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. 2

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 3

Scientific Committee 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 4

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. 5 Davies A. Oxford University Press; 2006. Hagen NA et al. Curr Pain Headache Rep. 2008;12(4):241-248.

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. 6

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. 7

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. 8

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. 9 http://radiology.casereports.net/index.php/rcr/article/viewarticle/15/174

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. 10

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 11

Baseline Pain Management: WHO Pain Relief Ladder 13 Adapted from World Health Organization. Cancer pain relief. 1996.

Short- and Long-Acting Opioids 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 14 Tramadol * * usually combined with a nonopioid. CR=controlled-release; IR=immediate-release; IV=intravenous; TD=transdermal 4-6 (IR); 24 (CR) 4-6 (IR); 24 (CR) 5-7 Argoff CE et al. Mayo Clin Proc. 2009;84(7):602-612.

Opioid Dependence and Chronic Pain 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. Principles of opioid therapy for chronic noncancer pain can be applied to cancer patients. 15 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. 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.

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 16

Classifications of Pain Type Structures Pain Symptoms Treatment Options NOCICEPTIVE 1. Somatic Bone Muscle Aching Stabbing Throbbing NSAIDs, steroids as first-line Opioids 2. Visceral Hollow viscus (tubular organ; e.g., intestine) Diffuse Gnawing Cramping NSAIDs, steroids as first-line Opioids Solid viscus (e.g., liver) Aching Sharp NEUROPATHIC MIXED PAIN Peripheral or central neural pathways Burning Lancinating Numbing Tingling Radiating Itching Allodynia Opioids Analgesic adjuvants (anticonvulsants, tricyclics) Methadone (etc.) Refers to a combination of nociceptive and neuropathic pain 18 Portenoy RK et al. Pain. 1990;41(3):273-281.

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? 19

Diagnostic Algorithm for Breakthrough Pain 21 Adapted from Davies A et al. Eur J Pain. 2009;13(4):331-338.

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

Characteristics of Breakthrough Pain Characteristics of BTP Time to peak severity Average Range 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 *Neuropathic BTP shorter in duration with more episodes/day 23 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.

Classifications of Breakthrough Pain Subtype of BTP INCIDENT PAIN (~ 50% of BTP episodes) ( precipitated pain, movement-related pain ) 1.Volitional (predictable) 2.Non-volitional (unpredictable) 3.Procedural SPONTANEOUS PAIN ( idiopathic pain ) Causes 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) 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 24 *sometimes not regarded as true BTP

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 25

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 26

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

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 28

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 30 Swanwick 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 31 Bennett D et al. Pharmacy and Ther. 2005;30(5):296-301.

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 32 Fine 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.

Rapid-Onset Opioids (ROO) Rapid-Onset Opioid Bioerodible mucoadhesive fentanyl buccal soluble film Sublingual fentanyl disintegrating tablet Fentanyl buccal effervescent tablet Intranasal fentanyl citrate spray (INFS) Dose Range ( g) Approved in Canada Onset of Analgesia (Peak Pain Relief) (minutes) Duration of Effect (hours) 200-1200 < 15 Up to 1 100-800 < 15 Up to 1 Not Approved in Canada 100-800 < 15 Up to 2 50-400 < 15 Up to 1 34 Oral transmucosal fentanyl citrate lozenge (OTFC) 200-1600 < 15 Up to 2

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

Question 6 David also complained of a diffuse tenesmic rectal pain with bowel movements, lasting approximately 5 minutes per episode; pain scale rating: 9/10. What type of pain is David experiencing? Non-volitional incident BTP 37 Hagen NA et al. J Palliat Med. 2007;10(1):47-55. Mercadante S et al. J Pain Symptom Manage. 2010;40(2):183-190. Zeppetella G. Eur J Cancer Care (Engl). 2009;18(4):331-337.

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 38

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 episode; pain scale rating: 7/10. What type of pain is David experiencing? 40

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 42

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 43 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.

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 44

Question 11 How should David s spontaneous pain be managed? Assess the etiology of the pain before proceeding Dose ahead of time with IR opioid as needed Use an ambulatory infusion pump at a steady dose, plus bolus as needed Use of an adjuvant analgesic Add NSAIDs as needed 46

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 48

Summary: Treatment Options for BTP 50 William L et al. Drugs. 2008;68(7):913-924.

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. 51 Bennett D et al. Pharmacy and Ther. 2005;30(5):296-301. Davies AN et al. Eur J Pain. 2009;13(4):331-338. Mercadante S et al. Cancer. 2002;94(3):832-839. Mercadante S et al. J Pain Symptom Manage. 2010;40(2):183-190. Rauck R et al. Ann Oncol. 2010;21(6):1308-1314.

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. 52 Bennett D et al. Pharmacy and Ther. 2005;30(5):296-301. Davies AN et al. Eur J Pain. 2009;13(4):331-338. Hagen NA et al. J Palliat Med. 2007;10(1):47-55. Mercadante S et al. Cancer. 2002;94(3):832-839. Mercadante S et al. J Pain Symptom Manage. 2010;40(2):183-190. Selvaggi K et al. Nat Clin Pract Oncol. 2006;3(8):458-461; quiz following 461. Zeppetella G. Eur J Cancer Care (Engl). 2009;18(4):331-337.