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Abstract

Breakthrough pain (BTP) management is an unmet clinical need. BTP is poorly diagnosed, rarely evaluated and inadequately treated. BTP is transitory exacerbation of pain experienced by the patient who has relatively stable and adequately controlled baseline pain. BTP is reported to be common in adults and children with cancer as well as in non-cancer diseases associated with acute/chronic pain. Successful management of breakthrough pain depends on adequate assessment, appropriate treatment (cause of pain and symptomatic) and adequate reassessment. Ideal medication for BTP should be characterized with good efficacy and minimal side effects. Pharmacodynamic profile should mimic dynamics of BTP. Strong, short acting analgesics (e.g. opioids) administrated by route which allow quick action had potential to fulfil criteria for ideal ‘rescue’ medication for BTP. Fentanyl Buccal tablets (FBT; Fentora^®, Frazer, PA, Cephalon Inc.) is novel delivery system for fentanyl citrate. FBT utilize OraVescent (r) technology to improve bioavability and speed of transmucosal delivery. Alternate routes of administration could further improve efficacy of BTP management. Intranasal and intrapulmonary routes are under exploration. Recently introduced new delivery systems for opioids medication do represent an improvements in BTP management, however BTP is still a major challenge to pain and palliative physicians.

Keywords

cancer pain breakthrough pain opioids analgesia fentanyl buccal tablets

Introduction

Breakthrough pain (BTP) remains on of the most challenging clinical problems for physicians and patients alike. Itt is poorly diagnosed, rarely evaluated and inadequately treated.¹ BTP is reported to be common in adults and children with cancer^2–6 as well as in non-cancer syndromes associated with acute/chronic pain.^7,8 Currently there is growing interest in BTP management generated by a greater awareness of the problem of breakthrough pain (secondary to improvement in the management of background pain) as well as its significant negative impact on quality of life, and fuelled by an increasing range of pharmacological options for the treatment of breakthrough pain.⁹ BTP has a significant negative impact on quality of life.^10,11 Complications of BTP are summarized in Table 1.^3,5,10–12

Table 1

Breakthrough pain could lead to following complications.

•

Physical (decreased functioning)–-predominantly due to mobilizing difficulty and sleep disturbances

•

Psychological–-predominantly mood disturbances, anxiety and depression

•

Social–-predominantly due to movement related pain

•

Economical–-BTP is associated with increased use of health care services (e.g. longer stays in hospital) which lead to an increase in costs for the health service, patient and their corers

Definition of BTP

BTP is a transitory exacerbation of pain experienced by a patient who has relatively stable and adequately controlled baseline pain.¹³ Bennett proposed a similar definition: BTP is an abrupt, short lived and intense pain that ‘breaks through’ the around the clock analgesia that controls persistent pain.¹⁴ Other names include: episodic pain, exacerbation of pain, pain flare, transient pain, transitory pain.⁹ The Expert Working Group of the European Association for Palliative Care (EAPC) has suggested that the term ‘breakthrough pain’ should be replaced by the terms ‘episodic pain’ or ‘transient pain’.¹⁵ Common clinical features of BTP are summarized in Table 2.¹⁰

Table 2

Common clinical features of breakthrough pain.

•

Frequent in occurrence

•

Acute in onset

•

Short in duration

•

Moderate to severe in intensity

•

Related to background pain

Classification of BTP

Classification of BTP is presented in Table 3 (modified from¹²). End-of dose failure is not a subtype of breakthrough pain it should rather be simply classified as inadequately controlled pain.¹² Patients with no background pain but who have severe episodic bouts of pain are classified as having transitory pain¹⁶ and patients with poorly controlled background pain with or without severe transitory episodic exacerbations of pain are classified as having uncontrolled pain.¹⁶

Table 3

Classification of breakthrough pain.

•

Spontaneous pain (idiopathic pain)–-pain occurs unexpectedly

•

Incident pain (precipitated pain)–-pain related to specific event^*

•

Volitional incident pain–-precipitated by voluntary act (e.g. walking)

•

Non-volitional incident–-pain precipitated by involuntary act (e.g. coughing)

•

Procedural pain–-related to a therapeutical interventions (e.g. wound dressing)

•

End of dose failure–-due to insufficient overall dose of opioids^**

Incident pain related to movement (volitional or non-volitional) is called movement related pain.

Often not regarded as true breakthrough pain.

Prevalence of BTP

In a recent international survey, clinicians reported BTP in 23%–90% of adult cancer patients,^{3–6,11,16–19} and 74% in opioids treated non-cancer pain patients.⁸ BTP appears to be more common in patients with advance disease.²⁰ In majority of studies the prevalence of incident related BTP (range 43%–64%) was higher than the prevalence of spontaneous BTP (relevance range: 17%–38%).^{4,10,11,16,19} Only one study observed opposite prevalence (spontaneous 59%, incident 24%).⁶ Prevalence of BTP varies between different groups of patients²¹ and is affected by certain language/geographical variables.^17,22 BTP is a poor prognostic indicator.²³

Assessment of BTP

Breakthrough pain is not a single entity, but a spectrum of very different entities. The clinical features vary from individual to individual, and may vary within individuals over time.²⁴ Table 4 summarizes diagnostic criteria for BTP.¹⁶ Successful management of breakthrough pain depends on adequate assessment²⁵ (Table 5), appropriate treatment (cause of pain and symptomatic) and adequate reassessment.²⁶ Many patients have more than one type of breakthrough pain^10,16 and an association between the presence of breakthrough pain and the intensity/frequency of the background pain has been reported.^10,17 Circadian variation in the occurrence of BTP has been reported (86% patients experienced BTP during day and only 45% during night).⁴ Formal assessment tools for BTP are presented in Table 6.^12,16,27

Table 4

Diagnostic criteria for breakthrough pain.

•

The presence of stable analgesia in the previous 48 hours

•

The presence of controlled background pain in the previous 24 hours

•

The presence of temporary flares of severe or excruciating pain in the previous 24 hours

Table 5

Assessment of pain.

•

Onset of pain

•

Temporal pattern of pain

•

Site of pain

•

Radiation of pain

•

Quality of pain

•

Intensity of pain

•

exacerbating factors

•

Relieving factors

•

Response to analgesics

•

Response to other interventions

•

Associated physical symptoms

•

Associated psychological symptoms

•

Interference with daily activities

Table 6

Tools for assessment of BTP.

•

Breakthrough pain assessment algorithm (developed by portenoy R)

•

Episodic pain documentation sheet (Zappatello 2002)

•

Breakthrough pain questionnaires (Portenoy 1990) with later modifications

Treatments of BTP

Holistic/multimodal approachs for BTP treatment have been proposed. Principles of BTP management²⁴ are presented in Table 7. Physical, pharmacological, neuro-modulatory treatments and invasive procedures are used in BTP management^{4,12,15,18,21,24,28–33} (Table 8). Pharmacological management should be tailored to the type of breakthrough pain^34–36 (Table 9).

Table 7

Principles of BTP management.

•

Implementing primary therapies (surgery, radiotherapy, chemotherapy)

•

Optimising around the clock medication (long acting medication)

•

Specific pharmacological interventions (short acting, ‘recue’ medication)

Table 8

Treatment options for BTP.

•

Physical

•

Rubbing/massage

•

Application of heat

•

Application of cold

•

TENS (transcutaneous electric stimulation)

•

Distraction

•

Relaxation

•

Hypnotherapy/hypnosis

•

Pharmacological

•

Modification of the background analgesic regimen

•

Increase dose of analgesic

•

Using stronger analgesic

•

Opioid rotation

•

Addition of another analgesic

•

Addition of co-analgesic (predominantly: anticonvulsants, antidepressant)

•

Use of breakthrough (‘rescue’) analgesic

•

Non opioid analgesic: Paracetamol, NSAID, Ketamine, Nitrous oxide

•

Opioid analgesics: Morphine, fentanyl, diamorphine, codeine, hydrocodeine

•

Other medication (e.g. midazolam–-BTP due to muscle spasm)

•

Invasive procedures

•

Nerve blockade

•

Peripheral nerve blokade

•

Single injection of local anaesthetics

•

Single injection of local anaesthetics with adjuvant (e.g. corticosteroids)

•

Continous peripherial nerve/plexus blockade

•

Neuroaxial nerve blokade

•

Epidural injection/infusion

•

Intrathecal injection/infusion

•

Surgical procedures (e.g. surgical stabilization of relevant bone(s) or use of orthotic device)

•

Neuromodulatory

•

TENS

•

Spinal cord stimulation–-no data available for BTP, however this technique could deliver analgesia on-demmand, thus potentially could be effective for BTP

•

Accunpuncutre–-it is postulated that acupuncture can provide acute and prolonged pain relief. There is no data about efficacy of acupuncture for BTP

Table 9

Specific treatments for different types of breakthrough pain.

•

Incident pain

•

Pre-emptive use of a short acting opioid 30 minutes before activity

•

Initially use the same as the four-hourly dose of normal-release morphine (approximately 16% of the daily dose) when necessary

•

Titrate the dose of rescue medication

•

Idiopathic/spontaneous

•

Oral transmucosal fentanyl citrate (OTFC) was shown to be an effective treatment for breakthrough pain

•

End of dose failure

•

Alter the around the clock medication to increase the dose

Ideal ‘Rescue’ Medication for BTP

The ideal medication for BTP should be characterized by good efficacy and minimal side effects. The pharmacodynamic profile should mimic the dynamics of BTP (Table 10). A potent, short acting analgesic (e.g. opioid) administrated by a route which allows for a rapid onset of action has the potential to fulfil the criteria for an ideal ‘rescue’ medication for BTP. A new class of opioids, Rapid Onset Opioids (ROOs), has been developed in an attempt to address the “unmet need” of breakthrough pain management.

Table 10

Features of ideal ‘rescue’ medication for breakthrough pain.

•

Good efficacy

•

Rapid onset of action

•

Short duration of action

•

Minimal adverse effects

Patients on chronic intake of opioids would have developed some tolerance to opioid side effects. Since the side effects associated with taking a breakthrough dose of opioid are similar to those associated with taking any dose of opioids (e.g. somnolence, nausea, vomiting, and dizziness);³⁷ one can infer that significant increse in the intensity of side effects from BTP medications should be less likely to occur when BTP medication is administered to an opioid tolerant patient. This concept led to the use of these potent ROOs only in opioid tolerant patients. While only approved for use in cancer pain, the utility of ROOs for pain in opioid tolerant non-cancer pain patients has been reported.^38–40

Traditionally it has been suggested that one should use the same opioid to treat background and breakthrough pain.⁴¹ The current approach utilizes opioids according to their pharmacodynamic properties and their pharmakokinetics: long acting for background pain and short acting (and preferably rapid onset) for breakthrough pain. Sometimes the same opioid is used for background and BTP as when a fentanyl patch is used to treat background pain and a rapid onset buccal or nasal fentanyl (transmucosal) preparation is used to treat BTP. At other times an opioid such as a controlled or sustained release morphine product is used for background pain and a transmucosal fentanyl is used for breakthrough pain.¹²

Traditionally, it was recommended to use a fixed ratio of the total daily dose of opioids to treat the breakthrough pain.⁴¹ Randomize trials have demonstrated that there is no correlation between the dose of opioid needed to control background pain and the dose of OTFC needed to control the breakthrough pain.^37,42,43 Thus, the dose of breakthrough pain medication should be titrated in the same manner as dose of background medication.¹⁵ That is, the background pain medication and the BTP medication should be titrated independently. The World Health Organization (WHO) guidelines promote the use of the oral route for the management of cancer pain.⁴⁴ There route has the highest patient acceptability for route of administration.⁴⁵ The oral route is usually effective for the treatment of background pain; however, there are significant disadvantage of the oral route for breakthrough pain management. The oral route is associated with delayed onset of action (~20–30 minutes for oral morphine),⁴⁶ delayed peak effect (~60 minute for oral morphine)¹⁵ and long duration of action (~3–6 hours).⁴⁶ Advantages and disadvantages of the oral route for BTP management^{12,15,41,45–47} are summarized in Table 11. Alternative routes of administration was proposed: oral transmucosal^{5,14,37,42,43,48}Intravenous,⁴⁹ Subcutaneous,⁵⁰ Intranasal,⁵¹ and Intrapulmonary.⁵²

Table 11

Oral route for BTP ‘rescue’ medications.

•

Advantages of oral route

•

Familiar/acceptable for patients and healthcare professionals

•

Convenient for patients and healthcare professionals

•

Large variety of opioid drugs and formulation available

•

Cost effective

•

Disadvantages of oral route

•

Not suitable for patient suffering for

•

Dysphasia

•

Nausea

•

Vomiting

•

Dysfunction of upper gastrointestinal tract

•

Variation in oral bioavability

•

Slow onset of action (~20–30 minutes for oral morphine)

•

Delayed peak effect (~60 minute for oral morphine)

•

Long duration of action (~3–6 hours)

•

Some oral preparation contain alcohol (e.g. Oromorph oral solution 10 mg/5 ml) which makes them unsuitable for use in patients with certain religious beliefs

Fentanyl Buccal Tablets

The fentanyl buccal tablet (FBT; Fentora^®, Frazer, PA, Cephalon Inc.) is a novel delivery system for fentanyl citrate. Fentanyl is a well studied, highly lipophylic, μ-opioid agonist. The toxicological, pharmacologic effects and mechanisms of action of fentanyl are well characterized. FBT utilizes the oral transmucosal route of administration. The advantages/disadvantages of transmucosal route of administration^45,53 are presented in Table 12. Transmucosal absorption allows fentanyl to bypass first-pass cytochrome P450 3A4 (CYP3A4) -mediated gastrointestinal and/or hepatic metabolism and allow more fentanyl to enter the systemic circulation compared with gastrointestinal absorption of oral fentanyl.^54,55 FBT utilizes OraVescent (r) technology to improve bioavability and speed of transmucosal delivery. At the site of administration FBT produces an effervescent reaction which causes a pH decrease followed by a pH increase. These changes of pH are hypothesized to optimize pill dissolution and membrane permeability facilitating rapid absorption.^54–56 This rapid absorption should decrease the time to onset of analgesia making FBT highly suitable for the management of breakthrough pain.⁵⁷ Properties of FBT are summarized⁵⁸ in Table 13. The effect of FBT has been studied out to 2 hours and analgesic effect has been shown to persist for the 2 hour study period. In studies on cancer pain FBT has demonstrated a 15 minute onset of action.⁵⁹ Fentanyl buccal tablets (FBT) is novel delivery system for fentanyl citrate. FBT utilises OraVescent^® technology to improve bioavailability and speed of drug delivery.

Table 12

Transmucosal route of administration for BTP management.

•

Advantage of transmuccosal route

•

Acceptable and convenient to patients

•

Acceptable to health care professionals

•

Suitable for patients which can't use oral medications (dysphasia, vomiting, nausea, dysfunction of upper GI tract)

•

Potentially fast onset of action

•

Avoidance degradation by gastric acid and gastric enzymes

•

Avoidance of first pass metabolism

•

Cost effective than certain other (invasive) routes of administration

•

Disadvantages

•

Required special formulation (OTFC, OraVescent technology)

•

Not suitable for patient with

•

Dryness of mouth

•

Oral pathology

•

Severe disability (cannot agitate the preparation)

•

Severe fatigue (cannot agitate preparation)

•

Limited number of suitable medication and formulation

•

Variation in oral transmuccosal bioavailability

Table 13

Fentanyl bucal tablet.

Mechanism of action

Fentanyl is a well studied, highly lipophylic, μ-opioid agonist. The novelty of this compound is a new trans-mucosal delivery system called OraVescent^®.

Pharmacokinetics

•

After application fentanyl from Fentanyl Buccal Tablet (FBT) is rapidly absorbed.

•

AUC0-t and Cmax are linearly proportional to dose up to dose equal 800 μg.

•

Lack of bioequivalence of four 100 μg tablet with one 400 μg. Probably due to differences in tablet surface.

•

Steady state is reached with 5 days for FBT 400 μg administrated every 6 hours.

•

The mean ratio of the multiple dose/single dose Cmax is equal 2.0.

•

Direct PK comparison of FBT vs. OTFC showed shorter Tmax (median Tmax 47 vs. 91 minute respectively) and better bioavailability: FBT = 65% vs. OTFC = 47%).

Clinical efficacy

Greater efficacy vs. placebo was proved for BTP episodes associated with cancer, low back and neuropathic pain.

65% of cancer patients, 81% of low back pain patients and 78% neuropathic pain patients were able to identify effective dose of FBT for BTP at open label titration phase.

Majority of low back patients (56%) reach highest available dose of FBT (800 μg) during titration phase.

Higher doses than 800 μg dose is not exist. we assume that this is related to a lack of PK linearity above this dose.

13% of cancer BTP episodes, 20% low back pain episodes and 23% of neuropathic pain episodes achieved 33% improvement of pain intensity in 15 minutes.

60 minutes after medication administration efficacy (defined as % BTP episodes with 33% improvement of pain intensity) was equal 75% for cancer patient (placebo = 48%) and 58% for low back patient (placebo = 26%).

Easy of administration comparing with iv route is obvious, however described paradigm of buccal administration could lead to mistakes (e.g. instant swallowing the tablets, not waiting enough time before swallowing…) especial for elderly population.

Safety and tolerability

FBT is generally well tolerated.

Mild adverse effects are associated with opioid receptor mediated effects or with local effervescent reaction.

Local side effects could accumulate in time when patients will use FBT for long period of time.

Significant number of patient withdrawal from the studies or not achieved pain improvement during titration phase (43% for cancer BTP study, 29% for low back study, 23% for chronic neuropathic pain study).

There is potential risk of abuse in non-cancer population.

Drug interaction

There is potential interaction with ritonavir. Oral ritonavir might decrease clearance of iv administrated fentanyl by 67%, resulting in 174% increase in fentanyl AUC_0-∞.

Coadministration of FBT and ritonavir has not been studied, however, an increase in fentanyl AUC is expected.

Future Perspectives

Alfentanyl and Sufentanyl are the synthetic opioid analgesics, chemically similar to fentanyl but with more rapid onset and shorter duration of action when given parenterally.⁶⁰ Sublingual Alfentanyl⁶¹ and sublingual/buccal Sulfentanyl^62,63 have been reported as being effective in small groups of patients for BTP treatment. Recently results of intranasal application of non-opioid medication for small group of non-cancer pain patients was published. Intranasal NMDA agonist (S)ketamine was succesful in rapid reduction of neuropathic pain⁶⁴ and may therefore be potential future medication for BTP.

Alternate routes of administration could further improve the efficacy of BTP management. Intranasal and intrapulmonary routes are under exploration. The nose can accommodate 150–200 microlitters of drug solution in each nostril. A special feature of the nasal route is the close association of the brain to the olfactory area and the unique physiology of this area (i.e. an absence of the normal blood-brain barrier): this may enable a fraction of the drug to enter the intrathecal space directly.⁶⁵

Intranasal fentanyl spray (INFS) was investigated in phase III, double blind, randomised, placebo controlled, crossover, multicenter trial. INFS was titrated to an effective dose (50, 100 or 200 microgram). Efficacy (compared with placebo) as well as safety and tolerability was demonstrated.⁶⁶ INFS was also directly compared with OTFC in open-label, randomised, crossover trial. INFS demostrated faster median time to onset of ‘meaningful’ pain relief compared to OTFC⁶⁷ (Table 14). Interestingly, there was only a weak association between effective INFS doses and effective OTFC doses.⁶⁷

Table 14

Direct comparison of oral transmucosal fentanyl citrate (OTFC) vs. intranasal fentanyl spray (INFS).

	OTFC	INS
Time to onset of ‘meaningful’ pain relief [minutes]	16	11
PID₁₀ [NRS]	1.08	2.27
PID₃₀ [NRS]	3.39	4.15

Abbreviations: PID₁₀, pain intensity difference at 10 minutes; PID₃₀, pain intensity difference at 30 minutes.

Several explorative studies have looked at the use of intranasal opioids for the treatment of break-trough pain: fentanyl, morphine, diamorphine, and alfentanyl¹² have been studied and this route appears promising. Some agents may not be amenable for nasal administration, for example, methadone administrated by intranasal route caused a burning sensation in healthy volunterers.⁶⁸

A case report (two patients) of BTP successfully treated with intrapulmonary fentanyl administration was published.⁵² This route may offer a speed of onset rivaling intravenous drug administration due to rapid access to the circulation via the pulmonary capillary bed. Further studies are needed to define the role of intrapulmonary medications in the management of breakthrough pain.

Conclusion

Recently introduced delivery systems for opioid medications represent major improvements in BTP management; however, the ideal drug or delivery system for BTP management is still an unfulfiled. The time to peak analgesia of the new rapid onset opioids, such as FBT, is still longer than the time to peak pain of many BTP episodes. Thus, the ideal BTP medication is yet to be found. Studies are needed to expand our knowledge about the different patho-physiological mechanisms involved in BTP and to help us understand the variability of BTP within the individual patient. If the intensity of BTP is variable within the individual patient, the initial dose titration paradigm used to define the effective analgesic dose of BTP medication could be inappropriate, being too high for some BTP episodes and too low for others. The ideal BTP medication would provide dosing versatility to address this intra-patient variability of BTP intensity. New fentanyl delivery systems offer theoretical advantages over short acting (regular release) oral morphine and patients seem to prefer the rapid onset opioids over morphine for BTP management. Studies that directly compare a rapid onset fentanyl preparation (FBT) and oxycodone are underway in the USA. More studies that compare rapid onset opioids and standard drugs like morphine and oxycodone regular release (short acting) in diverse patient populations are needed to help us define the full benefit of matching the time course of action of the analgesic to the BTP.

Disclosures

This manuscript has been read and approved by all authors. This paper is unique and is not under consideration by any other publication and has not been published elsewhere. The authors report no conflicts of interest.

References

Mercadante

, Arcuri

Breaktrough pain in cancer patients. Pain Clinical Update. 2006; 14: 1–4.

Friedrichsdorf

S.J.

, Finney

, Bergin

, Stevens

, Collins

J.J.

Breakthrough pain in children with cancer. J Pain Symptom Manage. 2007; 34(2): 209–16.

Fortner

B.V.

, Okon

T.A.

, Portenoy

R.K.

A survey of pain-related hospitalizations, emergency department visits, and physician office visits reported by cancer patients with and without history of breakthrough pain. J Pain. 2002; 3(1): 38–44.

Fine

P.G.

, Busch

M.A.

Characterization of breakthrough pain by hospice patients and their caregivers. J Pain Symptom Manage. 1998; 16(3): 179–83.

Fortner

B.V.

, Demarco

, Irving

Description and predictors of direct and indirect costs of pain reported by cancer patients. J Pain Symptom Manage. 2003; 25(1): 9–18.

Zeppetella

, O'Doherty

C.A.

, Collins

Prevalence and characteristics of breakthrough pain in cancer patients admitted to a hospice. J Pain Symptom Manage. 2000; 20(2): 87–92.

Zeppetella

, O'Doherty

C.A.

, Collins

Prevalence and characteristics of breakthrough pain in patients with non-malignant terminal disease admitted to a hospice. Palliat Med. 2001; 15(3): 243–6.

Portenoy

R.K.

, Bennett

D.S.

, Rauck

Prevalence and characteristics of breakthrough pain in opioid-treated patients with chronic noncancer pain. J Pain. 2006; 7(8): 583–91.

Colleau

S.M.

The significance of breakthrough pain in cancer. Cancer Pain Release. 1999; 12(4): 1–4.

10.

Portenoy

R.K.

, Payne

, Jacobsen

Breakthrough pain: characteristics and impact in patients with cancer pain. Pain. 1999; 81(1-2): 129–34.

11.

Hwang

S.S.

, Chang

V.T.

, Kasimis

Cancer breakthrough pain characteristics and responses to treatment at a VA medical center. Pain. 2003; 101(1-2): 55–64.

12.

Davies

Cancer-related breakthrough pain. Oxford University Press; 2009.

13.

Portenoy

R.K.

, Forbes

, Lussier

Difficult pain problem: an integrated approach. In: Doyle

, Hanks

, Cherny

, Calman

Oxford Textbook of Palliative Medicine. 2004. p. 438–58.

14.

Bennet

Consensus panel recommendations for the assessment and management of breakthrough pain. Part 1 assessment. Pharmacy and Therapeutics. 2005; 30: 296–301.

15.

Mercadante

, Radbruch

, Caraceni

Episodic (breakthrough) pain: consensus conference of an expert working group of the European Association for Palliative Care. Cancer. 2002; 94(3): 832–9.

16.

Portenoy

R.K.

, Hagen

N.A.

Breakthrough pain: definition, prevalence and characteristics. Pain. 1990; 41(3): 273–81.

17.

Caraceni

, Martini

, Zecca

Breakthrough pain characteristics and syndromes in patients with cancer pain. An international survey. Palliat Med. 2004; 18(3): 177–83.

18.

Mercadante

, Arcuri

Breakthrough pain in cancer patients: pathophysiology and treatment. Cancer Treat Rev. 1998; 24(6): 425–32.

19.

Gómez-Batiste

, Madrid

, Moreno

Breakthrough cancer pain: prevalence and characteristics in patients in Catalonia, Spain. J Pain Symptom Manage. 2002; 24(1): 45–52.

20.

Colleau

S.M.

Breaktrhrough (episodic) vs. baseline (persistent) pain in cancer. Cancer Pain Release. 2004; 17: 1–3.

21.

Zeppetella

, Ribeiro

M.D.C.

Pharmacotherapy of cancer-related episodic pain. Expert Opin Pharmacother. 2003; 4(4): 493–502.

22.

Caraceni

, Portenoy

R.K.

An international survey of cancer pain characteristics and syndromes. IASP Task Force on Cancer Pain. International Association for the Study of Pain. Pain. 1999; 82(3): 263–74.

23.

Bruera

, Schoeller

, Wenk

A prospective multicenter assessment of the Edmonton staging system for cancer pain. J Pain Symptom Manage. 1995; 10(5): 348–55.

24.

Portenoy

R.K.

Treatment of temporal variation in chronic cancer pain. Seminars in Oncology. 1997; 5(S16): 7–12.

25.

Doyle

, Hanks

, Cherny

, Calman

Oxford Textbook of Palliative Medicine. 2004: 298–316.

26.

Hillier

, Finlay

, Miles

The effective management of Cancer Pain. London: Aesculapius Medical Press; 2002: 23–8.

27.

Zeppetella

, Ribeiro

M.D.C.

Episodic pain in patients with advanced cancer. Am J Hosp Palliat Care. 2002; 19(4): 267–76.

28.

Swanwick

, Haworth

, Lennard

R.F.

The prevalence of episodic pain in cancer: a survey of hospice patients on admission. Palliat Med. 2001; 15(1): 9–18.

29.

Petzke

, Radbruch

, Zech

, Loick

, Grond

Temporal presentation of chronic cancer pain: transitory pains on admission to a multidisciplinary pain clinic. J Pain Symptom Manage. 1999; 17(6): 391–401.

30.

Christina

Liossi

. Clinical Hypnosis in Paediatric Oncology: A Critical Review of the Literature. Sleep and Hypnosis. 2000; 5: 268–74.

31.

Wild

M.R.

, Espie

C.A.

The efficacy of hypnosis in the reduction of procedural pain and distress in pediatric oncology: a systematic review. J Dev Behav Pediatr. 2004; 25(3): 207–13.

32.

Twyrcoss

, Wilcock

, Charlesworth

, Dickman

Palliative Care Formulary. Abingdon: Radcliffe Medical Press; 2002.

33.

Doyle

, Hanks

, Cherny

, Calman

Oxford Textbook of Palliative Medicine. 2004: 118–223.

34.

McCarberg

B.H.

The treatment of breakthrough pain. Pain Med. 2007; 8 Suppl 1: S8–13.

35.

Hanks

G.W.

, Conno

, Cherny

Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Cancer. 2001; 84(5): 587–93.

36.

Zeppetella

, Ribeiro

M.D.C.

Opioids for the management of breakthrough (episodic) pain in cancer patients. Cochrane Database Syst Rev. 2006; (1): CD004311.

37.

Coluzzi

P.H.

, Schwartzberg

, Conroy

J.D.

Breakthrough cancer pain: a randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulfate immediate release (MSIR). Pain. 2001; 91(1-2): 123–30.

38.

Simpson

D.M.

, Messina

, Xie

, Hale

Fentanyl buccal tablet for the relief of breakthrough pain in opioid-tolerant adult patients with chronic neuropathic pain: a multicenter, randomized, double-blind, placebo-controlled study. Clin Ther. 2007 Apr; 29(4): 588–601.

39.

Portenoy

R.K.

, Messina

, Xie

, Peppin

Fentanyl buccal tablet (FBT) for relief of breakthrough pain in opioid-treated patients with chronic low back pain: a randomized, placebo-controlled study. Curr Med Res Opin. 2007 Jan; 23(1): 223–33.

40.

Landy

S.H.

Oral transmucosal fentanyl citrate for the treatment of migraine headache pain in outpatients: a case series. Headache. 2004 Sep; 44(8): 762–6.

41.

Patt

R.B.

, Ellison

N.M.

Breakthrough pain in cancer patients: characteristics, prevalence, and treatment. Oncology (Williston Park, N.Y.). 1998; 12(7): 1035–46; discussion 1049–52.

42.

Christie

J.M.

, Simmonds

, Patt

Dose-titration, multicenter study of oral transmucosal fentanyl citrate for the treatment of breakthrough pain in cancer patients using transdermal fentanyl for persistent pain. J Clin Oncol. 1998; 16(10): 3238–45.

43.

Portenoy

R.K.

, Payne

, Coluzzi

Oral transmucosal fentanyl citrate (OTFC) for the treatment of breakthrough pain in cancer patients: a controlled dose titration study. Pain. 1999; 79(2-3): 303–12.

44.

WHO. Cancer Pain Relief (2nd edition). 1996.

45.

Walker

, Wilcock

, Manderson

, Weller

, Crosby

The acceptability of different routes of administration of analgesia for breakthrough pain. Palliat Med. 2003; 17(2): 219–21.

46.

Twyrcoss

, Wilcock

, Thorp

Palliative Care Formulary. Abingdon: Radcliffe Medical Press; 1998.

47.

Doyle

, Hanks

, Cherny

, Calman

Oxford Textbook of Palliative Medicine. 2004: 213–25.

48.

Farrar

J.T.

, Cleary

, Rauck

, Busch

, Nordbrock

Oral transmucosal fentanyl citrate: randomized, double-blinded, placebo-controlled trial for treatment of breakthrough pain in cancer patients. J Natl Cancer Inst. 1998; 90(8): 611–6.

49.

Mercadante

, Villari

, Ferrera

, Bianchi

, Casuccio

Safety and effectiveness of intravenous morphine for episodic (breakthrough) pain using a fixed ratio with the oral daily morphine dose. J Pain Symptom Manage. 2004; 27(4): 352–9.

50.

Enting

R.H.

, Mucchiano

, Oldenmenger

W.H.

The “pain pen” for breakthrough cancer pain: a promising treatment. J Pain Symptom Manage. 2005; 29(2): 213–7.

51.

Pavis

, Wilcock

, Edgecombe

Pilot study of nasal morphine-chitosan for the relief of breakthrough pain in patients with cancer. J Pain Symptom Manage. 2002; 24(6): 598–602.

52.

Zeppetella

Nebulized and intranasal fentanyl in the management of cancer-related breakthrough pain. Palliat Med. 2000; 14(1): 57–8.

53.

Zhang

, Zhang

, Streisand

J.B.

Oral mucosal drug delivery: clinical pharmacokinetics and therapeutic applications. Clin Pharmacokinet. 2002; 41(9): 661–80.

54.

Pather

S.I.

, Siebert

J.M.

, Hontz

Enchanced buccal delivery of fentanyl using the OraVescent drug delivery system. Drug Deliv Tech. 2001; 1: 54–7.

55.

Durfee

, Messina

, Khankari

R.K.

Fentanyl efferescent buccal tablets: Enchanced buccal absorption. Am J Drug Deliv. 2006; 4: 1–5.

56.

Eichman

J.D.

, Robinson

J.R.

Mechanistic studies on effervescent-induced permeability enhancement. Pharm Res. 1998; 15(6): 925–30.

57.

Darwish

, Tempero

, Kirby

, Thompson

Relative bioavailability of the fentanyl effervescent buccal tablet (FEBT) 1,080 pg versus oral transmucosal fentanyl citrate 1,600 pg and dose proportionality of FEBT 270 to 1,300 microg: a single-dose, randomized, open-label, three-period study in healthy adult volunteers. Clin Ther. 2006; 28(5): 715–24.

58.

Lecybyl

, Hanna

Fentanyl buccal tablet: faster rescue analgesia for breakthrough pain?

Future Oncol. 2007; 3(4): 375–9.

59.

Portenoy

R.K.

, Taylor

, Messina

, Tremmel

A Randomized, placebo-controlled study of fentanyl buccal tablet for breakthrough pain in opioid-treated patients with cancer. Clin J Pain. 22(9): 805–11.

60.

Scholz

, Steinfath

, Schulz

Clinical pharmacokinetics of alfentanil, fentanyl and sufentanil. An update. Clin Pharmacokinet. 1996; 31(4): 275–92.

61.

Duncan

The use of fentanyl and alfentanil sprays for episodic pain. Palliat Med. 2002; 16(6): 550.

62.

Kunz

K.M.

, Theisen

J.A.

, Schroeder

M.E.

Severe episodic pain: management with sublingual sufentanil. J Pain Symptom Manage. 1993; 8(4): 189–90.

63.

Gardner-Nix

Oral transmucosal fentanyl and sufentanil for incident pain. J Pain Symptom Manage. 2001; 22(2): 627–30.

64.

Huge

, Lauchart

, Magerl

Effects of low-dose intranasal (S)-ketamine in patients with neuropathic pain. Eur J Pain. 2009 Sep 2. [Epub ahead of print].

65.

Dale

, Hjortkjaer

, Kharasch

E.D.

Nasal administration of opioids for pain management in adults. Acta Anaesthesiol Scand. 2002; 46(7): 759–70.

66.

Kress

G.H.

, Oronska

, Kaczmarek

, Kaasa

, Colberg

, Nolte

Efficacy and tolerability of intranasal fentanyl Spray 50 to 200 microgram for breakthrough pain in patiens wih cancer: A phase III, multinational, randomized, double-blind, placebo-controlled, crossover trial with a 10-month, open-label extension treatment period. Clin Ther. 2009; 31(6): 1177–91.

67.

Mercadante

, Radbruch

, Davies

Comparison of intranasal fentanyl spray with oral transmucosal fentnyl citrate for the treatment of breakthrough cancer pain: an open-label, randomised, crossover trial. Curr Med Res Opin. 2009; 25(11): 2805–15.

68.

Dale

, Hoffer

, Sheffels

, Kharasch

E.D.

Disposition of nasal, intravenous, and oral methadone in healthy volunteers. Clin Pharmacol Ther. 2002; 72(5): 536–45.

Breakthrough Pain: Focus on Fentanyl Buccal Tablet

Abstract

Keywords

Introduction

Definition of BTP

Classification of BTP

Prevalence of BTP

Assessment of BTP

Treatments of BTP

Ideal ‘Rescue’ Medication for BTP

Fentanyl Buccal Tablets

Future Perspectives

Conclusion

Disclosures

References