Specialist Palliative Care Pharmacist
St Christopher’s Hospice
Cancer pain is normally present most of the time, and if a patient presents with pain the choice of analgesic is based on the principles of the World Health Organization cancer pain relief guidance.1 This three-step analgesic ladder has been a useful tool for more than 40 years (see Figure 1). If pain occurs, there should be prompt administration of drugs in the following order: non-opioids (aspirin and paracetamol); then, as necessary, mild opioids (codeine); then strong opioids such as morphine; if pain is present, increasing levels of analgesia should be administered rather than maintaining analgesia at the same ‘rung’ of the ladder.
Once patients require strong opioids, the dose will be titrated, as illustrated by Figure 2 (Titrating the dose). This is normally done using an immediate-release opioid (ideally morphine four-hourly) although a few practitioners titrate with slow-release products from the start. Although the overall aim is to provide effective and complete analgesia around the clock, this is not always possible. However, if pain relief is achieved by the same four-hourly dose after approximately 48 hours, the prescription will usually be converted to an equivalent dose of a slow-release opioid for patient convenience. When this is prescribed, it has become regular practice to provide a dose for ‘breakthrough pain’, which has traditionally been one sixth of the total daily dose, i.e. equating to the four-hourly dose.
What is breakthrough pain?
Breakthrough pain is defined as ‘an abrupt, short-lived and intense pain that ’breaks through’ the round-the-clock analgesia that controls persistent pain.’2 However, it has been used historically to describe a number of different pain phenomena such as:
- Incident pain – related to specific triggers such as movement, changing wound dressings, and coughing
- Spontaneous pain – sometimes idiopathic and often unrelated to the cancer pain
- End of dose failure – when pain returns before the next dose of regular analgesia is due.
Management of breakthrough pain
Now the different causes of breakthrough pain have been established, the management can be approached in a more and appropriate way.
Incident pain can usually be predicted because it occurs in response to an obvious physical activity. Patients might be comfortable at rest while taking their regular medication but pain can start if they need to move – perhaps on standing, on going to the toilet or if a procedure is required. The duration of the pain correlates closely to the activity, and its duration can be variable.
Spontaneous pain is often idiopathic, indicating the pain is caused by damage or irritation to a nerve, may have a neuropathic element and can reach a crescendo between three and five minutes. This type of pain typically lasts for no longer than 30 minutes.
End of dose failure
End of dose failure signifies that it is time to increase the background opioid dose. The usual step is to increase the total daily dose by between 30% and 50% (see Figure 2) but there is a small number of patients who metabolise opioids quickly and very occasionally, it is appropriate to shorten the dose interval.3 Similarly there are anecdotal reports of patients needing a new fentanyl patch applied after 48 hours rather than the usual 72 hours, but prescribing in this way is only appropriate with specialist palliative care guidance.
Is the ‘four-hourly dose’ best for pain management?
As mentioned, the traditional treatment for breakthrough pain has been to administer the equivalent of the fourhourly dose of morphine or, alternatively, oxycodone. However, the onset of analgesic action for oral morphine preparations is around 20-30 minutes and the effects last for four hours. Oxycodone provides analgesia for between four and six hours. The logic of using drugs and formulations with this profile for all types of breakthrough pain is clearly questionable. There is evidence that most spontaneous pain lasts for no longer than 30 minutes3 so by the time the oral preparation begins to work, the pain may have subsided, andthe patient having been treated with a dose of strong opioid unnecessarily. In such scenarios, patients are likely to experience increased side effects such as drowsiness. This is also the case if these drugs are used for short-lived episodes of incident pain. Now that other drugs have come onto the market, it is time to take a closer look at this highly significant area of therapeutics.
An expert working group of the European Association for Palliative Care produced a consensus document in 2002.4 A task group of the Science Committee of the Association for Palliative Medicine of Great Britain and Ireland was convened in 2009 with a view to produce up to date, evidence-based and practical clinical guidelines. These were published in the European Journal of Pain and offer a clearer view and some new approaches to the management of breakthrough pain.5 As a result breakthrough pain is now 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.”6
In the opinion of these experts, the term ‘breakthrough pain’ should be reserved only for pain that fits the criteria specified and should not be used for end of dose failure or the pain that occurs during the titration process. Studies of the prevalence of breakthrough pain show that most patients report an average of four episodes in 24 hours.6 The current opinion is that if a patient is reporting more than four episodes then the strategy for managing his/her pain needs to be reviewed. It is not always easy to differentiate uncontrolled background pain from controlled pain interspersed with episodes of breakthrough pain especially if there are many episodes of breakthrough pain. In such cases, achieving better management of the background pain by increasing the dose of regular opioid could mean that management of breakthrough pain becomes unnecessary. However, a thorough assessment should make the picture clearer; although there is no validated tool for assessing breakthrough pain, standard pain questionnaires are available and can be used. Some of the questions could include:
- Onset of pain
- Frequency of pain
- Site of pain
- Radiation of pain
- Quality (character) of pain
- Intensity (severity) of pain
- Duration of pain
- Exacerbating factors
- Relieving factors
- Response to current/past analgesia
- Response to other interventions
- Associated symptoms
- Interferences with the activities of daily living.
Once a comprehensive picture of the pain is ascertained, a treatment protocol can be devised. Effective pain management must always be individualised. This is because pain is often multi-factoral, and might have a variety of pathophysiologies, and that each patient reacts to analgesics in individual, and sometimes unpredictable, ways.7
The traditional treatment of breakthrough pain has been with ‘normal-release’ morphine and, more recently, with oxycodone. The practice of using these drugs is not evidence based and since the introduction of newer products, their use has been questioned. Because the onset of the average episode of breakthrough pain is within minutes and lasts for about half an hour, we perhaps need to question whether the pharmacokinetic profile of morphine makes it the best choice for treatment. In many episodes of ‘typical’ breakthrough pain, the pain will have come and gone before morphine has started to work. A range of fentanyl products is now available, which have been produced and licensed specifically to manage breakthrough pain in cancer. Fentanyl is lipophilic and is absorbed rapidly through mucous membranes and has been formulated into oral transmucosal lozenges, buccal and sublingual tablets, and nasal sprays. The data for the products vary but pain relief should be obtained within 10-15 minutes depending on the product. Fentanyl has a much shorter duration of action than morphine or oxycodone. The first product to be marketed (oral, transmucosal fentanyl citrate; Actiq®) has been the subject of a Cochrane review.8 The review concluded that the drug was an effective treatment for breakthrough pain and produced more rapid and more effective analgesia than oral. This novel product is in ‘lollipop’ form and requires the patient to move the lozenge on the stick around the inside of the mouth for 15 minutes to obtain full pain relief. Some patients find this difficult as they tire easily, and the lozenge is not easy to use if the patient has a very dry mouth.
However, this formulation permits patients to control the level of analgesia they need for a specific episode because the lozenge can be removed easily once they are free from pain. The newer formulations dissolve rapidly under the tongue with a sip of water to moisten the mouth if required. In addition, nasal sprays are available to patients who are not suited to using buccal or sublingual products.
Whichever fentanyl product is chosen, the titration of the dose involves a completely new way of thought. Rather than take a proportion of the total daily dose of opioid, the fentanyl dose is titrated according to the pain experienced. Most of these products have a lowest dose of 100 microgram fentanyl and all offer detailed prescribing guidance for titrating up the dose range if necessary.
Prescribers must refer to the summary of product characteristics for each product and also ensure that they specify the trade name when prescribing as the products are not interchangeable. All of the products are licensed only for patients with cancer-related breakthrough pain who are currently on a stable dose of 60mg oral morphine in 24 hours or a 25 microgram/hour fentanyl patch or equivalent. This is extremely important because to use a potent, strong opioid with fast onset would be very dangerous in an opioid-naïve patient because it could induce respiratory depression.
It could be some time before a consensus is available that governs which immediate-release opioid is best suited for breakthrough pain in any given scenario. It may be that it is preferable to use morphine in advance of a period of movement or complicated dressing change whereas it may be preferable to use a fentanyl product during a potentially shorter period of incident pain, such as during toileting. Although the fentanyl citrate nasal spray has an approximate duration of action of 30 minutes, there is also some uncertainty as to the duration of long the buccal and sublingual fentanyl products in the system. It is now common to see prescriptions for a range of opioids because it is not always necessary to use the same drug for both round-the-clock and breakthrough pain. In the meantime, a wider range of products for the effective management of breakthrough pain in cancer is now available and a growing body of evidence to allow us to manage this problematic symptom for our patients more safely and effectively.
1. World Health Organization. Cancer Pain Relief. 2nd edn. Geneva, World Health Organization; 1996
2. Bennett D. Pharmacy Ther 2005;30: 296–301
3. Adams D et al. Pain Medicine 2002;3:185.
4. Mercadante S et al. Cancer 2002;94; 832–9
5. Davies A et al. Eur J Pain 2009;331–8
6. Zeppetella G et al. J Pain Sympt Manage 2000;20:87–92
7. Davies A ed. Cancer-related Breakthrough Pain. Oxford: Oxford University Press 2006;31–32
8. Zeppetella G & Ribiero M. Opioids for the management of breakthrough (episodic) pain in cancer patients. Cochrane Database Syst Rev 2006(1):CD0004311