Pharmacologic management of adult breakthrough cancer pain

Traditional management

When the stable opioid dose for control of the background pain has been determined, the breakthrough dose is calculated. Typically, 5% to 20% (usually 10%) of the total daily analgesic dose is used as a guideline for determining the appropriate initial breakthrough dose, and this is given every hour as needed orally or every 30 minutes as needed in a subcutaneous equivalent. Another method of calculating the breakthrough dose is 50% of the every-4-hour dose (whether orally or subcutaneously). If the background dose is increased, then the breakthrough dose has to be increased accordingly.

The same medication that is used for control of the background pain is typically used as an SAO for the breakthrough pain. The common exception to this is with the use of the fentanyl transdermal patch because administering fentanyl orally is not effective and subcutaneous and transmucosal routes for fentanyl use have traditionally been limited. Usually the choice of short-acting morphine, oxycodone, or hydromorphone depends on the particular clinical situation. Approximate breakthrough doses for the fentanyl transdermal patch are shown in Table 1.¹⁰

For predictable BTCP (eg, dressing change or other procedure), the traditional SAO is given in advance (45 to 60 minutes for oral administration; 30 minutes for subcutaneous route). The Palliative Care Formulary editions provide further details on traditional approaches.^11,12

Using injectable fentanyl or sufentanil sublingually

It should be stressed that injectable fentanyl or sufentanil administered sublingually is an off-label use of these products. This option is chosen in some Canadian centres when fast-onset analgesia with short duration of action is desired but the new ROOs are not available or are believed to be too costly. The focus of the use of these medications has been predictable triggers (eg, procedures). Onset of analgesic effect is 5 to 10 minutes.¹³ There are no studies that compare this option directly with any of the new ROOs.

These are very potent medications and should be handled with care. A 10-mg dose of subcutaneous morphine, a 100-μg dose of fentanyl, and a 10-μg dose of sufentanil are approximate equivalent doses (ie, sufentanil is approximately 10 times more potent than fentanyl is). These approximate equivalent doses are for information purposes only; this information is not intended to be solely used when rotating one product to another, as incomplete cross-tolerance has to be considered.

For administering injectable fentanyl sublingually, an oral syringe or a spray bottle is used to deliver doses of 25 to 50 μg. The solution must be held in the mouth for 2 minutes. If necessary, the fentanyl dose is increased to between 50 and 100 μg; many patients do not need more than this. Fentanyl doses greater than 100 μg are impractical because 2 mL is the maximum volume that can be reliably kept in the mouth for transmucosal absorption.¹² For higher doses, consider switching to sufentanil or alfentanil.

An alternative approach is to restrict the use of injectable fentanyl to only those patients who take low-dose opioids and use sufentanil in those patients who take higher doses.¹⁰ The starting sufentanil dose is 6.25 to 12.5 μg. The peak analgesic effect of sufentanil occurs within 15 to 30 minutes and its duration of effect is 30 to 40 minutes. Sufentanil injection should be given 10 to 15 minutes in advance for incident pain control.

Rapid-onset opioids

Rapid-onset opioids are highly lipid-soluble, pure μ-opioid agonists. They were developed specifically for breakthrough pain that is rapidly escalating and of short duration (< 60 minutes) (eg, when a patient with bony metastasis is walking). The onset of analgesia for SAOs is typically 30 to 45 minutes, while for the ROOs it is 5 to 15 minutes. The SAOs often last longer than the pain episode, which results in sedation. Patients often avoid SAOs because of slow onset and prolonged duration and would rather “just put up with the pain.”

The ROOs are approved only for treatment of cancer pain and only for those cancer patients who are considered to be opioid tolerant. These are patients who take background opioid doses of at least 60 mg of oral morphine daily, at least 25 μg of transdermal fentanyl per hour, at least 30 mg of oral oxycodone daily, at least 8 mg of oral hydromorphone daily, or an equivalent dose of another opioid daily for 1 week or longer.

The dosing schedule for ROOs is a challenge for both the patient and the provider. The goal is adequate analgesia with minimal adverse effects. The guiding principle is that the background (basal) analgesic does not predict the BTCP dose. This means that the doses are titrated for all the ROOs and are not proportional to the background dose. This can be initially frustrating until the optimum dose is determined. Sometimes the initial dose chosen is inadequate to control the pain and an SAO has to be added. A higher ROO dose is then used for future breakthrough episodes. The ROO cannot be repeated until 4 hours after the SAO. Titration usually takes 24 to 48 hours and often necessitates regular contact with the patient for reassurance and advice. The maximum number of effective ROO treatments for BTCP in 24 hours is generally 4. If more treatments are required, then the background dose should be increased.

Some authorities challenge this titration principle, especially for those taking a higher background opioid dose.¹⁴ They note that those taking higher background doses tend to need higher breakthrough doses. However, there are not enough data to recommend a proportional-dose approach.

The side effect profile is typical of all opioids (sedation, somnolence, nausea, vomiting, constipation, dry mouth, fatigue, respiratory depression, etc). All ROOs also have particular local adverse effects. The ROOs are not interchangeable. The titration schedule has to be repeated if the ROO is changed. Some ROOs can be swallowed, which might give a longer-than-expected duration of effect.

Fentanyl is primarily metabolized in the liver by the enzyme cytochrome P450 3A4. Medications that inhibit this enzyme can increase the fentanyl levels and might result in sedation, other adverse effects, and fatal overdose. A partial list of inhibitors for this enzyme includes the macrolide antibiotics, azole antifungals, certain protease inhibitors (eg, ritonavir, indinavir), verapamil, aprepitant, diazepam, hydroxyzine, selective serotonin reuptake inhibitors, venlafaxine, and grapefruit juice. Medications that induce this enzyme can decrease the fentanyl levels and decrease its effectiveness. Care must be taken in starting or stopping these inducers. A partial list of inducers for this enzyme includes carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, modafinil, and St John’s wort.

Rapid-onset opioids are highly potent opioids. They must be handled safely and dosed appropriately, and the risks of diversion and poisoning must be considered. Rapid-onset opioids can be fatal to children. The Transmucosal Immediate Release Fentanyl Risk Evaluation and Mitigation Strategy program in the United States provides risk management plans for the serious risks associated with ROOs.¹⁵ Patients, pharmacists, and prescribers all must complete educational materials and registries provided for these products. A similar national program does not exist in Canada.

Table 2^8,9,16 shows a list of internationally approved ROOs. Although buccal soluble film had been previously approved in Canada and the United States, it was withdrawn mainly because of problems associated with the manufacturing process. (It is available in the United Kingdom.) Taylor¹⁷ and the Palliative Care Formulary¹¹ provide more in-depth reviews of internationally available ROOs.