to use at step two?

All opioids are not the same. They differ in their pharmacodynamics and pharmokinetics, and clinically in their range of effects (Table 1).

Codeine is a prodrug that must be metabolised to morphine by the liver enzyme CYP2D6 to achieve most of its analgesic effect. Because of genetic differences some individuals (e.g. 6–10% of Caucasians) lack the enzyme CYP2D6 and cannot metabolise codeine effectively and therefore obtain limited pain relief while experiencing all the adverse effects.

Dihydrocodeine is similar to codeine in both its structure and its analgesic effect. It is primarily metabolised by CYP2D6 and CYP3A4 to dihydromorphine and nordihydrocodeine, however it is unclear whether the parent drug, metabolites or a combination of both result in dihydrocodeine’s analgesic activity.

Tramadol is chemically unrelated to morphine. Tramadol is also metabolised by CYP2D6 and CYP3A4. Similar to codeine and dihydrocodeine some individuals tolerate tramadol poorly and may have increased adverse effects.

Tramadol and its metabolites have combined opioid and monoaminergic properties. Less than half of the analgesic effect is via the mu-opioid receptors. The remainder is from inhibiting the re-uptake of noradrenaline and serotonin. This dual action produces a different analgesic effect compared with the simple opioid analgesics and less respiratory depression or risk of addiction compared with the strong opioids. However, there is also a wider range of side effects, with the additional risk of serotonin toxicity (see BPJ 8 for details) and a reduced seizure threshold. For this reason tramadol is contraindicated in individuals taking MAOIs and those with epilepsy. It should also be used with caution, or avoided if possible, in those already taking a serotonergic medication (e.g. most antidepressants) or in people taking drugs that reduce seizure threshold (e.g. TCAs). In general, tramadol is associated with less constipation but increased nausea and vomiting, sedation, dizziness and orthostatic hypotension when compared to other step two opioids.

Is tramadol an option at step two?
Tramadol has been shown to be no more effective than other weak opioids but adverse effects may be problematic and drug interactions need to be considered. Tramadol is not currently subsidised and so cost to the patient is also a factor.

The most recent Scottish Intercollegiate Guidelines Network (SIGN) publication for the treatment of cancer pain suggests that there is still insufficient evidence available to make a recommendation on the use of tramadol.

For many patients, codeine when used concurrently with paracetamol will be as effective as tramadol and may be better tolerated.

Strong opioids such as morphine are more effective for severe pain and this combined with the fact that tramadol has a ceiling dose of 400 mg/day means that it is not considered an alternative to morphine for severe pain.