Opioids in palliative care: emerging clinical trends

For the last three decades, cancer pain management has been dominated by the World Health Organization’s analgesic ladder concept. This consists of three steps: (i) ‘simple’ non-opioid (e.g. aspirin or paracetamol) for ‘mild’ pain, (ii) ‘weak’ opioid (e.g. codeine) for moderate pain and (iii) ‘strong’ opioids for severe pain. The ‘gold standard’ ‘strong’ opioid has been morphine (or diamorphine, especially in the United Kingdom), although opioid choice around the world has also been strongly influenced by local availability. The ladder was largely intended to overcome resistance to adequate and appropriate opioid prescribing and promote an incremental approach, with opioid dose escalation at the pinnacle. Despite having a significant favourable effect on global standards of pain relief, this simple view of pain management no longer adequately describes modern palliative care and pain management practice. This is particularly so for refractory pain (which we define as failure to achieve sustained patient-acceptable control on an antiinflammatory and/or at least one neuropathic agent together with escalating opioid dosing). The second step of the ladder is virtually redundant; the strong/weak distinction is not particularly helpful, and codeine is not a useful analgesic for cancer pain where other more potent opioids are available. Codeine is a pro-drug for morphine and many people lack the necessary enzyme anyway. It is now widely acknowledged that severity is only one dimension of pain, and that mechanism of pain generation is also relevant because analgesic response may vary depending on whether there are somatic, visceral or neuropathic features present. It is also increasingly clear that opioid responsiveness of pain and opioid adverseeffect profile may vary considerably between patients, and within the same patient during the course of a patient’s illness trajectory. Patients with refractory pain due to neuropathic, and incident (movement-related) somatic mechanisms (usually due to bone metastases), are heavily represented in this category, and commonly experience adverse effects and poor pain control. There is also accumulating clinical experience, and some evidence, to suggest that individual response – particularly adverse-effect profile for a given opioid – is subject to considerable variation. Therefore, switching from one member of the drug class to another – opioid ‘substitution’ (the term ‘rotation’ is also used) – may be beneficial. This observation, coupled with the availability of a broader range of opioid options in most countries, means that morphine is no longer always the automatic first-line opioid of choice. Fentanyl, oxycodone, methadone and hydromorphone are all now in common use in Australia as secondand first-line opioids. The opioid-like drug tramadol has recently been introduced to the market in Australia, and there is renewed interest in the partial agonist buprenorphine. Caution is certainly required with opioid substitution until there is more evidence. However, it is always worth asking whether symptoms – particularly nausea, vomiting and disturbance of higher cognition – are attributable as opioid-adverse effects, and whether these, in turn, reflect poor opioid pain responsiveness, and/or excessive dosage. If this is suspected, consideration may be given to opioid dose reduction, route change, or a trial of substitution to another opioid. The mechanism(s) of these apparent individual differential responses are not understood, however differential opioid receptor subtype binding, genetically determined drug metabolism differences, and incomplete cross tolerance are all possibilities. Methadone has been suggested to have potential advantages in neuropathic pain treatment due to its N-methyl-D-aspartate (NMDA) blockade properties shown in animal studies, although clear clinical evidence is still lacking. Fentanyl and hydromorphone may be better tolerated in renal failure. Fentanyl patches may be preferable for patients who have difficulty swallowing, or prefer the convenience of the transdermal route. The roles of tramadol and buprenorphine in palliative care are yet to be determined. Spinal cord sensitization and clinical wind up is increasingly being recognized as an important clinical entity. This results in pain spreading beyond the immediate area of nociception and allodynia (pain in response to a normally non-painful stimulus, such as light touch), hyperalgesia (an increased sensitivity to painful stimuli) Correspondence to: Kate Jackson, Palliative Care Unit, Monash Medical Centre, Southern Health, Clayton, Vic. 3168, Australia. Email: k.jackson@southernhealth.org.au