This program is supported by an educational grant from...

This program is supported by an educational grant from Meda Valeant Pharma Canada Inc.

Introduction

This CME program was developed to enhance the

awareness of physicians on the assessment and

management of breakthrough pain in cancer patients.

In addition, this educational program was created to

educate physicians in Canada to a novel approach in

the treatment of breakthrough pain in cancer patients

through the introduction of a new class of opioids known

as rapid-onset opioids.

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Conflict Disclosure Information

Presenter: Dr. Nadia R. Plach

Affiliation: Palliative Care Consultant,

Family Medicine, McMaster University

Financial Disclosure

Grants / Research Support / Consulting Fees: None

Speakers Bureau: Valeant, Pfizer Searle, Palladin

Purdue Pharma

I have NOT received financial or in-kind support from any

commercial organization for this presentation

Yvon Beauchamp, MD, CCFP

Montreal, Quebec

Jennifer Morwen-Smith, MD, MCFP

Vancouver, British Columbia

David Henderson, MD, CCFP, FCFP

Truro, Nova Scotia

May Ong-Lam, MD, FRCPC

Vancouver, British Columbia

Pravin Mehta, MD, CCFP, FCFP

Winnipeg, Manitoba

Sol Stern, BSc, MSc, MD, MCFP

Oakville, Ontario

Scientific Committee

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Impact of Breakthrough Pain

40%-80% of patients with advanced cancer

experience breakthrough pain (BTP).

Of all cancer patients:

83% indicated that BTP affects their desire to

participate in certain activities.

76% indicated that BTP affects their ability to perform

everyday household chores.

73% indicated that BTP wakes them from a deep

sleep at least once a month.

44% indicated that their pain is not adequately

controlled.

Davies A. Oxford University Press; 2006.

Hagen NA et al. Curr Pain Headache Rep. 2008;12(4):241-248.

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Learning Objectives

By the end of the program, participants will be able to

evaluate current and evolving information regarding BTP in cancer patients, including its definition, classification, and diagnostic criteria;

implement assessment and monitoring methods, including the identification of precipitating and predictive factors of BTP in cancer patients;

apply effective management strategies of BTP in cancer patients, as well as review the strengths and weaknesses of current and emerging treatment options.

Patient Presentation

David is a 74-year-old Caucasian man, widowed and currently lives with his son.

David has a past history of alcohol abuse and has not had alcohol for 5 years; he never smoked cigarettes.

During his last physical exam in June 2008, David described experiencing frequent bloating, and a routine blood test revealed he was slightly anemic.

Recommended follow-up tests and colonoscopy were never followed through by David.

Recently, David has been feeling fatigued and has been experiencing a loss of appetite; he has lost over 15 lbs. in the past 3 months.

He presents with chronic, persistent pain in his rectum, as well as an unrelenting pain in his pelvis.

He occasionally has pain in his left buttock and lower back, radiating to the left posterolateral thigh.

He is currently not taking any medications or supplements, and has no allergies documented.

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Medical History: August 2009

A colonoscopy revealed a large tumour in the left colon

with local involvement of the anterior wall of the rectum and

obturator muscles.

David had surgery to debulk the tumour, followed by

radiotherapy and chemotherapy.

Medical History: December 2009

A radionuclide bone scan

image of the posterior

pelvis revealed

metastases in the left iliac

bone and sacrum.

A CT image showed a

large, lytic bone metastasis

of the left pelvis with

invasion of the left iliacus

and gluteus muscles.

David received further radiotherapy.

http://radiology.casereports.net/index.php/rcr/article/viewArticle/15/1749

Patient Assessment

David began complaining of constant, generalized, left hip and

sacroiliac pain after the identification of the bony metastases and

the second round of radiotherapy.

A physical examination indicated tenderness to touch along the left sacrum and sciatic notch.

- David denies any lower extremity numbness or incontinence.

His main complaint is the pain experienced, which is accentuated by any sudden movement or prolonged sitting. This has led to

- the interruption of daily activities (eating, walking, playing with his grandchildren);

- the inability to sleep;

- the inability to sit upright, and finding comfort primarily by laying

down for extended periods on his right side.

His symptoms and the severity of the pain are continually assessed with the Brief Pain Inventory and numerical rating scale.

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Question 1

Taking David’s medical history into account, and that he is

opioid naïve, what options could be considered to manage his

pain (average pain rating of 6/10)?

Use non-opioids such as acetaminophen or NSAIDs

(ibuprofen), a coxib (celecoxib), or dexamethasone

Use a transdermal fentanyl patch

Use oral controlled-release (CR) opioids

Use an immediate-release (IR) opioid

Adjuvant therapies such as bisphosphonates,

calcitonin, gabapentin, or TCA

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Question 1

Taking David’s medical history into account, and that he is

opioid naïve, what options could be considered to manage his

pain (average pain rating of 6/10)?

Use non-opioids such as acetaminophen or

NSAIDs (ibuprofen), a coxib (celecoxib), or

dexamethasone

Use a transdermal fentanyl patch

Use oral controlled-release (CR) opioids

Use an immediate-release (IR) opioid

Adjuvant therapies such as bisphosphonates,

calcitonin, gabapentin, or TCA

Vielvoye-Kermeer AP et al. J Pain Symptom Manage. 2000;19(3):185-192.

Baseline Pain Management: WHO Pain Relief Ladder

Adapted from World Health Organization. Cancer pain relief. 1996.

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Short- and Long-Acting Opioids

14Argoff CE et al. Mayo Clin Proc. 2009;84(7):602-612.

*usually combined with a nonopioid. CR=controlled-release; IR=immediate-release; IV=intravenous;

TD=transdermal

Opioid Frequency

(hours)

Duration of

Effect

(hours)

Plasma

Half-Life

(hours)

Buprenorphine Up to 7 days (TD) Up to7 days ~ 26

Codeine* 3-6 4-6 3

Fentanyl 1-2 (IV, severe pain)

72 (TD)

0.5-1(IV);

72 (TD)

3-7

13-22

Hydromorphone 3-4 (IR);

12-24 (CR)

4-5 (IR);

12-24 (CR)

2-3

Methadone (Controlled Drugs and Substances Act)

6-8 4-6 24-56

Morphine 3-4 (IR);

12-24 (CR)

3-6 (IR);

24 (CR)

2-3.5

Oxycodone* 3-6 (IR);

12 (CR)

3-4 (IR);

8-12 (CR)

2.5-3

Tramadol* 4-6 (IR);

24 (CR)

4-6 (IR);

24 (CR)

5-7

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Principles of opioid therapy for chronic noncancer pain can be applied to cancer patients.

No reliable data to support the separation of cancer from noncancer chronic pain in the assessment and management of potential opioid dependence:

Long-term opioid therapy requires serious initial consideration and reconsideration over time to meet therapeutic goals and minimize future risk of abuse and addiction.

Clinicians must know how to apply the principles and practices of addiction medicine to all patients.

Regular assessment of the “six As” of pain medicine: analgesia, activity, affect, adverse reactions, aberrant behaviour, and adequate documentation.

Opioid Dependence and Chronic Pain

Ballantyne JC. Curr Pain Headache Rep. 2007;11(4):276-282.

Gourlay DL et al. Pain Medicine. 2009;10(S2):S115-S123.

Miaskowski C. Oncol Nurs Forum. 2008;35 Suppl:20-24.

Passik SD et al. Pain Medicine. 2008;9(2):261-265.

WHO. International Statistical Classification of Diseases and Related Health Problems (ICD-10). 2007.

As more patients survive cancer and require

management of chronic pain, healthcare professionals

must learn to balance cancer pain effectively and be

mindful of the potential risks for the misuse of, abuse

of, or addiction to opioid analgesics.

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Question 2

David is started on hydromorphone-CR, and the dose is titrated up to

Hydromorph Contin 6 mg orally every 12 hours and Hydromorphone 1

mg orally every hour as needed for breakthrough pain. David requires

4-5 breakthrough doses per day. However, he continues to describe a

persistent pain in his left lower back (pain scale rating of 8/10). He

also mentions an almost negligible tingling radiating down his left leg

and toes.

What is David experiencing?

Poorly controlled baseline pain

Breakthrough pain

Nociceptive somatic pain

Nociceptive visceral pain

Neuropathic sensations

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Question 2

David is started on hydromorphone-CR, and the dose is titrated up to

Hydromorph Contin 6 mg orally every 12 hours and Hydromorphone 1

mg orally every hour as needed for breakthrough pain. David requires

4-5 breakthrough doses per day. However, he continues to describe a

persistent pain in his left lower back (pain scale rating of 8/10). He

also mentions an almost negligible tingling radiating down his left leg

and toes.

What is David experiencing?

Poorly controlled baseline pain

Breakthrough pain

Nociceptive somatic pain

Nociceptive visceral pain

Neuropathic sensations

Classifications of Pain

Portenoy RK et al. Pain. 1990;41(3):273-281.

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Type Structures Pain Symptoms Treatment Options

NOCICEPTIVE

1. Somatic

2. Visceral

Bone

Muscle

Hollow viscus

(tubular organ;

e.g., intestine)

Solid viscus

(e.g., liver)

Aching

Stabbing

Throbbing

Diffuse

Gnawing

Cramping

Aching

Sharp

NSAIDs, steroids as

first-line

Opioids

NSAIDs, steroids as

first-line

Opioids

NEUROPATHIC Peripheral or

central neural

pathways

Burning

Lancinating

Numbing

Tingling

Radiating

Itching

Allodynia

Opioids

Analgesic adjuvants

(anticonvulsants,

tricyclics)

Methadone (etc.)

MIXED PAIN Refers to a combination of nociceptive and neuropathic pain

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Question 3

It is noted in David’s biweekly pain assessment interviews

that his baseline pain is being controlled by 12 mg of

hydromorphone-CR every 12 hours and hydromorphone 2 mg

orally every hour as needed for BTP. He experiences

flare-ups of pain in his lower back, which is exacerbated by

most types of movement, considerably so when trying to stand

upright. These episodes occur several times throughout the

day and last for about 20 minutes each; pain scale rating:

10/10.

What type of pain is David experiencing?

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Question 3

Breakthrough pain

It is noted in David’s biweekly pain assessment interviews

that his baseline pain is being controlled by 12 mg of

hydromorphone-CR every 12 hours and hydromorphone 2 mg

orally every hour as needed for BTP. He experiences

flare-ups of pain in his lower back, which is exacerbated by

most types of movement, considerably so when trying to stand

upright. These episodes occur several times throughout the

day and last for about 20 minutes each; pain scale rating:

10/10.


Diagnostic Algorithm for Breakthrough Pain

Adapted from Davies A et al. Eur J Pain. 2009;13(4):331-338.21

22Schematic from http://www.cephalon-europe.com

Working Definitions of Breakthrough Pain

1990: “A transitory exacerbation of pain that occurs on a background of otherwise stable pain in a patient receiving chronic opioid therapy.”

2009: “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.”

Other terms also used:

Episodic pain

Exacerbation of pain

Pain flare

Transient pain

Transitory pain

Characteristics of Breakthrough Pain

Characteristics of

BTP

Average Range

Time to peak

severity

3-5 minutes 10 seconds to 180

minutes

Intensity Severe to excruciating;

average pain scale

rating (8/10)

Mild to excruciating

Duration* 15-60 minutes 1 second to > 24 hours

Number of

episodes/day*

1-5 < 1 to 3600

American Pain Foundation. Target Chronic Pain Notebook: Taking Charge of Your Pain Care. 2008.

Bennett D et al. Pharmacy and Ther. 2005;30(5):296-301.

Mercadante S et al. J Pain Symptom Manage. 2010;40(2):183-190.

Portenoy RK et al. Pain. 1999;81(1-2):129-134.

*Neuropathic BTP shorter in duration with more episodes/day

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Subtype of BTP Causes

INCIDENT PAIN (~ 50% of BTP episodes)

(“precipitated pain”, “movement-related

pain”)

1.Volitional (predictable)

2.Non-volitional (unpredictable)

3.Procedural

Precipitated by a voluntary act

(e.g., walking)

Precipitated by an involuntary act

(e.g., coughing)

Related to a therapeutic intervention

(e.g., wound-dressing change)

SPONTANEOUS PAIN(“idiopathic pain”)

Occurs unexpectedly

Not induced by readily identifiable cause

Most commonly caused by underlying

neurological disorders

END-OF-DOSE* Related to analgesic dosing and declining

analgesic blood levels

Gradual in onset

Longer duration than incident and idiopathic pain

*sometimes not regarded as true BTP

Classifications of Breakthrough Pain

Assessing for Breakthrough Pain

Factors to consider when assessing for BTP:

The presence of breakthrough pain

The frequency and number of episodes per day

The duration (time in minutes)

The intensity and the time to peak in severity

The patient’s description of breakthrough pain

Any precipitating factors

A current and previous analgesic history

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Question 4

From what was reported in question 3, what type of pain is

David experiencing?

End-of-dose pain

Volitional incident BTP

Non-volitional incident BTP

Spontaneous BTP

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Question 4

From what was reported in question 3, what type of pain is

David experiencing?

End-of-dose pain

Volitional incident BTP


Spontaneous BTP

Zeppetella G. Eur J Cancer Care (Engl). 2009;18(4):331-337.

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Question 5

What measures might be taken to manage David’s

predictable volitional incident BTP?

Increase the frequency of oral controlled-release (CR)

opioids to every 8 hours

Change route of administration of CR opioids from oral

to parenteral

Occupational therapy assessment

Apply an ice pack and immobilize the patient

Dose ahead of time with an immediate-release opioid

or a rapid-onset opioid as needed

Use an ambulatory infusion pump at a steady dose,

with bolus as needed

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Question 5

What measures might be taken to manage David’s

predictable volitional incident BTP?

Increase the frequency of oral controlled-release (CR)

opioids to every 8 hours

Change route of administration of CR opioids from oral

to parenteral

Occupational therapy assessment

Apply an ice pack and immobilize the patient

Dose ahead of time with an immediate-release

opioid or a rapid-onset opioid as needed


with bolus as needed


Bennett et al. P&T. 2005b;30:354-361.

Non-pharmacological Approaches

Non-pharmacological Methods in the

Management of Breakthrough Pain

Physical Changing position

Physical and occupational therapy

Exercise – stretch, warm up, maintain good posture

Hot/cold compress, massage

Transcutaneous electrical nerve stimulation

Orthotic aids to stabilize painful pathologic site

Behavioural New sequencing of events to perform tasks

Pacing of activity to cope with pain/fatigue

Assist in developing adaptive behaviours

Psychological Visualization, guided imagery, hypnosis,

counselling, music therapy

30Swanwick M et al. Palliat Med. 2001;15(1):9-18.

Immediate-Release (IR) Opioids


IR Opioid

Onset of

Analgesia

(minutes)

Duration of Effect

(hours)

Hydromorphone 30 4

Morphine 30-40 4

Oxycodone 30 4

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Emerging Therapy: Rapid-Onset Opioids (ROOs)

Rapid onset of action, within 10-15 minutes

Acceptable route of administration (noninvasive) and convenient

to patients

Absorbed through the mucous membranes and enters the

bloodstream faster, providing quicker pain relief

Avoidance of first-pass metabolism by liver enzymes

32Fine P. In: The Diagnosis and Treatment of Breakthrough Pain, 2008.

Fentanyl Formulations

Formulations:

- bioerodible mucoadhesive film*

- oral transmucosal fentanyl citrate

- fentanyl effervescent buccal tablet

- sublingual fentanyl tablet*

- fentanyl solution nasal spray

High lipophilicity

- allows for rapid penetration into CNS structures relative to hydrophilic opioids (morphine, oxycodone, hydromorphone)

Highly potent analgesic with a rapid onset and a short duration of action

- compared to other opioids, fentanyl behaves differently and the transdermal route cannot be equated with other routes when calculating relative potency.

33*ROOs approved and available in Canada.

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Rapid-Onset Opioids (ROO)

Rapid-Onset

Opioid

Dose Range

(g)

Onset of

Analgesia

(Peak Pain Relief)

(minutes)

Duration of

Effect

(hours)

Approved in Canada

Bioerodible

mucoadhesive fentanyl

buccal soluble film

200-1200 < 15 Up to 1

Sublingual fentanyl

disintegrating tablet

100-800 < 15 Up to 1

Not Approved in Canada

Fentanyl buccal

effervescent tablet

100-800 < 15 Up to 2

Intranasal fentanyl

citrate spray (INFS)

50-400 < 15 Up to 1

Oral transmucosal

fentanyl citrate lozenge

(OTFC)

200-1600 < 15 Up to 2

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Rapid-Onset Opioids:

Adverse Effects, Safety, and Toxicity

Adverse drug events

- most commonly reported: nausea, vomiting, somnolence,

dizziness and headache

- other less common side effects include constipation, dry mouth,

urinary retention, and sedation or cognitive impairment

Patients must not be opioid naïve

Optimal dose requires titration

Overdose and accidental poisoning may occur:

Safe storage, caution should be observed in patients at high risk for addiction

Safe disposal

Universal precautions when prescribing opioids (contract with patient, blood urine testing, or other measures to improve monitoring)

Onsolis [package insert]. Solna, Sweden: Meda AB; 2009:4-5.

Onsolis [U.S. package insert];2009.

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David also complained of a diffuse tenesmic rectal pain with

bowel movements, lasting approximately 5 minutes per

episode; pain scale rating: 9/10.


Question 6

37

David also complained of a diffuse tenesmic rectal pain with

bowel movements, lasting approximately 5 minutes per




Question 6

Hagen NA et al. J Palliat Med. 2007;10(1):47-55.



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Question 7

How should David’s non-volitional incident BTP be managed?

Change route of administration of CR opioid from oral

to parenteral

Use transdermal fentanyl patch

Dose ahead of time with IR opioid as needed

Use ambulatory infusion pump at a steady dose, with

bolus as needed

None of the above

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Question 7

How should David’s non-volitional incident BTP be managed?

Change route of administration of CR opioid from oral

to parenteral

Use transdermal fentanyl patch


Use ambulatory infusion pump at a steady dose, with

bolus as needed

None of the above

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Question 8

David’s left sacroiliac pain was well controlled with

hydromorphone-CR (pain scale rating went from 8/10 to 3/10)

but he began experiencing gradual onset left lower back pain.

David still has BTP episodes, presenting around 60 minutes

before the next scheduled dose and lasting ~ 60 minutes per



41

Question 8

David’s left sacroiliac pain was well controlled with

hydromorphone-CR (pain scale rating went from 8/10 to 3/10)

but he began experiencing gradual onset left lower back pain.

David still has BTP episodes, presenting around 60 minutes

before the next scheduled dose and lasting ~ 60 minutes per



End-of-dose pain

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Question 9

How should David’s end-of-dose pain be managed?

Use of transdermal fentanyl patch

Use of an IR opioid, as needed

Increase the frequency or the dose of hydromorphone-CR

None of the above

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Question 9

How should David’s end-of-dose pain be managed?

Use of transdermal fentanyl patch

Use of an IR opioid, as needed

Increase the frequency or the dose of hydromorphone-CR

None of the above

Breitbart W et al. Oncology (Williston Park). 2000;14(5):695-705; discussion 705, 709-617.

Grond S et al. Pain. 1997;69(1-2):191-198.

Hanks GW et al. Br J Cancer. 2001;84(5):587-593.

Oxycodone Hydrochloride [package insert]; 2009.

Payne R. Anticancer Drugs. 1995;6 Suppl 3:50-53.

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Patient Assessment II – March 2009

Question 10

David had a bone scan that revealed osteolytic

metastases in the lumbar vertebrae of the spine.

He presented with a lancinating and burning

pain that radiates down his legs several times a

day, which he described as an “electric shock”,

independent of movement, lasting about 45

minutes each; pain scale rating: 9-10/10.

What type of pain is David experiencing?Image courtesy of Dr. Beauchamp

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Patient Assessment II – March 2009

Question 10

David had a bone scan that revealed osteolytic

metastases in the lumbar vertebrae of the spine.

He presented with a lancinating and burning

pain that radiates down his legs several times a

day, which he described as an “electric shock”,

independent of movement, lasting about 45

minutes each; pain scale rating: 9-10/10.


Spontaneous neuropathic BTP

Image courtesy of Dr. Beauchamp

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Question 11

How should David’s spontaneous pain be managed?

Assess the etiology of the pain before proceeding



plus bolus as needed

Use of an adjuvant analgesic

Add NSAIDs as needed

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Question 11

How should David’s spontaneous pain be managed?

Assess the etiology of the pain before proceeding



plus bolus as needed

Use of an adjuvant analgesic

Add NSAIDs as needed

Davies AN et al. Eur J Pain. 2009;13(4):331-338.


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Question 12

David is complaining that his spontaneous BTP is not being

treated quickly enough for him to feel any relief; what do you

do?

Increase the frequency of BLP analgesic

(hydromorphone) dosing

Increase BLP analgesic dose

Increase IR opioid dose

Change route of IR opioid from oral to parenteral

Use a rapid-onset opioid

Use adjuvant analgesics such as gabapentin and

tricyclic antidepressants

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Question 12

David is complaining that his spontaneous BTP is not being

treated quickly enough for him to feel any relief; what do you

do?

Increase the frequency of BLP analgesic

(hydromorphone) dosing

Increase BLP analgesic dose

Increase IR opioid dose

Change route of IR opioid from oral to parenteral

Use a rapid-onset opioid

Use adjuvant analgesics such as gabapentin and

tricyclic antidepressants

Portenoy RK et al. In: Oxford Textbook of Palliative Medicine, 2004.

Rauck R et al. Ann Oncol. 2010;21(6):1308-1314.

Summary: Treatment Options for BTP

50William L et al. Drugs. 2008;68(7):913-924.

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Key Learning Points

BTP is defined as a specific clinical entity that occurs as

pain flare-ups over and above well-controlled baseline pain.

40%-80% of patients with advanced cancer experience

BTP.

The clinical features of BTP are understood to be rapid

onset with short duration. The pain is moderate-to-severe in

intensity and frequent in occurrence.

Assessment tools for BTP, such as patient interviews, need

to be universally adopted in practice as they provide crucial

information regarding precipitating factors and aid in the

appropriate management of BTP.



Mercadante S et al. Cancer. 2002;94(3):832-839.


Rauck R et al. Ann Oncol. 2010;21(6):1308-1314.

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Key Learning Points

Incident, spontaneous, and end-of-dose pain are subtypes

of BTP that have different predictive factors and

pharmacological management options.

It is important to assess the etiology of BTP, as nociceptive

and neuropathic pain have different management

strategies.

Emerging opioid therapies include rapid-onset opioids,

which can help to deliver faster relief to cancer patients

with BTP.



Hagen NA et al. J Palliat Med. 2007;10(1):47-55.

Mercadante S et al. Cancer. 2002;94(3):832-839.


Selvaggi K et al. Nat Clin Pract Oncol. 2006;3(8):458-461; quiz following 461.


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