The majority of patients with cancer pain can be adequately treated with oral analgesics usually provided ‘around the clock’, with rescue doses for breakthrough pain. However, some patients may not respond to increasing dosages of opioids because they develop adverse effects before achieving acceptable analgesia, or the analgesic response is poor, despite a rapid dose escalation. Cancer pain is not always responsive to a single opioid. Moreover, in some circumstances opioids, intended to produce analgesic effects, may lead to opioid-induced hyperalgesia. This phenomenon is an emerging syndrome due to complex biochemical processes, particularly occurring during rapid dose escalation. Opioid switching may significantly improve the balance between analgesia and adverse effects.1
Rationale and evidence base
The analgesic effect of opioids is believed to be mainly due to their inhibitory actions. Opioid agonists act via G-protein-coupled receptors to inhibit adenyl cyclase, increase potassium currents, inhibit calcium channel activity and activate mitogen-activated protein kinase. These actions culminate in the attenuation of neuronal activity by inhibiting neurotransmitter release and altering neuronal excitability. Receptor activation produces analgesic or adverse effects, peripherally or centrally.
Successful opioid therapy requires that the benefits of analgesia outweigh the adverse events. Each opioid has different characteristics, leading to plastic changes at opioid receptors and different patterns of individual response.2 It is also becoming evident that chronic opioid treatment leads not only to the loss of the analgesic effect, but also causes abnormal opioid-mediated pain. This leads to activation of a pronociceptive system, manifested as a reduction of the nociceptive threshold.
The differences in equianalgesic potencies from opioid-naive to highly tolerant patients can be quite profound. These observations, implying the presence of incomplete cross-tolerance among opioids, have contributed to the belief that the mu-opioid analgesics differ from one another. This contradicts the concept of a uniform category of mu-receptor opioid agonists similar to morphine with respect to their mechanism of action.
Aim of opioid switching
No single opioid is optimal for all patients, although there are some clinical considerations that can aid the selection of the first opioid. After initiation and titration, the initial clinical efficacy of a given opioid may taper off gradually or abruptly, leading to increased dosages which in some cases do not provide the expected analgesia, and further dosage increments that are ineffective.
Alternatively, adverse effects may occur, that are difficult to control with symptomatic therapies. The aim of opioid switching is therefore to achieve a better clinical response in a patient who has an unfavourable balance between analgesia and adverse effects.3
What is opioid switching?
Originally called opioid rotation,4 opioid switching consists of the substitution of one opioid for another in order to obtain a more favourable clinical response. As physicians cannot predict a patient’s treatment response, the first opioid exposure should be considered as a therapeutic trial allowing determination of the individual response.
Due to asymmetric individual tolerance to opioids, it is expected that the second opioid will produce better analgesia with a lower dosage, thus limiting the occurrence of adverse effects. This substitution requires knowledge of equipotency as well as good clinical experience when selecting the dosage of the second opioid, The equivalency tables should be considered approximate in the clinical setting of opioid switching. As a consequence there is the risk of under- or over-dosage. Strict surveillance is needed until dose stabilisation, particularly in patients receiving high dosages of the first opioid.1,5
Indications and method of switching
Opioid switching is mandatory in patients who have adverse effects uncontrolled by symptomatic therapy. It is most frequently seen in patients unsuccessfully escalating opioid dosages in an attempt to improve analgesia, with adverse effects occurring before they achieve analgesia. Opioid switching may also improve analgesia with lower doses. Rapid opioid dosage escalation with poor analgesic benefit, should indicate an early need for opioid switching, as more adverse effects are likely to occur. In some cases there are associated clinical manifestations of neuronal excitability, considered an expression of hyperalgesia. The choice of conversion ratio and the general management is quite difficult in these circumstances, and requires expertise and a specialised setting for appropriate and intensive monitoring.6 Finally, there are patients who can be switched for convenience, such as when a route of administration is no longer available.
Advantages and disadvantages
Opioid switching has been reported to restore the opioid response, especially in patients where adverse effects limit further dose escalation. It has been estimated that about 80% of patients may benefit from opioid switching.1,6
Unfortunately, it is quite difficult to conduct randomised controlled studies in the setting of uncontrolled pain in the presence of adverse effects, and a formal evidence-based approach is unlikely.1 The most important problem that has arisen from the opioid-switching literature is the conversion ratio among opioids, particularly in highly tolerant patients, due to unpredictable levels of asymmetric tolerance among opioids. Switching to methadone is challenging and requires good experience and strict clinical monitoring.1
- Dr Sebastiano Mercadante is director, anaesthesia and intensive care unit, and pain relief and palliative care unit, La Maddalena Cancer Center, Palermo, Italy