INTRODUCTION
In 2009, a task group of the Association for Palliative Medicine of Great Britain and Ireland published recommendations on the management of breakthrough cancer pain [1]. On the basis of a review of the literature, the task group was unable to make recommendations about any individual interventions, but was able to make a series of twelve recommendations about certain generic strategies (Figure 1). The evidence was graded according to the Scottish Intercollegiate Guidelines Network grading system for recommendations in evidence-based guidelines [2]. It should be noted that most of the recommendations were based on limited evidence (i.e. grade of recommendation - D) [2]. Thus, most of the recommendations were based on non-analytical studies or so-called “expert opinion”.

The following article is an abridged version of these recommendations.

RECOMMENDATIONS

1.    Patients with pain should be assessed for the presence of breakthrough pain (Grade of recommendation - D).
It is important to differentiate patients with uncontrolled background pain experiencing transient exacerbations of that pain from patients with controlled background pain experiencing episodes of breakthrough pain. Thus, the optimal management of the former scenario may be completely different from the optimal management of the latter scenario. Moreover, adequate management of the uncontrolled background pain in the former scenario may lead to the elimination of the transient exacerbations of pain.

2.    Patients with breakthrough pain should have this pain specifically assessed (Grade of recommendation - D).
The successful management of breakthrough pain depends on adequate assessment of the patient. The objectives of assessment are to determine the aetiology of the pain, the pathophysiology of the pain, and any factors that would indicate or contra-indicate specific interventions. Inadequate assessment may lead to the utilisation of ineffective and / or inappropriate treatment.

3.    The management of breakthrough pain should be individualised (Grade of recommendation - D).
Breakthrough pain is not a single entity, but a spectrum of very different entities. The optimal management of breakthrough pain depends on a variety of pain-related factors, including the aetiology of the pain (cancer-related, treatment-related, concomitant illness), the pathophysiology of the pain (nociceptive, neuropathic, mixed), and the clinical features of the pain [3]. Moreover, the management of breakthrough pain depends on a variety of patient-related factors, including the stage of the disease (early, advanced), the performance status of the patient (good, poor), and the personal preferences of the patient.

4.    Consideration should be given to treatment of the underlying cause of the pain (Grade of recommendation - D).
In most (65-76%) cases, the underlying cause of the pain is a direct effect of the cancer [4]. The options for treatment are potentially numerous, with new treatments emerging all the time, and so it is important that there is close liaison with the relevant oncology team. It should be noted that whilst there is good evidence for the efficacy of many oncological treatments in managing background pain, there is relatively little evidence for the efficacy of these treatments in managing breakthrough pain (e.g. conventional radiotherapy). The main reason for the lack of evidence undoubtedly relates to a lack of relevant studies, rather than a lack of efficacy per se. However, there is emerging evidence to suggest certain oncological treatments may indeed be effective in managing certain types of breakthrough pain [5,6].

5.    Consideration should be given to avoidance / treatment of the precipitating factors of the pain (Grade of recommendation - D).
Avoidance or treatment of precipitating factors should be considered in patients with incident-type breakthrough pain. However, only certain precipitants are amenable to specific interventions [4].

Movement-related pain is a particularly common problem in patients with bone metastases. Many patients will benefit from strategies to minimise the amount of movement required, such as provision of simple adaptations to their surroundings, and provision of additional practical support with the activities of daily living [7].

6.    Consideration should be given to modification of the background analgesic regimen / “around the clock medication” (Grade of recommendation - D).
Modification of the background analgesic regimen has been shown to be a useful approach in managing breakthrough pain [8], and may involve one or more of the following treatment strategies:

• Titration of opioid analgesics – titrating the opioid can be effective in reducing the intensity and / or frequency of movement-related volitional incident pain [9].  However, this strategy is often limited by the existence / development of dose-dependent adverse effects (e.g. sedation) [10].
• Switching of opioid analgesics – switching the opioid and / or the route of administration of the opioid can also be effective in reducing the severity of movement-related volitional incident pain [11,12].
• Addition of “adjuvant analgesics” – adjuvant analgesics (“co-analgesics”) are agents whose primary function is not analgesia, but which provide pain relief in certain circumstances. This strategy can be effective in reducing the impact of specific breakthrough pain syndromes (e.g. antiepileptics for neuropathic pain, antispasmodics for visceral pain) [13].
• Addition of other “adjuvant drugs” – adjuvant drugs are agents whose function is not analgesia, but which provide relief from the adverse effects of analgesic drugs (or the complications of the pain). This strategy can be effective in allowing titration of the analgesic drugs, which in turn can be effective in reducing the impact of breakthrough pain (e.g. psychostimulants for opioid-related sedation) [14].
• Other strategies – in theory, alteration and / or addition of non-opioid analgesic drugs could also lead to improvements in breakthrough pain (e.g. paracetamol, non-steroidal anti-inflammatory drugs) [13].

7.    Opioids are the “rescue medication” of choice in the management of breakthrough pain episodes (Grade of recommendation - D).
The cornerstone of the management of breakthrough pain episodes is the use of so-called “rescue medication”. Rescue medication is taken as required, rather than on a regular basis: in the case of spontaneous pain or non-volitional incident pain the treatment should be taken at the onset of the breakthrough pain; in the case of volitional incident pain or procedural pain the treatment should be taken before the relevant precipitant of the pain. In most cases the most appropriate rescue medication will be an opioid analgesic, rather than a non-opioid or an adjuvant analgesic.

The decision to use a specific opioid preparation should be based on a combination of the pain characteristics (onset, duration), the product characteristics (pharmacokinetics, pharmacodynamics), the patient’s previous response to opioids (efficacy, tolerability), and particularly the patient’s preference for an individual preparation. Indeed, it is extremely unlikely that any one opioid preparation will be suitable for all patients with breakthrough pain.

8.    The dose of opioid “rescue medication” should be determined by individual titration (Grade of recommendation - B).
Traditionally, it has been advised that the dose of opioid rescue medication should be a fixed proportion of the dose of the opioid background medication. Data from controlled trials with oral transmucosal fentanyl formulations suggest that there is no relationship between the most effective dose of these preparations and the effective dose of the background opioid medication [15-19]. Moreover, data from one of these studies suggests that there may be no relationship between the most effective dose of oral morphine for breakthrough pain and the effective dose of the background opioid medication [17]. Thus, on the basis of the emerging data with newer products, and anecdotal data with conventional products [17,20], the task group recommends that the dose of all opioid rescue medication should be determined by individual titration (Figure 2).

9.    Non-pharmacological methods may be useful in the management of breakthrough pain episodes (Grade of recommendation - D).
A variety of non-pharmacological methods are used by patients, including rubbing / massage [21,22], application of heat [21,22], application of cold [21,23], distraction techniques [10,23], and relaxation techniques [10,21]. However, there is relatively little evidence to support the use of these interventions in the treatment of breakthrough pain episodes.

10.    Non-opioid analgesics may be useful in the management of breakthrough pain episodes (Grade of recommendation - D).
Paracetamol (acetaminophen) is sometimes used by patients to treat breakthrough pain episodes [24,25], although there appears to be little or no data on its use in this situation. It has an onset of action of 15-30 min when administered via the oral route [26]. Similarly, non-steroidal anti-inflammatory drugs (NSAIDs) are sometimes used by patients to treat breakthrough pain episodes [24,25], although again there appears to be little or no data on their use in this situation. Ibuprofen has an onset of action of 15-25 min when administered via the oral route (and a peak effect at 30-90 min) [26]. Other NSAIDs have a somewhat longer onset of action (i.e. 30-60 min) [26].

A number of other non-opioid analgesics have been utilised by clinicians to manage episodes of breakthrough pain, including ketamine [27], midazolam [28] and nitrous oxide [29]. Again, there is relatively little evidence to support the use of these interventions in the treatment of breakthrough pain episodes. Nevertheless, these interventions probably have a role to play in the management of certain patients with breakthrough pain.

11.    Interventional techniques may be useful in the management of breakthrough pain (Grade of recommendation - D).
Interventional anaesthetic techniques may be required to manage certain clinical problems associated with breakthrough pain. A variety of different techniques are available [30], including neuraxial drug infusion [11], neural blockade [31], neuromodulation (e.g. transcutaneous nerve stimulation: TENS) [32], and neuroablation [7]. Similarly, interventional radiological techniques may also be useful to manage certain clinical problems associated with breakthrough pain. Again a variety of different techniques are available [33], including direct tumour ablation, cementoplasty (e.g. vertebroplasty) [34], and balloon kyphoplasty.

12.    Patients with breakthrough pain should have this pain specifically re-assessed (Grade of recommendation - D).
The successful management of breakthrough pain depends on adequate re-assessment of the patient. The objectives of re-assessment are to determine the efficacy of the treatment, the tolerability of the treatment, and any change in the nature of the breakthrough pain. Inadequate re-assessment may lead to the continuance of ineffective and / or inappropriate treatment.

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