Merseyside and Cheshire Regional Audit Group 15th September 2011

Dr Amara Nwosu Dr Kate Marley Dr Esraa Sulaivany Mr Andrew Dickman Dr Clare Littlewood

Dr Matt Makin

Dr Esraa Sulaivany Sep 2011

D Haugen , M Hjermstad et.al [1]

2010 systematic literature review for assessment and classification of

cancer breakthrough pain.

51 articles

- Terms used for breakthrough pain.

- Definitions of breakthrough pain.

-Assessment of breakthrough pain.

-Classification of breakthrough pain.

Terms used

for BTCP

• Terms vary from

country to country.

• BTP - English term no

literal translation other

languages.

• BTP dominated the

literature commonly

agreed upon.

Portenoy RK ,Hagen NA in 1990 [2) A transitory exacerbation of pain that

occurs against a background of otherwise stable pain in patients receiving

chronic opioid therapy”.

Mercadante et.al in 2002 [3] and Zeppetella & Riberio in 2006 [4], ” a

transient increase in pain intensity over background pain”

Davies et.al [5] 2009 “ transient exacerbation of pain that occurs either

spontaneously or in relation to a specific predictable or unpredictable

trigger despite relative stable and adequately controlled background pain

Large numbers of definitions, descriptive and not explanatory, rather broad

and imprecise reflecting that BTP encompasses different entities.

Breivik H, Cherny N et.al 2009: a pan European survey of prevalence,

treatment and patient attitudes to BTP concluded that the assessment

of BTP is poor. [6]

D Haugen et al 2010: found different assessment tools but BTP

questionnaire was the most frequently used.

Based on this review an ideal BTP assessment tool should include

-number of different BTPs

- relation to background pain

- intensity

- Temporal factors( frequency,onset,duration,course,relation to

fixed analgesia).

- localisation (body map).

- pain quality.

- Treatment related factors( exacerbating and relieving factors,

predictability and treatment response).

- interference with daily activities.

Yes

Yes

Does the patient have background pain?

Is the background pain is adequately controlled?

Yes

No

Patient does not have BTP

Are there exacerbations of pain?

Patient has BTP

Yes

Davies et.al 2008 [5], followed by Mercadante et al 2009[7] & A Dickman 2011 [8]

They all agreed on this simple assessment algorithm to help HCP to identify BTP.

No

No

BTP

Spontaneous Incident

Volitional Non-volitional

procedural

D Haugen, M Hjermstad et al 2010 [1]: No formal classification system for BTP was identified.

Davies A in 2006 and Davies A , Dickman A et al 2009 APM[5] agreed the following classification of

BTP

Russell K , Portenoy et al Oxford textbook of PM 2008 [9]

prevalence of BTP varies with definition / population investigated.

41% -63% oncology , 89% home care and hospices inpatient.

Zeppetella G 2000 [10] prevalence of BTP non cancer terminal illness

63% reported BTP.

Caraceni A, Martini Z, et al 2004 [11]:large international survey

prevalence BTP 65%.

Mishra S, Bhatnagar S, et al 2009[12], looked at the predictability of BTP

55-80% ppt factors identified

48.2% never predictable

12-15% always predictable

Portenoy et al 1999 [13], Hwang et al 2003 [14], Fortner et al 2002 [15], and A

Dickman 2011 [8] profound impact of BTP:

- decreased functioning

- social and psychological impact

- anxiety and depression

- sleeping difficulties

- work performance is impacted

- economic impact on healthcare system

American pain foundation 2010 [16]

− 85% patients stated that BTP negatively affected their quality of life.

− 91% believed that their quality of life would improve if their BTP was

controlled.

Portenoy & Hagen 1990[2] Bennett D et al 2005 [17] stressed importance

differentiate patients with uncontrolled background pain than those with BTP and

listed the typical features to look for in assessing BTP:

Gomez-Batiste et al 2002[18] looked at the duration of BTP episodes and reported

31,64,and 87% of episodes last for < 15, 30,and 60 min respectively.

Time to peak severity 3-5 min

Severity Severe to excruciating

Duration 15-30 min

Number of episodes per day 1-5

Simmonds. 1999[19] Zeppetella , Riberio 2003 [20] Dickman A 2009 [21] looked

at the optimal BTP treatment would:

- Be efficacious

- Closely match the temporal characteristics of BTP.

- Have a fast onset of action.

- Have a short duration of action.

- Be patient friendly – non invasive, well tolerated and simple to administer.

- Have minimal adverse side effects.

I R Opioid Onset Duration

effect A=Advantages D= Disadvantage

Oral

morphine

30-40 min 4 hrs A- multiple dosage and liquid concentrate

D- slow onset

Oral

Oxycodone

30 min 4 hrs Same as morphine

Oral

Hydromor-

phone

30 min 4hrs D- no liquid concentrate, slow onset

Oral

Methadone

10-15 min 4-6 hrs A- faster onset of analgesia

D- complex pharmacology

Fentanyl TM 5-10min 1-2 hrs A- fast onset

D- requires ongoing patient cooperation in

use

Lipophilic

Hydrophilic

Bennett et al. 2005[17] characteristics of normal – release opioids considered for BTP:

Zeppetella G, Ribeiro MDC 2006[22] Cochrane review of opioids for the

management of breakthrough( episodic) pain in cancer patients.

Four studies(393 pts) the use of OTFC (actiq) in the management of BTP.

(2) OTFC titration, (1) OTFC V OM, and (1) OTFC V placebo

Review showed that OTFC was an effective treatment for BTP when compared to

placebo & morphine, OTFC reported to produce greater analgesic effect, better

global satisfaction, more rapid onset of action.

Concluded - no meaningful relationship between the successful dose of OTFC and

ATC oral or transdermal opioid medication. Recommended to titrate the rescue dose

until successful dose found.

Result of this review did not support the EAPC recommendation (4) on the use of

rescue medication.

Oral Opioids Parenteral Opioids Rapid Onset Opioids (ROOS)

Current dosing

recommendation(1/6th) for

BTP are based entirely on

anecdotal experience.

Recommendations have

underlined that orally

administered opioids may be

unsuitable for pains with short

onset & duration.

They appear effective when

given timely before pain

occurs and in a well

characterized BTP event e.g.

15-30min prior to physical

activity or with predictable

pain e.g. dressings.

Very short onset of action

Found to be highly effective

Safe and fewer adverse

effects even with large doses.

The s/c route is commonly

preferred in hospice setting

although the onset may not

be fast enough.

While the i/v route is feasible

in acute units, it is not easily

manageable in hospice or

home settings.

Currently this means

delivering Fentanyl by non

invasive routes

All studies performed on

ROOs recommend these

drugs should be prescribed

for opioid - tolerant patients

receiving doses of oral

morphine of at least

60mg/24hrs (or equivalent).

They may be administered

via the buccal, sublingual, or

nasal route.

Clinical studies have shown

these preparations may be

effective as early as 10 min

and well tolerated

Mercadante S. The use of rapid onset opioids for breakthrough cancer pain: The challenge of its dosing. Crit Rev Oncol Hematol. 2011

Fentanyl- impregnated lozenge six strengths dissolves 15 mins

Oral mucosa highly permeable, vascularised, large surface area ,relatively uniform temp. .

Farrar et al ,1998[24], (double blinded RCT): statistically significant change in pain intensity greater than Placebo.

Coluzzi PH, Conroy JD et.al 2001 [25] (RCT): OTFC produces faster onset and greater pain relief at 15, 30, & 60 compared to MSIR

Aronoff G, Brennan M et al, in 2005[26]: evidence based OTFC dosing guidelines., serum Fentanyl levels achieved with OTFC are proportional to the dose administered. Absolute availability 50%; 25% absorbed by mouth only

Cochrane review concluded that they are more effective than IRMS in treating BTP.

FBT. two double blind, randomised placebo- controlled cross over phase III trials 160

patients.

Portenoy et al study 2006[27], 68 pts. single effective dose up to 800mcg.

Clinically significant improvement pain score occurred more in the FBT V placebo at

all points.

Slatkin et al study 2007[28], 78 pts, clinically significant improvement in pain

scores of > 33% & 50% with FBT compared to placebo, analgesic effect with FBT

were sustained through out 2 hrs observation period.

Darwish M, et al, 2005/2007/2008 [29] pharmacokinetics of FBT .

bioavailability of FBT double that of OTFC( 48% V 22%), FBT is absorbed in equal

proportion through oral mucosa and GIT versus 22% and 78% for OTFC.

Reasonable salivation needed and mild mucositis did not affect the absorption of

FBT.

Two clinical studies assessed the clinical efficacy of SLF.

Lennernas et al , 2010 [30], 23 patients completed the full four treatment doses.

Statistically significant improvement from 15min onward with the 400mcg when

compared with placebo. Improvement 100 & 200mcg did not reach statistical

significance..

Rauck et al ,2009 [31] (placebo controlled study) 61pts

Pts identified single effective tolerable dose up to max 800mcg. Significantly greater

improvements in PID compared to placebo 10 min after treatment.

Lennernas et al. 2004[39] , Prostrakan UK Ltd 2010, product summery [32],

absolute bioavailability of SLF has not been studied but estimated at 70%.

Kress HG et al. 2009 [33]:

phase III, multinational ,randomised, double blind, placebo controlled, crossover trial with a

10 month open label extension treatment period.

significant pain relief as early as 10 min post-dosing for all INFS doses (50-200mcg) , PID

(2.6 V 1.3 for placebo).

Kassa S et al. 2010 [34]

Pharmacokinetics INFS, quickly absorbed through the nasal mucosa, peak plasma

concentrations within 12 min for all dosage strength examined (50-200mcg).

Mercadante S et al. 2009 [35]:

Open label, randomised, cross over trial , compared INFS to OTFC for the treatment of BTP.

139 pts .86 completed the study,

Decrease in pain intensity significantly greater with INFS than OTFC as early as 5 min post

dosing. Greater difference in PID was seen at 10-15min (3.18 V 1.83). More patients 77%

preferred INFS to OTFC.

This was the only study directly compared two different ROOs

Portenoy RK et al. 2010 [36]: multicentre USA, Four part study ,screening, open

label dose titration, double blind placebo controlled randomised crossover, &open

label treatment. 83 pt FPNS provided clinically meaningful pain relief(>2 points) in

1/3rd of pts from 10min post dose

Fallon M et al. 2009: [37] FPNS V IR Morphine, multicentre Europe and India,

double blind double dummy, randomised ,crossover study. 110 pts, recorded PI and

PR at 5,10,15,30,45 & 60 min post treatment. And patient satisfaction. FPNS had

faster onset of action, greater pain relief at 10, 15 min than IRM, pts satisfaction was

recorded at 30 min (83.5% V 72%).

Large evidence base demonstrated superiority

Effentora, Abstral, Actiq, Instanyl & Perfect V oral morphine and placebo in the

management of BTP.

Level of the evidence is mostly at level 1+ ( well conducted meta-analysis,

systematic reviews or RCT with low risk bias)

Existing literature is therefore largely “ proof of principle” in nature with a number of

single- product efficacy studies Vs. placebo or OM.

NO head-to head studies that have directly compared the efficacy of any of these

products ( oral to oral /nasal to nasal), only INFS was compared to OTFC.

Such comparisons are warranted in order to elucidate subtle differences between

different product formulations and method of delivery

Cephalon(9/11) Meta-analysis comparing the performance of Effentora with

Abstral, Actiq & Oral morphine in the treatment of BTP.

Mixed treatment comparison Meta-analysis will not demonstrate superiority of one

product over another.

Mixed treatment meta-analysis Will provide, based on the current relevant data, a

Probability that a particular treatment will have a better outcome compared to

another if they were used in the same population.

Used in NICE technology appraisal process and accepted in the absence of head to

head trials.

Effentora

Placebo Abstral Actiq

Rauck et al 2009

Farrar et al 1998

Oral

Morphine

Coluzzi et al 2001

Slatkin et al 2007

Portenoy et al 2006

Results can be interpreted as indicating a:

2:1 (66%) Effentora will produce better pain relief than Abstral.

2:1 (68%) Effentora will produce better pain relief than Actiq.

13:1 (93%) Effentora will produce better pain relief than OM.

Results were combined to give an over all comparison for pain relief during the first

60 min after dosing, data was incomplete to conduct the 5 min comparison post

dosing.

Actual PID Vs. placebo

Effentora provided a meaningful PID only after 30 min post dosing when compared

to Abstral and Actiq.

1. Patients with pain should be assessed for the presence of BTP.

2. Patients with BTP should have this pain specifically assessed.

3. The management of BTP should be individualised.

4. Consideration should be given to the treatment of the underlying cause of pain.

5. Consideration should be given to avoidance/treatment of the precipitating factors for

BTP.

6. Consideration should be given to modification of the background analgesia

medication.

7. Opioids are the “rescue medication” of choice in the management of BTP.

8. The dose of opioid ”rescue medication” should be determined by individual titration.

9. Non- pharmacological methods may be useful in the management of BTP.

10. Non- opioid analgesics may be useful in the management of BTP.

11. Interventional techniques may be useful in the management of BTP.

12. Patients with BTP should have this pain specifically re-assessed.

Fentanyl more closely matches the profile of the ideal rescue treatment for BTP.

Administration of this drug via Buccal, sublingual, or nasal provides more rapid

absorption and onset of action when compared with oral morphine

.

5 preparations OTFC (Actiq) , FBT ( Effentora), SLF ( Abstral), INFS ( Instanyl), &

FPNS (Pecfent) available All are effective for treatment of BTP. Clinically relevant

analgesia shown to occur as early as 10min.

Treatment should be individualised to patients needs, care taken while switching

from one to another as significant bioavailability

Brand names should be used when prescribing as different products are available to

administer via same route.

Risk management strategies are in place to reduce the risk of abuse, misuse and

diversion.

1. Haugen DF, Hjermstad MJ, Hagen N, Caraceni A, Kaasa S. Assessment and classification of cancer breakthrough pain: a systematic literature review. Pain. 2010 Jun;149(3):476-82.

2. Portenoy RK, Hagen NA. Breakthrough pain: definition, prevalence and characteristics. Pain. 1990 Jun;41(3):273-81.

3. Mercadante S, Radbruch L, Caraceni A, Cherny N, Kaasa S, Nauck F, et al. Episodic (breakthrough) pain: consensus conference of an expert working group of the European Association for Palliative Care. Cancer. 2002 Feb 1;94(3):832-9.

4. Zeppetella G, Ribeiro MD. Opioids for the management of breakthrough (episodic) pain in cancer patients. Cochrane Database Syst Rev. 2006(1):CD004311.

5. Davies AN, Dickman A, Reid C, Stevens AM, Zeppetella G. The management of cancer-related breakthrough pain: recommendations of a task group of the Science Committee of the Association for Palliative Medicine of Great Britain and Ireland. Eur J Pain. 2009 Apr;13(4):331-8.

6. Breivik H, Cherny N, Collett B, de Conno F, Filbet M, Foubert AJ, et al. Cancer-related pain: a pan-European survey of prevalence, treatment, and patient attitudes. Ann Oncol. 2009 Aug;20(8):1420-33.

7. Mercadante S, Villari P, Ferrera P, Mangione S, Casuccio A. The use of opioids for breakthrough pain in acute palliative care unit by using doses proportional to opioid basal regimen. Clin J Pain. 2010 May;26(4):306-9.

8. Dickman A. Integrated strategies for the successful management of breakthrough cancer pain. Curr Opin Support Palliat Care. 2011 Mar;5(1):8-14.

9. Russell K, Portenoy et.al. Difficult pain problems:an integrated approach. Oxford textbook of palliative medicine. Third edition. 2007, pg 444-449.

10. Zeppetella G, O'Doherty CA, Collins S. Prevalence and characteristics of breakthrough pain in cancer patients admitted to a hospice. J Pain Symptom Manage. 2000 Aug;20(2):87-92.

11. Caraceni A, Martini C, Zecca E, Portenoy RK, Ashby MA, Hawson G, et al. Breakthrough pain characteristics and syndromes in patients with cancer pain. An international survey. Palliat Med. 2004 Apr;18(3):177-83.

12. Mishra S, Bhatnagar S, Chaudhary P, Rana SP. Breakthrough cancer pain: review of prevalence, characteristics and management. Indian J Palliat Care. 2009 Jan;15(1):14-8.

13. Portenoy RK, Payne D, Jacobsen P. Breakthrough pain: characteristics and impact in patients with cancer pain. Pain. 1999 May;81(1-2):129-34.

14. Hwang SS, Chang VT, Kasimis B. Cancer breakthrough pain characteristics and responses to treatment at a VA medical center. Pain. 2003 Jan;101(1-2):55-64.

15. Fortner,B.V. Et.al. A survey of pain-related hospitalization, emergency department visits and physician office visits reported by cancer patients with and without BTP. Journal of pain ,2002 (3):38-44.

16. American pain foundation. Breakthrough cancer pain survey fact sheet. www.painfoundation.org [Accessed march 2010] 17. Bennett D, et.al. Consensus panel recommendations for the assessment and management of breakthrough pain, part

1:Assessment, P&T.2005;30(5):296-301. 18. Gomez-Batiste X, Madrid F, Moreno F, Gracia A, Trelis J, Nabal M, et al. Breakthrough cancer pain: prevalence and

characteristics in patients in Catalonia, Spain. J Pain Symptom Manage. 2002 Jul;24(1):45-52. 19. Simmonds MA. Management of breakthrough pain due to cancer. Oncology (Williston Park). 1999 Aug;13(8):1103-8;

discussion 10, 13-4. 20. Zeppetella G, Ribeiro MD. Pharmacotherapy of cancer-related episodic pain. Expert Opin Pharmacother. 2003 Apr;4(4):493-

502. 21. Dickman A. Basics of managing breakthrough cancer pain. Pharm J 2009, 283:213-216. 22. Zeppetella G, Ribeiro MD. Opioids for the management of breakthrough (episodic) pain in cancer patients. Cochrane Database

Syst Rev. 2006(1):CD004311. 23. Mercadante S. The use of rapid onset opioids for breakthrough cancer pain: The challenge of its dosing. Crit Rev Oncol

Hematol. 2011 Jan 5. 24. Farrar JT, Cleary J, Rauck R, Busch M, Nordbrock E. Oral transmucosal fentanyl citrate: randomized, double-blinded,

placebo-controlled trial for treatment of breakthrough pain in cancer patients. J Natl Cancer Inst. 1998 Apr 15;90(8):611-6. 25. Coluzzi PH, Schwartzberg L, Conroy JD, Charapata S, Gay M, Busch MA, et al. Breakthrough cancer pain: a randomized trial

comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulfate immediate release (MSIR). Pain. 2001 Mar;91(1-2):123-30. 26. Aronoff GM, Brennan MJ, Pritchard DD, Ginsberg B. Evidence-based oral transmucosal fentanyl citrate (OTFC) dosing

guidelines. Pain Med. 2005 Jul-Aug;6(4):305-14.

27. Portenoy RK, Taylor D, Messina J, Tremmel L. A randomized, placebo-controlled study of fentanyl buccal tablet for breakthrough pain in opioid-treated patients with cancer. Clin J Pain. 2006 Nov-Dec;22(9):805-11.

28. Slatkin NE, Xie F, Messina J, Segal TJ. Fentanyl buccal tablet for relief of breakthrough pain in opioid-tolerant patients with cancer-related chronic pain. J Support Oncol. 2007 Jul-Aug;5(7):327-34.

29. Darwish M, Tempero K, Kirby M, Thompson J. Pharmacokinetics and dose proportionality of fentanyl effervescent buccal tablets in healthy volunteers. Clin Pharmacokinet. 2005;44(12):1279-86.

30. Lennernas B et al. Sublingual administration of fentanyl to cancer patients is an effective treatment for breakthrough pain:results from phase II study. Palliative medicine 2010;24(3): 286-293.

31. Rauck RL, Tark M, Reyes E, Hayes TG, Bartkowiak AJ, Hassman D, et al. Efficacy and long-term tolerability of sublingual fentanyl orally disintegrating tablet in the treatment of breakthrough cancer pain. Curr Med Res Opin. 2009 Dec;25(12):2877-85.

32. Summery of product characteristics: Abstral sublingual tablets. Prostraken , 2010 accessed via www.emc.medicines.org.uk.

33. Kress HG, Oronska A, Kaczmarek Z, Kaasa S, Colberg T, Nolte T. Efficacy and tolerability of intranasal fentanyl spray 50 to 200 microg for breakthrough pain in patients with cancer: a phase III, multinational, randomized, double-blind, placebo-controlled, crossover trial with a 10-month, open-label extension treatment period. Clin Ther. 2009 Jun;31(6):1177-91.

34. Kaasa S, Moksnes K, Nolte T, Lefebvre-Kuntz D, Popper L, Kress HG. Pharmacokinetics of intranasal fentanyl spray in patients with cancer and breakthrough pain. J Opioid Manag. 2010 Jan-Feb;6(1):17-26.

35. Mercadante S, Radbruch L, Davies A, Poulain P, Sitte T, Perkins P, et al. A comparison of intranasal fentanyl spray with oral transmucosal fentanyl citrate for the treatment of breakthrough cancer pain: an open-label, randomised, crossover trial. Curr Med Res Opin. 2009 Nov;25(11):2805-15.

36. Portenoy RK, Burton AW, Gabrail N, Taylor D. A multicenter, placebo-controlled, double-blind, multiple-crossover study of Fentanyl Pectin Nasal Spray (FPNS) in the treatment of breakthrough cancer pain. Pain. 2010 Dec;151(3):617-24.

37. Fallon M et al. Efficacy, safety, and patient acceptability of fentanyl pectin nasal spray compared with immediate release morphine sulphate tablets in the treatment of breakthrough cancer pain: A multicentre, double blind, double dummy, multiple cross-over study. Poster 254. presented at the joint 15th congress of the European society for medical oncology; 20-24 sep 2009; Berlin, Germany.

38. Davies AN, Dickman A, Reid C, Stevens AM, Zeppetella G. The management of cancer-related breakthrough pain: recommendations of a task group of the Science Committee of the Association for Palliative Medicine of Great Britain and Ireland. Eur J Pain. 2009 Apr;13(4):331-8.

39. Lennernas B et.al. Pharmacokinetics and tolerability of different doses of fentanyl following sublingual

administration of rapidly dissolving tablet to cancer patients: a new approach for the treatment of incident pain. Br J Clin Pharmacol 2004; 59(2):249-253.

Development of 2 surveymonkey questionnaires: 1. Reflection on the management of BTcP in 1 patient 2. Survey of experience of rapid onset Fentanyl products

Multi-disciplinary

Forms circulated electronically throughout 4 host ICNs Aintree Warrington West Lancs, Southport & Formby Whiston

BTcP questionnaire 28

IR Fentanyl questionnaire 29

9

7

2

9

0

1

2

3

4

5

6

7

8

9

10

Aintree Warrington West Lancs, southport andFormby

Whiston

80.8

19.2

0

10

20

30

40

50

60

70

80

90

yes no

Pe

rce

nta

ge

%

Background pain controlled?

88

12

0

10

20

30

40

50

60

70

80

90

100

yes no

Pe

rce

nta

ge

%

Does the pain occur spontaneously?

61.5

38.5

0

10

20

30

40

50

60

70

yes no

Pe

rce

nta

ge

%

Does Pain Occur in response to a Trigger?

96.2

3.8

0

20

40

60

80

100

120

yes no

Pe

rce

nta

ge

%

6

0

1

9

0

1

0

1

0

4

0

2

1

0

1

2

3

4

5

6

7

8

9

10

Nu

mb

ers

1

5

0 0 0 0 0 0

2 1

19

0

2

4

6

8

10

12

14

16

18

20N

1

5

10

2 2

5

7

6

4

1

7

0

2

4

6

8

10

12

0 1 2 3 4 5 6 7 8 9 10 NoPainscoredone

N

Pain Score

Painscore Before

Painscore After

28

56

16

0 0

10

20

30

40

50

60

0-14 minutes 15-29 minutes 30-59 minutes > 60 minutes

Pe

rce

nta

ge

%

9

4

12

4

8

5 5

2

9

0

3 3

4

6

9

4

3 3

0

2

4

6

8

10

12

14

Effentora Actiq Abstral Instanyl PecFent None

Nu

mb

ers

Hospice

Hospital

Community

Of the people who had side effects with their analgesia:

2 Were taking Abstral, 1 took Hydromorphone, 1 Oxynorm and 1 Oramorph

4 had Incident pain due to bony metastases and 1 had a fungating wound

Of the patients who were not satisfied with their breakthrough analgesia:

2 were on Abstral, 1 was on Oxynorm

Their pains were the same as above

9

2

14

2

6

11

0

2

4

6

8

10

12

14

16

Effentora Actiq Abstral Instanyl PecFent None

Nu

mb

ers

13

2

6

2

7

12

0

2

4

6

8

10

12

14

Onset of Action Decreased Frequencyof Side Effects

Improved AnalgesicEffect

Patient Preference Route ofAdministration

Not Applicable

Nu

mb

ers

GPs reluctant to prescribe PecFent due to cost.

I prescribed a repeat prescription for PecFent and was challenged by medicines management as the Merseyside Medicines Management Board have advised it should not be used routinely for breakthrough pain. I did explain that it was not a 'routine' prescription and had been originally prescribed by the hospice.

Concerns over appropriate use of the fentanyl products by the patient (i.e. would they overdose on doses if they are self-regulating). Also concerns about whether GPs and district nurse would know how to manage patients with these preparations (e.g. what advice would be given in consultations, would there be a reluctant to prescribe repeat prescriptions).

Titration and regular monitoring. Delay in community pharmacy acquiring supply - now plan to

contact GP / pharmacist on discharge as with methadone / ketamine.

no problems experienced. dose finding was complete though before patient went home. Most of us would use this for inpatients mainly.

GPs reluctant to prescribe. Unfamiliar and expensive Effentora is complex to prescribe for patient at home during titration phase

Use on Acute Wards I think that waiting for administration of the analgesia is a problem in hospital but

this would also be the same for traditional immediate release opioids Difficult on busy acute wards due to staffs lack of knowledge of products and

time factor of staying with patient Titrating is complex and I would not normally suggest using these products on a

general ward. I don't prescribe them in the hospital setting as staff are unfamiliar with using

them Abstral is a nightmare to prescribe in the acute setting. i personally feel that it

requires a separate prescription chart; i.e. Warfarin/Insulin for safe prescribing & administration. The titration sequence doesn't safely fit a normal prescription chart within my trust. I have highlighted my concerns, as there could potentially be a drug error.

Lack of Access to Drug for Patients limited products available due to formulary restrictions

Storage and prescription. Length of time taken to administer to patient as short

staffed. Prescription chart and titration not known by generalists

Potential For Drug Errors Due to staff being unfamiliar with this type of analgesia, there is felt to be an

increased risk of user error.

Difficulties of dose titration. Uncertainty of how to prescribe doses on kardex so nursing staff are clear on what dose is to be given.

Administration and knowledge of how to use these products would be my main concern

Although I see the benefit of the rapid onset fentanyl products I have experienced a number of the above issues with its implementation. If hospice inpatient units struggle to titrate patients effectively on these products, we cannot expect generalists to be able to manage with little or no education.

Aware that cannot be given in community without administration sheet. This has delayed support to families in Administration of break through doses.

Some GPs struggle with transdermal fentanyl and do not understand dosing, I think IR fentanyl is likely to cause more confusion. My advice to them would be not to commence without specialist advice.

So much time is spent when prescribing Abstral for 1st time to patient, with patient/staff education, then the exhaustive exercise of prescribing it, getting charts, product information attached to patients prescription chart (I personally add patients addressograph to this info). I always feel uneasy when prescribing Abstral, not because of the drug per se, but potential drug errors in the hospital setting. I assume it would be much easier in the community.

BTcP was defined appropriately in most instances Most BTcP episodes managed with oxynorm and oramorph Side effects uncommon – most common was drowsiness Most episodes of BTcP relieved with 30 minutes Abstral most popular rapid onset Fentanyl product across all

settings

Concerns over storage, disposal, delay in access to medications

Many concerns over prescription issues (e.g. Documentation issues)

There are presently no validated assessment tool for the diagnosis of BTcP. Therefore, the diagnosis of BTcP should be made according to accepted definitions in the literature1;2 (figure 1). [Level 4]

Patients with BTcP should have this pain specifically assessed to determine the

aetiology of the pain, the pathophysiology and to highlight any factors that would indicate or contra-indicate specific interventions. [Level 4]

The optimal management of BTcP requires an individual approach. [Level 4] The underlying cause of the pain should be defined and where possible

treated3.[Level 4] Consideration should be given to avoidance/treatment of the precipitating

factors of the pain. [Level 4] Consideration should be given to modification of the background analgesic

regime. Dose titration and rotation of opioids may be required (see Guidelines on Opioid Substitution). Adjuvants and non-opioids should be used as appropriate. [Level 4]

Immediate-release opioids are the rescue medication of choice in the management of breakthrough pain episodes. Rapid onset fentanyl products may be useful for the typical BTcP episode3;5. [Level 1]

The decision to use a specific opioid preparation should be based on a combination of

the pain characteristics, the product characteristics, the patients’ response to opioids (in terms of efficacy and tolerability) and the patient’s preferences for the individual preparation3. [Level 4]

Non-pharmacological methods such as massage, heat packs, relaxation therapy may

be useful in the management of breakthrough pain episodes. These options should be explored if thought to be of potential benefit to the patient3 (Level 4).

Non-opioid analgesia (e.g. paracetamol, non steroidal anti-inflammatory drugs

(NSAIDs)) may be useful in the management of breakthrough pain episodes3. [Level 4]

Interventional techniques (e.g. surgical, anaesthetic, radiotherapy) may be indicated.

These options should be discussed early with the appropriate specialist whilst the patient remains fit enough to tolerate any procedure (see Guidelines on Interventional Pain Techniques). [Level 4]

Rapid-onset fentanyl citrate products should only be used in patients receiving maintenance opioid who are taking at the opioid equivalence of at least 60 mg of oral morphine daily (e.g. at least 25 micrograms of transdermal fentanyl per hour, at least 30 mg of oxycodone daily, at least 8 mg of oral hydromorphone daily) for a week or longer15-19.

The dose of the rapid onset fentanyl citrate products should be titrated in

accordance to the product-specific dose titration guidance. This process should be clearly documented in the medical record or prescription charts. [Level 4]

The dose of rapid-onset fentanyl citrate preparations required should be

determined by individual titration2;6;12;20. (Level 2) Patients using rapid onset fentanyl citrate preparations may still receive

alternative immediate release opioids (e.g. oramorph) on an as-required basis for their BTcP epsiodes1.

Patients taking rapid onset fentanyl citrate products should be regularly assessed to monitor compliance and adverse effects1. [Level 4]

Fentanyl is metabolized by the CYP3A4 isoenzyme in the liver and

intestinal mucosa. Therefore caution is required in patients taking CYP3A4 inhibitors such as macrolide antibiotics (e.g. erythromycin), azole antifungals (e.g. ketoconazole, itraconazole, and fluconazole) and certain protease inhibitors (e.g. ritonavir). These medications may increase the bioavailability of fentanyl and may also decrease its systemic clearance which may result in increased or prolonged opioid effects. Similar effects could be seen after concurrent ingestion of grapefruit juice, which is known to inhibit CYP3A4.

Patients’ opioid usage should be monitored carefully in the community

with particular attention to their maintenance therapy and potential accidental over-exposure. 1 [Level 4]

Name of drug Route PRN Fentanyl Dose Additional notes

Actiq Oral transmucosal lozenge 200,400,600,800, 1200,1600 micrograms lozenge

Application site reactions, including gum bleeding, irritation, pain and ulcer have been reported15.

Effentora Buccal tablets 100, 200, 400, 600 and 800 micrograms buccal tablets

Application site reactions including bleeding, pain, ulcer, irritation, paraesthesia, anaesthesia, erythema, oedema, swelling and vesicles16.

Abstral Sublingual tablets 100, 200, 400, 600, 800microgram sublingual tablets

Instanyl Intranasal spray Instanyl 50, 100, 200micrograms nasal spray, solution

Contraindicated if previous facial radiotherapy or recurrent episodes of epistaxis18. Concomitant use of nasally administered oxymetazoline has been shown to decrease the absorption. It is recommended that concomitant use of nasal decongestants is avoided18 Application site reactions such as epistaxis, nasal ulcer, rhinorrhoea have been reported18. If intranasal products have not been used for more than 7 days the pump must be sprayed once in the air before the next dose is taken18;19.

PecFent Intranasal spray 100, 400 micrograms nasal spray, solution fentanyl

Concomitant use of nasally administered oxymetazoline has been shown to decrease the absorption. It is recommended that concomitant use of nasal decongestants is avoided19. Application site reactions such as epistaxis, nasal ulcer, rhinorrhoea have been reported19. If intranasal products have not been used for more than 7 days the pump must be sprayed once in the air before the next dose is taken18;19.

All patients with cancer should be assessed for the presence of breakthrough

pain. [Grade D] The aetiology of the breakthrough pain should be identified in all patients.

[Grade D] A pain assessment tool (e.g. numeric pain score, pain diary) should be used to

assess pain and the response to inventions in all patients with breakthrough cancer pain. [Grade D]

When initiating rapid-onset fentanyl citrate products, all patients should have

their dose titrated using the product-specific manufacturers’ titration schedule, until their individual standard breakthrough dose is set. This process should be recorded clearly in the medical records or prescription charts in all instances. [Grade B]

Patients with uncontrolled breakthrough pain (i.e. >4 episodes of pain in 24hours)

should have at least weekly follow up as an outpatient, and 48 hourly reassessment if an inpatient. [Grade D]

(1) Dickman A. Integrated strategies for the successful management of breakthrough cancer pain. Curr Opin Support Palliat Care 2011; 5(1):8-14.

(2) Portenoy RK, Payne D, Jacobsen P. Breakthrough pain: characteristics and impact in patients with cancer pain. Pain 1999; 81(1-2):129-134.

(3) Davies AN, Dickman A, Reid C, Stevens AM, Zeppetella G. The management of cancer-related breakthrough pain: recommendations of a task group of the Science Committee of the Association for Palliative Medicine of Great Britain and Ireland. Eur J Pain 2009; 13(4):331-338.

(4) Portenoy RK, Burton AW, Gabrail N, Taylor D. A multicenter, placebo-controlled, double-blind, multiple-crossover study of Fentanyl Pectin Nasal Spray (FPNS) in the treatment of breakthrough cancer pain. Pain 2010; 151(3):617-624.

(5) Zeppetella G. Opioids for the management of breakthrough cancer pain in adults: a systematic review undertaken as part of an EPCRC opioid guidelines project. Palliat Med 2011; 25(5):516-524.

(6) Christie JM, Simmonds M, Patt R, Coluzzi P, Busch MA, Nordbrock E et al. 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):3238-3245.

(7) Coluzzi PH, Schwartzberg L, Conroy JD, Charapata S, Gay M, Busch MA et al. Breakthrough cancer pain: a randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulfate immediate release (MSIR). Pain 2001; 91(1-2):123-130.

(8) Farrar JT, Cleary J, Rauck R, Busch M, Nordbrock E. 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):611-616.

(9) Kaasa S, Moksnes K, Nolte T, Lefebvre-Kuntz D, Popper L, Kress HG. Pharmacokinetics of intranasal fentanyl spray in patients with cancer and breakthrough pain. J Opioid Manag 2010; 6(1):17-26.

(10) Kress HG, Oronska A, Kaczmarek Z, Kaasa S, Colberg T, Nolte T. Efficacy and tolerability of intranasal fentanyl spray 50 to 200 microg for breakthrough pain in patients with 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):1177-1191.

(10) Kress HG, Oronska A, Kaczmarek Z, Kaasa S, Colberg T, Nolte T. Efficacy and tolerability of intranasal fentanyl spray 50 to 200 microg for breakthrough pain in patients with 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):1177-1191.

(11) Mercadante S, Villari P, Ferrera P, Casuccio A, Mangione S, Intravaia G. Transmucosal fentanyl vs. intravenous morphine in doses proportional to basal opioid regimen for episodic-breakthrough pain. Br J Cancer 2007; 96(12):1828-1833.

(12) Portenoy RK, Taylor D, Messina J, Tremmel L. A randomized, placebo-controlled study of fentanyl buccal tablet for breakthrough pain in opioid-treated patients with cancer. Clin J Pain 2006; 22(9):805-811.

(13) Rauck RL, Tark M, Reyes E, Hayes TG, Bartkowiak AJ, Hassman D et al. Efficacy and long-term tolerability of sublingual fentanyl orally disintegrating tablet in the treatment of breakthrough cancer pain. Curr Med Res Opin 2009; 25(12):2877-2885.

(14) Slatkin NE, Xie F, Messina J, Segal TJ. Fentanyl buccal tablet for relief of breakthrough pain in opioid-tolerant patients with cancer-related chronic pain. J Support Oncol 2007; 5(7):327-334.

(15) electronic Medicines Compendium (eMC). Actiq - summary of product characteristics. http://www medicines org UK/EMC/medicine/11145/SPC/Actiq/ [ 2010 [cited 2011 Aug. 25];

(16) electronic Medicines Compendium (eMC). Effentora buccal tablets - summary of product characteristics. http://www medicines org UK/EMC/medicine/21401/SPC/Effentora+100%2c+200%2c+400%2c+600+and+800+micrograms+buccal+tablets/ [ 2010 [cited 2011 Aug. 25];

(17) electronic Medicines Compendium (eMC). Abstral sublingual tablets - summary of product characteristics. http://www medicines org UK/EMC/medicine/21371/SPC/Abstral+Sublingual+Tablets/ [ 2010 [cited 2011 Aug. 24];

(18) electronic Medicines Compendium (eMC). Instanyl - summary of product characteristics. http://www medicines org uk/EMC/medicine/22242/SPC/Instanyl+50%2c+100+and+200+mcg+dose+nasal+spray/ [ 2011 [cited 2011 Aug. 25];

(19) electronic Medicines Compendium (eMC). PecFent - summary of product characteristics. http://www medicines org uk/EMC/medicine/23962/SPC/PecFent/ [ 2011 [cited 2011 Aug. 25];

(20) Hanks GW, Conno F, Cherny N, Hanna M, Kalso E, McQuay HJ et al. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Cancer 2001; 84(5):587-593.