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Published on 30 September 2009

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Managing breakthrough pain in cancer – current and emerging

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Breakthrough pain is a heterogeneous condition that requires comprehensive assessment and an individualised approach to treatment

Andrew Dickman
MSc MRPharm
Senior Clinical
Pharmacist
Pharmacy Department
Liverpool Heart and
Chest Hospital
Liverpool, UK
Marie Curie Hospice
Woolton
Liverpool, UK

Pain is one of the commonest symptoms that patients with cancer can expect to experience, with a prevalence of up to 90%[1] and uncontrolled pain is often described as one of the most feared symptoms of cancer. Fortunately, background cancer pain (also referred to as baseline or persistent pain) can be treated successfully in most patients. However, even with well controlled background pain, cancer patients can still experience brief exacerbations of severe pain, known as breakthrough pain (BTP). Despite a great deal of interest in this phenomenon over the past two decades, there is no universally accepted definition, which is illustrated by the fact that studies suggest between 19-95% of patients with cancer pain experience BTP.[2] Nonetheless, in 2004, an international study determined a prevalence of 65%, despite being unable to agree on a definition.[3] The lack of consensus over the definition has undoubtedly led to inadequate assessment, diagnosis and treatment.

Definition and characteristics
BTP has been described as pain that simply “breaks through” background analgesia. While not wholly incorrect, this definition is unhelpful and non-specific. For example, it does not allow for the differentiation between exacerbations caused by poorly controlled background pain, or those that occur in patients with otherwise stable background pain. In each case, the approach to treatment is different and a more precise definition would aid management. Earlier this year, the Association for Palliative Medicine of Great Britain and Ireland recommended that BTP be 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.”[4] Using this definition, two subtypes of BTP exist:

  • Incident pain – may be predictable (caused by volitional events, such as walking) or unpredictable (caused by involuntary events, such as coughing).
  • Spontaneous pain – develops randomly in the absence of a specific trigger.

The clinical features of BTP vary tremendously such that some patients may only experience one type of pain, while others may experience several distinct pains; clinical features can even vary within a patient during the course of the disease.[5] Nonetheless, BTP is usually severe in intensity and the pathophysiology is often, but not always, the same as background pain. Episodes typically reach maximum severity after 3-5 minutes, with an average duration of 15-30 minutes. In general, patients can experience between 2-4 episodes of BTP per day; any more than 4 episodes daily warrants a reassessment of the background pain and optimisation of background analgesia.[6]

Management
The aim of BTP treatment is to reduce the impact of each episode with the understanding that absolute pain relief is likely to be an unrealistic goal. Presently, there is no option that can be considered a gold-standard, although this is to be expected given the heterogeneous nature of the condition. Successful management of BTP includes the following:

  • Assessment of the characteristics of both the pain (eg, temporal profile, aetiology) and patient (eg, disease, preferences).
  • Treatment of the underlying cause (eg, radiotherapy, chemotherapy, surgery).
  •  Management or avoidance of precipitating factors (eg, constipation, cough).
  • Adjustment of background analgesia (eg, optimising opioid analgesia, addition of adjuvant analgesics).
  • Symptomatic management (employing both pharmacological and non-pharmacological modalities).
  • Re-assessment.

The traditional method of treating BTP involves the administration of involves the administration of fixed doses of normal-release oral opioid preparations of morphine, oxycodone or hydromorphone, the dose typically being one sixth of the daily background opioid dose which is based on anecdotal evidence only.[7]

In most cases, an analgesic effect would not be seen for at least 30-40 minutes and the effect could persist for up to 4 hours. Since the pharmacokinetic parameters of these oral opioids do not match the temporal profile of most episodes of BTP, the analgesia provided occurs after the BTP has spontaneously subsided. If several episodes of BTP were to occur over a 24-hour period, the patient would require multiple doses of the normal-release oral opioid, with the result that the peak intensity of BTP is never effectively treated, but undesirable effects of the drug (ie, fatigue, sedation, confusion) become problematic. This approach is certainly not the most appropriate treatment for pain of quick onset and short duration, ie, the majority of BTP episodes, but it would be suitable for BTP of slower onset and duration of an hour or more, eg, patients with predictable incident pain could be given a rescue dose of oral opioid 30 minutes before physical activity.

The ideal treatment for the majority of BTP episodes is a rescue dose of a drug with pharmacokinetic properties that closely match the temporal characteristics of the BTP, in addition to being simple to administer with minimal risk of undesirable effects, ie, a shortacting opioid with quick onset and short duration of action. One such opioid that has been subject to extensive research is fentanyl. It is rapidly absorbed across mucosal membranes, with an onset of action and duration of effect that more closely matches the profile of the ideal rescue treatment for the majority of BTP episodes. The administration of fentanyl via the buccal, intranasal or sublingual routes provides a more rapid method of drug absorption and onset of action compared with the normal-release oral opioids. There are
presently three products marketed for the treatment of
BTP (see Table 1).

In all three cases, the rescue dose that successfully treats BTP cannot be predicted from the background opioid dose and each patient’s requirements must be individually titrated (refer to Table) Actiq® lozenges represent the first product developed specifically for the treatment of BTP. The patient is required to place the lozenge in the mouth and rub against the cheek, without sucking or chewing it and it should be consumed within 15 minutes. If the patient has a dry mouth, a small amount of water can used to moisten the buccal mucosa. A significant improvement in pain is seen within 15 minutes after taking the
medication.[8]

Effentora® buccal tablets use a delivery technology based on an effervescent reaction that enhances the rate and extent of fentanyl absorption through the buccal mucosa. The tablet should be placed in the upper portion of the buccal cavity (above an upper rear molar between the cheek and gum) and it should not be sucked, chewed or swallowed, nor should the patient eat or drink anything while the tablet is in the mouth. The tablet usually disintegrates within 14-25 minutes; after 30 minutes, the mouth can be rinsed to remove the remnants. Water may be used to moisten the buccal mucosa in patients with a dry mouth. It has been shown to produce an effect within 10 minutes of administration.[9]

Abstral® sublingual tablets are the latest product to be marketed for BTP. This product uses a delivery system based on the use of ordered units of fine drug particles attached to coarser excipient carrier particles that adhere to the sublingual mucosa, permitting rapid disintegration of the tablet and optimal drug exposure. The sublingual tablets should be administered directly under the tongue and at the deepest part. The patient must not swallow, suck or chew the tablet, nor should the patient eat or drink anything until the tablet has completely dissolved (happens within less than 1 minute). Water may be used to moisten the buccal mucosa in patients with a dry mouth. Although published data are presently lacking, Abstral® is stated to produce an analgesic benefit within 10 minutes (Data on file, ProStrakan 2009)

Within the next 4 months, an additional product for BTP should become available. Instanyl® is a preparation of fentanyl for intranasal delivery. Preliminary data show this product to be an effective treatment for BTP. Further away on the horizon are several other novel fentanyl- based formulations. Nasalfent® is a nasal spray in a pectin-based formulation that is believed to improve the tolerability of the product. Phase III clinical trials have been completed and this product should be available in 2010. In the US, a fentanyl buccal soluble film (marketed as Onsolis®) has just been launched. This product uses Bio-Erodible MucoAdhesive (BEMA®) drug delivery technology, which consists of a small, bioerodible polymer film for application to the inner lining of the cheek.

Conclusion
BTP is a heterogeneous condition that requires comprehensive assessment and an individualised approach to treatment. Although the use of a fixed (proportional) dose of an oral normal-release opioid preparation as rescue medication is widespread, it cannot be recommended as the most effective treatment for BTP. The availability of three transmucosal fentanyl preparations and the promise of more will undoubtedly have a significant role in the management of BTP. Pharmacotherapy is only one aspect of the management of BTP and other strategies should be considered.

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References

1. Foley KM. Acute and chronic cancer pain syndromes. Oxford University Press Oxford; 2004.
2. Zeppetella G, et al. Cochrane Database Syst Rev 2006(1):CD004311.
3. Caraceni A, et al. Palliat Med 2004;18(3):177-83.
4. Davies AN, et al. Eur J Pain 2009;13(4):331-8.
5. Portenoy RK. Treatment of temporal variations in chronic cancer pain. Sem Oncol 1997;5(Suppl 16):S16-7-12.
6. Zeppetella G, et al. J Pain Sympt Manage 2000;20:87-92.
7. Hanks GW, et al. Br J Cancer 2001;84:587-93.
8. Mystakidou K, et al. Am J Hosp Palliat Care 2005;22:228-32.
9. Slatkin NE,et al. J Support Oncol 2007;5(7):327-334.

 



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