Breakthrough cancer pain (BTcP) is 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.” Background pain, also known as ‘baseline pain’ and ‘persistent pain’, refers to ‘constant or continuous pain of long duration’.²

Characteristics of BTcP

BTcP is reported to affect up to 95% of all cancer patients who experience pain.³ Although variable, a typical BTcP episode is:

• Rapid in onset (median onset to peak pain intensity ~3-5 minutes)³
• Severe to excruciating in intensity^3,4
• Short-lived, with a median duration of 30-45 minutes^3,4
• Largely unpredictable in nature.^3-5

BTcP can have a significant negative impact on patients’ quality of life and it can be associated with increased health care costs through additional healthcare professional interactions, hospital admissions and longer inpatient hospital stays.^3,6

Traditional management approach to BTcP

The use of a pharmacological opioid ‘rescue’ dose has traditionally been used in the management of BTcP. Here, a supplemental ‘as required’ dose of analgesia is given along with the regularly scheduled baseline opioid using the same route of administration for both. The ‘rescue’ dose is titrated in line with the baseline dose (See Table 1).⁷

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A major limitation of these short-acting opioids is their relatively slow onset of action. Oral hydrophilic opioids, such as morphine, oxycodone, and hydromorphone, have a delayed absorption and, following oral administration, the average time for onset of pain relief is 30 minutes with an average duration of effect of four hours, by which time the BTcP episode may have come and gone. 

New routes of administration

One of the most extensively studied novel routes for medication administration is the transmucosal route. The oral mucosa has many advantages for systemic drug delivery. It is easily accessible, convenient, non-invasive, non-threatening and does not require technical equipment, expertise, preparation or supervision. 

The oral mucosa is highly vascularised, highly permeable and has a large surface area and uniform temperature, all of which facilitate rapid absorption. Oral transmucosal drug delivery avoids first pass metabolism and has properties of onset and peak activity similar to those of intravenous morphine. 

Nasal delivery of medications is associated with high patient acceptability and familiarity and this non-invasive route has been widely used in the delivery of medications in rhinitis, nasal congestion and migraine. Nasal delivery of medications does not suit hydrophilic medications, ie. morphine, however lipophilic drugs, ie. fentanyl, are rapidly and extensively absorbed via this route. 

Dose delivery can be precisely controlled via an easy to use metered nasal spray. Nasal delivery also avoids issues with oral pathologies eg. dry or ulcerated buccal membrane or in cases of nausea or vomiting.

Fentanyl

The ideal analgesic for the treatment of BTcP is an analgesic with good efficacy and potency, a rapid onset of action, a relatively short duration of action with minimal side-effects and a good safety profile. It also needs to be easy to administer and should be inexpensive (see Table 2).⁸

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Fentanyl is a potent, short-acting and well-established opioid, with many years of clinical use as an analgesic and is an ideal molecule for the treatment of BTcP. It is a synthetic opioid and, like morphine, it is a strong mu opioid receptor agonist but is approximately 100-fold more potent than morphine.⁹ It is absorbed faster than morphine, with a shorter half life.^10-12 Due to its high lipid solubility, fentanyl is distributed in all human tissues and, in contrast with morphine, crosses the blood-brain barrier easily and quickly, which explains its strong analgesic effect. Its high lipid solubility thus makes it ideal for delivery via a variety of routes including transmucosal, buccal, sublingual and nasal absorption. Fentanyl also has a lower intensity of the common adverse-effects associated with a central (nausea and vomiting) and peripheral (constipation) mode of action.

Fentanyl formulations

Oral transmucosal fentanyl citrate (Actiq)

Oral transmucosal fentanyl citrate (OTFC [Actiq]) was the first approved rapid-onset opioid. Each OTFC unit consists of a lozenge containing fentanyl on a handle. The lozenge is applied to the buccal mucosa, and as it dissolves in saliva, a proportion of the drug diffuses across the oral mucosa. The patient is required to move the lozenge around in the mouth and twirl the handle for a period of 15 minutes. 

Approximately 25% of the total dose of OTFC is rapidly absorbed from the buccal mucosa and becomes systemically available; the remaining 75% of the total dose is swallowed with the saliva and then is slowly absorbed from the gastrointestinal (GI) tract.^13,14 Transmucosal absorption into the bloodstream is rapid, with peak plasma concentrations achieved in 20 minutes with the onset of meaningful pain relief reported as < 10 minutes.^15,16

Several studies have shown the superiority of OTFC over placebo and over oral morphine in the treatment of BTcP.^7,17 As OTFC requires active patient collaboration, it may not be suitable for all patients.

Fentanyl buccatablet (Effentora)

Fentanyl buccal tablet (FBT [Effentora]) is an emerging treatment for BTcP, which uses the OraVescent delivery system. Buccal delivery generates release of CO2 and the OraVescent technology is designed to enhance dissolution and absorption of fentanyl and minimises first-pass effect. The tablet must be left in place for 15-25 minutes until it is dissolved. 

Approximately 50% of the total dose of FBT is absorbed transmucosally and becomes systemically available; the remaining half of the dose is swallowed and undergoes more prolonged absorption from the GI tract.¹⁸ Randomised controlled trials evaluating FBT have reported improvements in BTcP intensity within 10 minutes of administration among patients with chronic low back pain, non-cancer neuropathic pain and cancer-related breakthrough pain.^19-21 Availability of FBT has been shown to be higher in comparison with OTFC.^14,22 Effentora is also now licensed to be given sublingually as well as buccally.¹⁸

Sublingual fentanyl tablet (Abstral)

Abstral is a new sublingual fentanyl formulation with pharmacokinetics closely matching the profile of BTcP. Formulated as a rapidly disintegrating muco-adhesive sublingual tablet, Abstral is highly lipophilic with the fentanyl dissolving almost instantly and the active substance absorbed via the mucous membrane.²³

Abstral’s innovative technology means it requires less than 1ml of fluid to dissolve.  It is highly potent, crossing the blood-brain barrier rapidly in both directions, avoiding first-pass metabolism by the liver enzymes and offering approximately 70% bioavailability.²⁴ Studies have shown that the onset of pain relief was significantly faster for Abstral compared with placebo with significant differences evident at 10 minutes after administration and pain relief was sustained for 60 minutes.²⁴

Fentanyl pectin nasal spray (PecFent)

PecFent is a fentanyl pectin nasal spray powered by the innovative PecSys technology which enables rapid but controlled absorption of fentanyl. PecFent is a low volume, aqueous mist of similarly sized droplets delivered to the front areas of the nasal cavity. This technology ensures that the droplets gel when they come into contact with the nasal mucosal surface and thus enables rapid but controlled absorption of fentanyl through a gel matrix.^25-27

It has been shown to provide rapid onset to clinically meaningful pain relief at 10 minutes, consistent efficacy and high patient scores for acceptability, simplicity and convenience of use.^26,28,29 It has also been shown to be well tolerated with no significant nasal side-effects reported.^4,30

Intranasal fentanyl spray (Instanyl)

Intranasal fentanyl spray (IFNS, Instanyl) is another fast-acting nasal opioid approved for the management of BTcP. It bypasses the oral/GI route and thus offers advantages to patients with nausea or vomiting, oral mucositis and impaired gastrointestinal function. 

In an open-label, randomised, crossover trial, significantly more patients attained faster ‘meaningful’ pain relief with INFS than OTFC with more patients preferring INFS to OTFC.^31,32  The recent launch of the single-dose nasal spray will provide greater flexibility to patients and help to manage dose titration and dose modification, which together with the nasal spray’s safety and convenience should contribute to further improving the management of BTcP. 

Safety and practical considerations

In general, transmucosal products are well-tolerated and effective analgesics for BTcP. It is important to note that all these formulations require individual titration. The effective dose for relief of BTcP cannot be predicted from the regularly scheduled baseline opioid or from the previous rescue medication. These newer fentanyl formulations are only licensed for the management of cancer-related breakthrough pain and for patients on maintenance opioid therapy for chronic pain. Concerns exist over the cost of these agents, as well as the appropriate dose titration. Potential also exists for misuse. These formulations are not bio-equivalent, thus 100µg of Abstral does not equate with 100µg of Effentora. Therefore, contrary to what is considered best prescribing practice for other drugs, it is important that these agents are prescribed using proprietary rather that generic names.

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Conclusion

BTcP is an important clinical problem, often significantly impacting on a patients’ quality of life. It is likely that the new fentanyl agents will offer advantages over some of the more traditional products. It is vital that these agents are prescribed by a physician experienced in the management of opioid therapy in cancer patients. Adequate assessment and reassessment, along with titration of different analgesics and doses, tailored to the needs of the individual leads to the best management of this heterogeneous condition.

References

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