Dr Andrew Davies discusses current pharmacological options and the benefits that novel formulations can bring in the management of breakthrough cancer pain

  • Breakthrough cancer pain is a specific pain syndrome
  • It requires separate treatment from background pain and management needs to be tailored to the individual
  • Oral opioid formulations are not appropriate ‘rescue’ medication for most patients with breakthrough cancer pain
  • New opioid formulations (i.e. oral transmucosal, intranasal) will generally be more suitable than oral opioid formulations in the management of breakthrough cancer pain episodes
  • The use of ‘rescue medication’ is only one aspect of the management of breakthough cancer pain

Breakthrough cancer pain (BTCP) has been defined as, ‘A transient exacerbation of pain that occurs either spontaneously, or in relation to a specific predictable or unpredictable trigger, despite relatively stable and adequately controlled background pain.’1

In 2008, the task group of the Science Committee of the Association for Palliative Medicine of Great Britain and Ireland (APM) published recommendations on the management of BTCP (see Box 1).1,2 The task group commented that, ‘On the basis of the literature, we feel unable to make recommendations about any individual interventions, but do feel able to make recommendations about certain generic strategies.1 The aim of this article is to review the continued relevance of these recommendations, particularly in view of the increasing availability of novel pharmacological interventions for BTCP (i.e. rapid onset opioids).

Box 1: Summary of the recommendations for the management of breakthrough cancer pain from the Association for Palliative Medicine of Great Britain and Ireland1
  • Patients with pain should be assessed for the presence of breakthrough pain (D)
  • Patients with breakthrough pain should have this pain specifically assessed (D)
  • The management of breakthrough pain should be individualised (D)
  • Consideration should be given to treatment of the underlying cause of the pain (D)
  • Consideration should be given to avoidance/treatment of the precipitating factors of the pain (D)
  • Consideration should be given to modification of the background analgesic regimen/‘around the clock medication’ (D)
  • Opioids are the ‘rescue medication’ of choice in the management of breakthrough pain episodes (D)
  • The dose of opioid ‘rescue medication’ should be determined by individual titration (B)
  • Non-pharmacological methods may be useful in the management of breakthrough pain episodes (D)
  • Non-opioid analgesics may be useful in the management of breakthrough pain episodes (D)
  • Interventional techniques may be useful in the management of breakthrough pain (D)
  • Patients with breakthrough pain should have this pain specifically reassessed (D)
Reproduced from Davies A, Dickman A, Reid C et al. The management of cancer-related breakthrough pain: recommendations of a task group of the Science Committee of the Association for Palliative Medicine of Great Britain and Ireland. Eur J Pain 2009; 13 (4): 331–338, with kind permission from Elsevier

Burden of breakthrough pain

It should be reiterated that clinical studies demonstrate that BTCP is a significant cause of morbidity in patients with cancer, and is associated with a number of troublesome physical (e.g. immobility), psychological (e.g. depression), and social (e.g. isolation) complications.1,3 Furthermore, health economic studies show that BTCP is associated with more frequent use of healthcare services such as increased consultations and admissions, which result in higher levels of direct (e.g. prescription costs) and indirect (e.g. transportation costs) expenditure.1,4 Breakthrough cancer pain is also associated with increased use of social services.

Current management of BTCP

Unfortunately, clinical studies suggest that cancer pain remains poorly controlled in the primary, secondary, and tertiary care settings.5 The ‘barriers to pain control’ include:6

  • healthcare system-related factors (e.g. lack of resources)
  • healthcare-professional-related factors (e.g. lack of training)
  • patient-related factors (e.g. non-adherence with treatment)
  • pain-related factors (i.e. ‘difficult to control’ pain).7

Breakthrough cancer pain is often considered a ‘difficult to control’ pain, and is associated with poor overall pain control, and not surprisingly, decreased satisfaction with overall pain control.8 Nevertheless, studies suggest that appropriate management can lead to significant improvements in BTCP.9

One of the major barriers to BTCP control is a lack of understanding about the nature of this type of pain. It is a specific pain syndrome, although the term is often used to describe any exacerbation of pain.1 The APM guideline contains a diagnostic algorithm to differentiate patients with BTCP from patients with uncontrolled background/baseline pain (Figure 1).1 It is vital to differentiate these groups of patients, since the management of BTCP is fundamentally different from the management of uncontrolled background pain. Indeed, the novel pharmacological interventions for BTCP (i.e. rapid onset opioids) should not be used in patients with uncontrolled background pain.

Further barriers to BTCP control include inadequate assessment, inappropriate treatment, inadequate reassessment, and failure to refer patients with difficult-to-control BTCP.1 The options for treatment are numerous (see Box 1, above),1 and the choice of therapy depends on a variety of different factors. Indeed, there is no ‘standard treatment’ for BTCP, and the use of rescue medication/‘breakthrough medication’ is only one aspect of the management of this pain syndrome. It should be noted that the use of oral opioid analgesics (e.g. immediate-release morphine sulphate) is not appropriate in most patients with BTCP as the onset of action of these drugs is delayed (initial effect at 20–30 minutes; peak effect at 60–90 minutes),1 and often corresponds with the spontaneous resolution of the BTCP.

Figure 1: Diagnostic algorithm for breakthrough cancer pain1

figure 1


Reproduced from Davies A, Dickman A, Reid C et al. The management of cancer-related breakthrough pain: recommendations of a task group of the Science Committee of the Association for Palliative Medicine of Great Britain and Ireland. Eur J Pain 2009; 13 (4): 331–338, with kind permission from Elsevier

Novel pharmacological interventions

Currently, there are four products with a marketing authorisation for the treatment of BTCP:10,11

  • oral transmucosal fentanyl citrate
  • fentanyl buccal tablet
  • fentanyl sublingual tablet
  • fentanyl intranasal spray.

However, a number of other products are in late-phase development. The published data suggest that these novel formulations have advantages over conventional treatments (i.e. oral opioid analgesics) in terms of quicker onset of action and shorter duration of effect.11 In other words, the pharmacodynamics of these drugs are a better match for the temporal characteristics of BTCP. However, these drugs are not a panacea for BTCP, and (as discussed above) rescue medication is only one aspect of management of BTCP.

It is clear that many patients would benefit from the novel formulations, although relatively few patients are currently being prescribed these drugs. The reasons for the lack of use of these products include widespread misconceptions about the efficacy/tolerability of oral opioid analgesics
(i.e. that oral opioid analgesics are effective in treating BTCP), concerns about the cost of the new formulations (i.e. that they are considerably more expensive than oral opioid analgesics), and concerns about the addiction/diversion risk of the new formulations. As discussed above, BTCP has a significant health economic impact, and studies suggest that these novel formulations can reduce the health economic burden.4 Moreover, there is an ethical imperative to treat cancer-related pain adequately.

The use of these novel formulations is supported by the APM guideline.1 The recommendations state that, ‘oral opioids are not the optimal rescue medication for most breakthrough pain episodes’, and that these ‘new products will offer significant advantages over the current products.’1 The authors comment that the decision to use a specific formulation should be based on a combination of the pain characteristics, the product characteristics, and in particular the patient’s preference for an individual preparation. The authors also state that it is extremely unlikely that a formulation will be developed that is suitable for all patients with BTCP.1

Currently, there are no plans to update the recommendations. However, the emergence of clinical studies comparing the novel formulations may soon enable the task group to develop new recommendations about individual interventions (as well as update the recommendations about generic strategies).

Role of the GP

General practitioners and other community based healthcare professionals have a vital role in:

  • identifying patients with BTCP
  • initiating new management strategies
  • monitoring the response to new management strategies
  • referring patients for specialist treatment.

Monitoring of patients involves assessment of the efficacy/tolerability of any intervention (and the ease of use of the intervention) and changes in the character of the BTCP over time. Specialist treatment may involve input from oncologists, palliative care specialists, interventional anaesthetists, or a range of other healthcare professionals.

Equally important, is the vital role that general practitioners and other community-based healthcare professionals play in identifying/treating patients with uncontrolled background pain (i.e. not BTCP). The management of uncontrolled background pain may involve a number of strategies, including treatment of the underlying disease,1 pharmacological interventions, non-pharmacological interventions, and interventional techniques. It should be noted that the management of uncontrolled background pain may lead to the identification of ‘true’ BTCP, and therefore the requirement of a new treatment strategy.

Conclusion

Breakthrough cancer pain is often considered a difficult-to-control pain, although studies suggest that appropriate management can lead to significant improvements in this type of pain. The APM recommendations provide a framework for management, and many of these strategies can be implemented and/or maintained within the primary care setting. An important aspect of management is the use of rescue medication, and novel pharmacological interventions (i.e. transmucosal opioids) appear to have significant advantages over conventional pharmacological interventions (i.e. oral opioids).

  • Breakthrough cancer pain is common and can be difficult to treat adequately with traditional analgesic preparations
  • The careful and thorough assessment of background and breakthrough pain is key for patients with cancer
  • The APM guideline recommends that oral opoid analgesics are not appropriate in most cases of breakthrough pain; yet they are still commonly prescribed
  • Commissioners should consider designing a local algorithm to direct both pharmacological and other therapies for breakthrough cancer pain and give confidence to primary care healthcare professionals to respond effectively to this clinical syndrome
  • Newer transmucosal agents (nasal and buccal) are effective but expensive at c. £5 a dosea
APM=Association for Palliative Medicine of Great Britain and Ireland
aBritish National Formulary. BNF 59. London: Royal Pharmaceutical Society, 2010
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  8. Zeppetella G, O’Doherty C, Collins S. Prevalence and characteristics of breakthrough pain in cancer patients admitted to a hospice. J Pain Symptom Manage 2000; 20 (2): 87–92.
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  10. Electronic Medicines Compendium website. www.emc.medicines.org.uk (accessed 25 March 2010).
  11. Breakthrough Cancer Pain website. www.breakthroughcancerpain.org (accessed 25 March 2010).G