The WHO analgesic ladder illustrates that, as pain intensity increases, there should be a parallel and appropriate increase in the potency of analgesics used.

Step 1 (for mild pain)

Simple analgesia, such as:

• Paracetamol
• Asprin*
• Even at Step 1, a diagnosis should be made of the pain (see Diagnosis), and an appropriate adjuvant prescribed.
• Step 1 medications are usually given ‘as needed’.  If they are needed regularly, it is an indication to move to Step 2.
• Aspirin is rarely used because of concerns about Reye Syndrome (though it may have a role for children in palliative care in whom this risk is negligible).

Step 2 (for moderate pain)

Drugs at Step 2 should be added to those already used in Step 1 (that is, they should be used alongside simple analgesics, rather than replacing them).

Codeine is no longer recommended as a minor opioid.  It is a weak precursor of morphine that is subject to pharmaco-genetic variation which means its effectiveness and side effects are unpredictable.  Further more, it is powerfully constipating and represents a considerable risk in a population of children already vulnerable to slow gut transit time.

• Low dose Morphine
  • Occupies therapeutic niche previously filled by Codeine
  • Dosage is approximately 1/10th of the equivalent dose of Codeine (that is, in a child for whom 15 mg of Codeine will have been appropriate, the appropriate dose of low dose Morphine would be 1.5 mg).
  • This is the only situation in which Morphine should be given only PRN; that is, in the absence of background opioids.
• Low dose Buprenorphine patch
  • OME 60
  • Semi synthetic opioid.
  • Available by transdermal patch for slow release and sublingually for immediate release.
  • Buprenorphine demonstrates genuine pharmacological ‘ceiling effect’ but only at higher doses than those usually used clinically.
  • Partial agonist, therefore there is a theoretically lower risk of some adverse effects e.g. respiratory depression, constipation.
  • For the same reason, harder to reverse using Naloxone if needed.
  • Considerable evidence of safety and effectiveness in some forms of pain in children.
  • Little systematic evidence of effectiveness and safety in palliative care.

Buprenorphine potentially has a particular role in the management of pain in children with non-malignant life-limiting conditions in ACT/RCPCH Groups III and IV (see table), because:

• This group is vulnerable to constipation and Buprenorphine probably carries less of a risk than other strong opioids.
• Pain in this group is often relatively mild so that Step 2 therapy is sufficient.
• A transdermal formulation is ideal since patients in this group are often gastrostomy or occasionally nasogastrically fed.
• BUT even small doses of Buprenorphine have been associated anectodally with nausea and vomiting and even respiratory depression.

• Tramadol (NB has additional non-opioid analgesic effects).
  • Tramadol is a derivative of Codeine.
  • OME 0.2, but effective potency greater than this due to non opioid analgesic effects via modulation of GABAergic, noradrenergic and serotonergic systems.
  • No evidence of specific benefit in neuropathic pain, though NMDA antagonism has been suggested.  Excitatory amino acid receptors – including NMDA receptors have an important role in the mediation of neuropathic pain.
  • Very poorly tolerated in a minority of patients due primarily to hypotension.
  • Favoured by some patients as it is not a major opioid or a controlled drug in the UK.
  • Evidence for safety and effectiveness in acute pain in children.
  • No evidence of effectiveness and safety in chronic or palliative care pain.

The role of Tramadol in paediatric palliative care has yet to be determined and is probably limited.  It is not a controlled drug which can be important to older children, such as boys with Duchenne muscular dystrophy, who are likely to need to be on the medication for a long time and want to avoid unnecessary stigma as long as possible.

Step 3 (for severe pain)

Step 2 is insufficient if:

• Codeine is needed regularly, or more than three times a day.
• Breakthrough pain is occurring more than once or twice a day despite regular Tramadol or Buprenorphine.
• The adverse effects of drugs on Step 2 are such that the burden outweighs their benefit.

In contrast with moving from Step 1 to Step 2, there is rarely a role for Step 2 and Step 3 opioids to be given concurrently.  Minor opioids on Step 2 should usually all be discontinued as soon as major opioids are commenced, as minor opioids do not induce adequate tolerance to the adverse effects of major opioids.
Exceptions to this rule include:

• A small dose of oral Morphine may be used for breakthrough alongside regular Tramadol (effective potency of Tramadol is greater than OME would suggest).
• A high dose transdermal Buprenorphine patch is effectively a major opioid, and therefore major opioids may also be appropriate for breakthrough doses.

Major opioids at Step 3 include:

• Morphine (first line)
• Diamorphine
• Fentanyl
• High dose Buprenorphine patch
• Methadone
• Hydromorphone

At all steps an appropriate adjuvant should be prescribed according to the cause of the pain (see Adjuvant therapies)