Oxycontin KOL Slide FINAL

OXYCODONESLIDE SET

OXYCODONE IN PAIN MANAGEMENTAchieving an effective and tolerable approachto the treatment of different types ofmoderate-to-severe chronic pain

INTRODUCTION AND DESCRIPTION OF PAINPain: introductionPain: assessmentPain: a multifactorial syndromePain: aetiology Pain: prevalence

Section I

1. International Association for the Study of Pain (IASP)

• Pain is "an unpleasant sensory and emotional experience associated with actual or potential tissue damage”1

• Acute Pain – Pain that stops with simple measures such as resting or

taking an analgesic is acute pain

• Chronic Pain– When it is intractable and develops into a condition it is

called chronic pain

4

Introduction to pain

Pain is a subjective experience, but it can be described and assessed using validated questionnaires and scales

• Categorical scales• Numerical scales • Visual analogue scales

5

Assessment of pain

Categorical Pain Relief Scale The patient is asked to rate pain relief experienced now with the following possible responses: 0 My pain is now worse compared with my usual pain 1 There is no change in my pain compared with my usual pain 2 There is slight improvement in my pain compared with my usual pain 3 There is moderate improvement in my pain compared with my usual pain 4 There is a lot of improvement in my pain compared with my usual pain 5 I have complete relief of my pain

Visual Analogue Pain Scale The scale is a 100-mm-long horizontal line drawn on a piece of paper. It ranges from 0 on the left axis, which indicates no pain, to 100 mm on the right axis, which indicates worst pain possible. At each time point, patients are asked to mark across the line with a pen as to the degree of pain they are expecting at that time. 0…………………………………………………………………………………….100 No pain Worst pain possible

Pain Relief Scale The scale is a 100-mm-long horizontal line drawn on a piece of paper It ranges from 0 on the left axis, which indicates no pain relief, to 100 mm on the right axis, which indicates complete pain relief. At each time point, patients are asked to mark across the line with a pen as to the degree of pain relief they are experiencing at that time 0……………………………………………………………………………………100 No pain relief Complete pain relief

Descriptions of the Categorical Pain Relief Scale, Visual Analogue Pain Scale, and Pain Relief Scale

6Adapted from Wermeling DP et al. Pharmacotherapy 2006;26(3):395-402.

Assessment of pain

7Adapted from Breivik H et al. Br J Anaesthesia 2008;101(1):17-24.

Commonly used one-dimensional pain intensity scales: the 11-point NRS, the VAS from no pain (=0) to worst pain imaginable [=10 (or 100)] and the four-point categorical

verbal rating scale (VRS)NRS – Numeric Rating Scale; VRS – Verbal Rating Scale; VAS – Visual Analogue Scale

Categorical scale

Basic requirement: measure amount of pain

Have you experienced unusual or ongoing pain recently? Yes____ NO_____

Location of pain____ (Provide body figure drawing if necessary)

Numeric rating scale (NRS)

Overall pain now (circle one)

Average over past week

Worst pain over past week

Least pain over past week

Acceptable level of pain

I would be happy with my treatment /could do the thing I want/return to work, etc. if I had a pain level of

What medication and other treatment do you use for pain relief

Level of pain relief (with current medication and other treatment)

No pain 0 Worst possible pain 10

No relief Complete relief

8Adapted from http://stahlonline.cambridge.org/content/ep/images/85702c15_tbl11.gif

Numerical scale

http://stahlonline.cambridge.org/content/ep/images/85702c15_tbl11.gif

This pain assessment tool is intended to help patient care providers assess pain according to individual patient needs. Explain and use 0-10 Scale for patient self-assessment. Use the faces or behavioural observations to interpret expressed pain when patient cannot communicate his/her pain intensity

NOHURT

0

HURTS LITTLEBIT2

HURTS LITTLEMORE

4

HURTS EVEN MORE

6

HURTS WHOLELOT

8

HURTSWORST

10

Adapted from Hockenberry MJ, Wilson D: Wong’s essentials of pediatric nursing, ed. 8, St. Louis, 2009, Mosby. Used with permission. Copyright Mosby.

1

9

UNIVERSAL PAIN ASSESSMENT TOOL

Visual analogue scale

Pain analysis

Pain managem

ent

Analgesic medicatio

n

Specialist involveme

nt

Anxiety

Panic

Low mood

Depression

Irritation

Housing

Financial status

Employment

Family

Friends

Why? Judgement Religion Values

TOTAL PAIN

Psychological factors

Social factors

Philosophical factors

Physical factors

Merskey IASP Press 1994; http://www.masp.org.my/index.cfm?menuid=19&parentid=12 10

Pain – a multifactorial syndrome

Siegel, der Klinikarzt, 2001;4. 11

Pain aetiology

Spine back, 28%

Arthritic conditions, 20%

Tumors, 2%Medical interventions, 4%

Neurological conditions, 4%

Injuries, 5%

Ischemic Heart Diseases, 5%

Symptomatic pain, 9%

Skeletal system,other,16%

Spine/Back

Arthrosis

Other

Ischaemic heartdisease

Symptomatic pain

Injuries

Neurologicalconditions

Medical interventions

Tumours

Siegel, der Klinikarzt, 2001;4. 12

Pain treatment and aetiology

Chronic non-malignant pain

19% of the population1 (up to

40%)2

Post-operative pain47- 80% dependent

on surgery type3

Cancer pain 50-70% dependent on disease stage4

1. Breivik H et al. Eur J Pain 2006;10(4):287-333; 2 . Verhaak et al. Pain 1998;77(3):231-239; 3. Perkins FM & Kehlet H, Anesthesiology 2000;93(4):1123-1133; 4. Higginson 1 Prog Pain Res Manage 1997;8:707-716. 13

Prevalence of pain

• Chronic pain is a major healthcare problem worldwide1

• Each year, acute pain affects 15–20%, while chronic pain affects 25–30% of the US population2

• Chronic pain is also a major healthcare problem in Asia Pacific where it has long been neglected due to a lack of understanding and awareness among the general public, health policy makers, and healthcare professionals1

• With chronic pain currently affecting one in five adults worldwide, it is poised to become one of the most critical healthcare issues1

• Chronic pain can drastically limit the quality of life and well-being of sufferers and places a considerable burden on healthcare systems1

1. Asia Pacific Declaration for Chronic Pain Relief. Backgrounder. 1st Congress of the Association of Southeast Asian Pain Societies 2006; (http://www.masp.org.my/index.cfm?menuid=19&parentid=12). 2. Bonica JJ, Loeser JD. Bonica’s Management of Pain. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:3–16. 14

Prevalence of pain

http://www.masp.org.my/index.cfm?menuid=19&parentid=12

PAIN: AN UNMET CLINICAL NEEDRisk of under-treatment of painUnder-treatment of painBarriers to pain managementPain an unmet clinical need in EuropeCancer pain an unmet needPain an unmet need in Asia Pacific

Section II

15

• When chronic pain sufferers have acute pain as well as chronic pain, they are at risk for under-treatment of pain1

• In many developing countries, pain is regarded as inevitable, and patients are encouraged to live with it

1. Donna VW. Non-Narcotic Options for Pain Relief with Chronic Neuropathic Conditions. J Nurse Practition 2008; http://www.medscape.com/viewarticle/576064 16

Risk of pain under-treatment is high

Chronic pain in America: roadblocks to relief. Survey Conducted for: The American Pain Society, The American Academy of Pain Medicine and Janssen Pharmaceutica Conducted by: Roper Starch Worldwide Inc. January 1999; http://www.ampainsoc.org/links/roadblocks/

• The under-treatment of pain has a tremendous impact on an individual’s Quality of Life

Almost of chronic pain sufferers have changed physicians at least once

while of severe pain sufferers have switched three times or more

50%

29%

17

Impact on Quality of Life and physician shift

Patient related

• Failure to report pain to the physician• Thinking one can “see pain through”• Underestimating the level of pain• Fear pain portends a serious illness or poor diagnosis

• Concerns about side effects of opioids• Association of the appropriate clinical use of opioids with addiction

• Resigned to live with pain

Physician related

• Failure to adopt a specific assessment tool• Limited time for optimal pain management• Lack of accountability for pain management practice

• Inadequate knowledge about pain treatment• Focus on treating only disease rather than disease and the pain

• Emphasis on outpatient care• Reimbursement policies

SMA News June 2007;39(6). 18

Barriers to pain management

Outcomes of attitudinal analysis (n=4839)

Pain

Employment

Clinical intervention

66% had moderate pain

34% had severe pain

61% less able or unable to work

Only 2% had been managed

by pain specialist

19% had lost their job

13% had changed their

job

60% had 2 to 9 doctor visits in last 6 months

Breivik H et al. Eur J Pain 2006;10(4):287-333. 19

Pain – an unmet clinical need

• On average, sufferers lived with chronic pain for a mean of 5.9 years

• One-fifth had suffered pain for >20 years


Duration of pain

PAIN

64% feel treatment is inadequate

28% believe healthcare professionals (HCPs) do not know how to treat

pain

Only 5% receive strong opioids

Most patients prescribed NSAIDS (44%)

Only 23% referred to pain specialist

43% believe HCPs focus on illness not pain

40% do not have adequate pain relief


Pain perceptions

• Pain is a common and devastating symptom of cancer

• Untreated or poorly treated pain has a negative impact on physical functioning and psychological well-being

• Persistent pain is devastating for Quality of Life (QoL)

22

Pain – an unmet clinical need in cancer

• Cancer pain is poorly recognised and treated

• Phase 1: EPIC survey evaluated pain in 4947 people with cancer– Prevalence of pain was 72%– 23% received no pain medication

• Phase 2: EPIC in depth analysis in 573 people– Incidence of breakthrough pain 63%– 58% experience pain frequently

Breivik H et al. Ann Oncol 2009; [online Feb 24, 2009; doi:10.1093/annonc/mdp001]. 23

Pain – an unmet clinical need in cancer

Breivik H et al. Ann Oncol 2009; [online 24th Feb 2009;doi10.1093/annonc/mdp001].

PAIN

11% of patients (NRS>5) receiving

no analgesia

38% felt only cancer treated, not pain

Most common side effect – constipation 37%

36% left in intolerable pain

63% had breakthrough pain

22% never asked about their pain

by HCPs

50% believe HCP does not consider QoL important Only 33% of HCPs use pain

scales

24

Patient perceptions in cancer pain

Breivik H et al. Ann Oncol 2009; [online 24th Feb 2009;doi10.1093/annonc/mdp001].

Pain is widespread

Pain is under-treated

Treatment is often sub-optimal

Breakthrough pain is under-treated

More than half of patients reported pain within the previous month

Almost one-tenth of those suffering moderate-to-severe pain were not receiving prescription analgesia

Treatment side-effects such as constipation are often not addressed

Breakthrough pain is common but the majority of sufferers do not receive

additional medication

25

Summary

1. Asia Pacific Declaration for Chronic Pain Relief. Backgrounder. 1st Congress of the Association of Southeast Asian Pain Societies 2006; (http://www.masp.org.my/index.cfm?menuid=19&parentid=12).

• Many people in Asia Pacific unnecessarily endure debilitating chronic pain, often because they do not seek treatment, believe chronic pain is a natural part of growing older, or cannot articulate symptoms to their doctor1

26

Pain – a burden in Asia Pacific region


GOAL OF PAIN MANAGEMENTPrinciples of pain managementWHO ladder of pain interventionChallenging the WHO 3 step ladder The need of the hour: a two step analgesic approach

Section III

27

28

Minimise pain and

Improve Quality of Life

Goal of pain management

1. Bond MR. Pain – its nature and treatment. Churchill Livingstone , 2006; 2. White A, et al. Rheumatology 2007;46(3):384-390.;3. Krismer M, et al. Best Pract Res Clin Rheumatol 2007;21(1):77-91.

Opioids for severe pain

Non-Opioid analgesics

Psycho-social

support

Alternate therapy Co-

analgesics

Opioids for mild pain

Treatment for side effects

PAIN

29

Pain management – principles and options

World Health Organization. Cancer pain relief: with a guide to opioid availability. 2nd ed. Geneva:The Organization;1996. 30

WHO 3 step ladder

1. Cleeland CS et al. NEJM 1994;330(9):592-596. 2. Maltoni M et al. Support Cancer Care 2005;13(11):888-894.

Despite widespread use of the WHO ladder Pain control remains sub-optimal

Barriers that hinder drug use

Guidelines poorly implemented

Chronic pain more difficult to treat than

expected

Utility of Step 2 questioned

31

Challenging the WHO 3 step

The need of the hour:- a two step analgesic approach

32

Patients receiving Step 3 opioidsearly had superior pain relief – patients had fewer days with pain intensity > 5 (NRS 0-10)

Fewer patients receiving Step 3opioids early were dissatisfied with therapy

*p<0.001, **p=0.023

Maltoni M et al. Support Cancer Care 2005;13(11):888-894.

Conventional treatment: treated according to WHO 3 step ladderInnovative treatment: direct move to Step 3 after Step 1

33

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100

Conventional treatment Innovative treatment

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A two step analgesic approach

AN OVERVIEWOxycodone

34

• Oxycodone has been used clinically for more than 80 years and is available in the following formulations:

– Immediate release (IR) oral capsules* (5, 10 and 20mg)

– Prolonged release (PR) tablets (5, 10, 20, 40 and 80mg)

35* Capsules are not available in all countries. Korea has IR tablet & Japan has powder formulation.

Oxycodone hydrochloride - formulations

1. Riley J et al. Curr Med Res Opin 2008;24(1):175-192; 2. Levy MH et al. Eur J Pain 2001;5(Suppl. A):113-116; 3. Biancofiore G. Ther Clin Risk Manage 2006;2(3):229-234. 4. Curtis GB et al. Eur J Clin Pharmacol 1999;55(6):425-429.

No ceiling dose2

Predictable PK profile2

Negligible clinical impact of metabolites2

Effective in a broad range of moderate-

to-severe chronic pain1 Metabolised by CYP3A4 /

CYP2D6

>60% oral bioavailability3

Analgesic potency twice that of morphine4

Some κ-agonist activity1

36

Characteristics of oxycodone

• Two hydrophobic polymers from a dual control matrix, resulting in biphasic release and absorption– Rapid release of oxycodone from the tablet surface allows early

onset of analgesia1, 2

– Sustained second phase of dissolution and diffusion through the tablet matrix maintains effective blood concentrations throughout the 12-hour dosing interval2,3

1. Curtis GB et al. Eur J Clin Pharmacol 1999;55(6):425-429; 2. Sunshine A et al. J Clin Pharmacol 1996;36(7):595-603; 3. Citron ML et al. Cancer Invest 1998;16(8):562-571. 37

Innovative delivery system

• Prolonged release oxycodone has demonstrated proven efficacy in moderate-to-severe:

– Neuropathic pain (diabetic neuropathy, postherpetic neuralgia)

– Somatic pain (lower back pain, osteoarthritis)

– Visceral pain

– Cancer pain

38

Oxycodone – proven analgesic efficacy in moderate-to-severe pain

EFFICACY OF OXYCODONE TABLETS IN PAIN MANAGEMENTNeuropathic painSomatic painVisceral painCancer pain

Section IV

39

Proven efficacy in neuropathic painOxycodone tablets

40

• Chronic neuropathic and inflammatory pain are often under-diagnosed and mismanaged in the Asia Pacific region, leading to prolonged patient suffering and additional strain on the healthcare system1


Neuropathic pain: an unmet clinical need in Asia Pacific region


• Chronic neuropathic pain is difficult for patients to describe and for doctors to diagnose. Unlike other forms of pain, neuropathic pain responds poorly, or not at all, to the standard analgesic drugs1


Asia Pacific declaration for neuropathic pain


• Peripheral neuropathic pain:– Painful diabetic neuropathy (PDN)– Postherpetic neuralgia (PHN)– Trigeminal neuralgia (TGN)

• Central neuropathic pain:– Stroke pain, pain in multiple sclerosis and post-spinal cord

injury

• Characterised by:– Burning, aching or shooting pain– Allodynia– Hyperalgesia

Hansson P. Eur J Pain 2002;6(Suppl. A):47-50. 43

Neuropathic pain conditions

• In a meta-analysis of RCTs, intermediate-term studies demonstrate significant efficacy of opioids over placebo for neuropathic pain1

Favours Opioid

Favours Control

441. Eisenberg E, et al. JAMA 2005;293(24):3043-3052.

Treatment of neuropathic pain with opioids

Post –treatment Pain Intensity (Mean [SD])

Opioid(n =263)

Placebo(n=258)

Type of pain condition: Diabetic neuropathy* 41.0 [27.0]

(n=82)53.0 [26.0](n=77)

Phantom limb** 33.0 [16.0](n=12)

40.0 [12.0](n=12)

Mixed neuropathic† 60.0 [40.0](n=19)

64.0 [19.0](n=19)

Post-herpetic neuralgia‡ 44.0 [24.0](n=76)

60.0 [20.0](n=76)

Post-herpetic neuralgia* 35.0 [25.0](n=38)

54.0 [25.0](n=38)

Diabetic neuropathy* 26.3 [24.7](n=36)

46.7 [26.9](n=36)

*Oxycodone CR; **Morphine CR; † Low-dose methadone; ‡ Morphine.

Ong EC. Oncology 2008;74(Suppl.1):72-75.

Baseline

Initiation of oxycodone (CR)

Follow-up 2-4 weeks

Non-malignant neuropathic pain

(n=35)

Malignant neuropathic pain (n=32)

VAS 8-10/10 (100%; n=35)

VAS 10/10 (100%; n=32)

VAS 1-2/10 (94%; n=33)

VAS 4-8/10 (6%; n=2)

VAS 2-4/10 (100%; n=100)

Oxycodone controlled-release tablets may be effective in neuropathic pain arising from diverse aetiologies

45

Efficacy of oxycodone controlled-release tablets in managing neuropathic pain

The mean daily dose of oxycodone controlled-release tablets during the final week of treatment was 45mg

Watson C and Babul N. Neurology 1998;50(6):1837-1841. 46

Oxycodone controlled-release tablets are effective for the relief of overall, steady, brief and skin pain in patients with post-herpetic

neuralgia, when compared with placebo

Mean daily pain intensity

Steady pain Brief pain Skin painMean

pain

VA

S p

ain

score

(m

m)

Efficacy of oxycodone controlled-release tablets in postherpetic neuralgia

Watson CP et al. Pain 2003;105(1-2):71-78.

Oxycodone controlled-release tablets are effective in the relief of neuropathic pain in diabetic neuropathy, when compared with active

placebo

47

Mean daily pain intensity

Steady pain Brief pain Skin painMean

pain

VA

S p

ain

score

(m

m)

Efficacy of oxycodone controlled-release tablets in painful diabetic neuropathy

Oxycodone controlled-release tablets are significantly more effective than placebo for the relief of pain in diabetic neuropathy

Gimbel JS et al. Neurology 2003;60(6):927-934.

When first-line therapies are inadequate, oxycodone controlled-release tablets are effective in low doses in controlling severe painful diabetic

neuropathy

Baseline Days 1-27 Days 28-42

Least

sq

uare

mean

s B

S-1

1p

ain

score

s (

boxes)

48

Efficacy of oxycodone controlled-release tablets in painful diabetic neuropathy

• Patients had neuropathic pain due to PHN (n=22) or DPN (n=35) • Maximum doses; morphine alone, 120mg; combination – morphine 60 mg, gabapentin (GBT) 2400 mg; GBT alone 3200 mg

P<0.001 GBT vs. GBT/morphineP=0.01 morphine vs. placeboP=0.04 morphine vs. GBT/morphine

Gilron I et al. NEJM 2005;352(13):1324-1334. 49

Gabapentin plus morphine provides pain control superior to either agent alone

Hanna M et al. Eur J Pain 2008;12(6):804-813.

Co-administration of oxycodone prolonged release tablets and existing gabapentin (GBT) therapy has a clinically meaningful effect in painful diabetic neuropathy (PDN)

50

Mean

BS

-11

pain

score

s (

boxes)

Oxycodone prolonged release tablets with gabapentin optimise pain relief in PDN

• Neuropathies included: *FBSS, Stenosis **MSC, PHN, DPN & radiculopathy

• Mean start doses:– Monotherapy:

oxycodone (CR) 24.1mg, pregabalin 85.6mg

– Combination therapy: oxycodone (CR) 19.4mg, pregabalin 108.1mg

• Doses titrated to efficacy

Gatti A, et al. Eur Neurol 2009;61(3):129-137. 51

Days of treatment

NR

S a

vera

ge s

core

* FBSS, failed back surgery syndrome; ** MSC, medullary spinal canal

Oxycodone controlled-release tablets and pregabalin – an effective combination in neuropathic pain

Gatti A, et al. Eur Neurol 2009;61(3):129-137.

52

Monotherapy (Oxycodone tablets(CR) n=106;

pregabalin n=134)

Combined therapy (Oxycodone tablets (CR)+

pregabalin n=169)

Study start Study startStudy end

Study end

Mean

dose

(mg

/day)

Oxycodone controlled-release tablets and pregabalin – combination therapy facilitates dose reduction

Hempenstall K et al. Analgesic therapy in postherpetic neuralgia: a quantitative systematic review. PLoS Med 2005;2:e164.

Tricyclic antidepressants, opioids, gabapentin, tramadol and pregabalin can be considered effective treatments for

postherpetic neuralgia

Intervention NNT (95% CI)

Oxycodone prolonged release tablets

Tricyclic antidepressants

Combined opioids

Gabapentin

Tramadol

Pregabalin

2.50 (1.74 - 4.41)

2.64 (2.1 - 3.54)

2.67 (2.07 - 3.77)

4.39 (3.34 - 6.07)

4.76 (2.61 - 26.97)

4.93 (3.66 - 7.58)

53

Analgesic therapy in postherpetic neuralgia

NNT to obtainone patient with>50% pain relief

No. of patients with >50% pain relief if 100 patients are treated

Adapted from Sindrup SH, Jensen TS. Pain 1999;83:389-400.

For every 100 patients treated with the TCAs amitriptyline or desipramine, 43 would achieve greater than 50% pain relief.

54

Oxycodone prolonged release tablets - an effective treatment in postherpetic neuralgia

Adapted from Sindrup SH, Jensen TS. Pain 1999;83:389-400.

For every 100 patients treated with gabapentin, 31 would achieve greater than 50% pain relief

55


No. of patients with>50% pain reliefif 100 patientsare treated


For every 100 patients with moderate-to-severe intensity pain treated with oxycodone, 40 would achieve greater than 50% pain relief.

Adapted from Sindrup SH, Jensen TS. Pain 1999;83:389-400. 56


No. of patients with>50% pain reliefif 100 patientsare treated


Proven efficacy in somatic painOxycodone tablets

57

• Caused by activation of pain receptors at the body surface, or in musculoskeletal tissue (‘deep pain’)– Deep pain is usually described as a localised dull, aching pain– Surface pain is usually sharper, and may be described as

‘burning’ or ‘pricking’

• Examples of somatic pain include:– Osteoporotic bone pain– Chronic low back pain– Joint pain– Post-surgical cutaneous pain

58

Challenges of somatic pain

• Randomised, double-blind, 3-month placebo-controlled study in patients with osteoarthritis

• Oxycodone prolonged release tablets led to significant improvement in WOMAC subscales and composite scores on days 30 and 60 compared with placebo group1

1. Markenson JA, et al. Clin J Pain 2005;21(6):524-535.

-25

-20

-15

-10

-5

0

Oxycodone tablets (PR)

Placebo (n=51)

*

*

** * p< 0.001

Pain Stiffness Physical function

Composite

Ad

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ean

ch

an

ge

(mm

) in

WO

MA

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m b

aselin

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0

59

Oxycodone prolonged release tablets – efficacy in osteoarthritis

601. Markenson JA, et al. Clin J Pain 2005;21(6):524-535.

Change in LS Mean BPI Interference score from

baseline at Day 90

P=0.001

P=0.012

P<0.001

P=0.006

P=0.018

Interference Composite

Enjoyment of Life

Sleep

Normal Work

Mood

• Randomised, double-blind, 3-month placebo-controlled study in patients with osteoarthritis

• Oxycodone prolonged release tablets led to a significant improvement in patients’ function compared with placebo1

Oxycodone prolonged release tablets – efficacy in osteoarthritis

Roth SH et al. Arch Intern Med 2000;160(6):853-860.

Mean dose

Mean pain intensity

Baseline pain intensity lead-in

Weeks

Mean

dose (

mg

/day)

Mean

pain

inte

nsity

61

• The figure shows that patients’ mean dose of oxycodone controlled-release tablets stabilised at approximately 20mg, 12-hourly after approximately four months’ treatment. Patients’ pain intensity was controlled below a ‘moderate’ level throughout the study

Around-the-clock, oxycodone controlled-release therapy for osteoarthritis related pain

McCroskery E et al. Proceedings of EFIC; 2000 Sep 26-29; Nice, France. 62

• All the pain scores were significantly lower with oxycodone prolonged release tablets than with placebo (The figure below shows the patients’ BS-11 pain scores recorded as part of the Brief Pain Inventory on Day 15 or at stable dosing.)

Pain

score

3-month efficacy and safety study of oxycodone prolonged release tablets in osteoarthritis

Pain

in

terf

ere

nce s

core

63

• Oxycodone tablets significantly reduced pain and associated interference with daily function in osteoarthritis patients compared with placebo (The figure shows the BS-11 scores for pain interference on Day 15 or at stable dosing.)

McCroskery E et al. Proceedings of EFIC; 2000 Sep 26-29; Nice, France.

3-month efficacy and safety study of oxycodone prolonged release tablets in osteoarthritis

• This was a randomised, double-blind, placebo-controlled, parallel group study in 110 patients with a 3-12 month history of chronic low back pain.

• Dose: At entry, patients were randomly allocated to treatment with oxycodone controlled-release tablets 10mg, 12-hourly, or placebo. Their dose of study medication was titrated until they achieved stable pain control.

• Conclusion: Oxycodone controlled-release tablets administered 12-hourly were effective for the treatment of persistent moderate-to-severe back pain, when compared with placebo.

Richards P et al. Pain Med 2002;3:176. 64

Efficacy of oxycodone controlled-release tablets in persistent moderate-to-severe back pain

• Open-label, uncontrolled registry study that evaluated the outcomes associated with the use of oxycodone controlled-release tablets for up to 3 years in the treatment of non-cancer pain.

• Patients: 233

• Conclusion: Patients with non-cancer pain experienced prolonged relief with tolerable side effects and modest need for dose escalation during long-term therapy with oxycodone controlled-release tablets.

Portenoy RK et al. Clin J Pain 2007;23:287-299. 65

Long-term use of oxycodone controlled-release tablets in non-cancer pain

• 104 patients with osteoarthritis were assessed for pain, arthritis, helplessness and coping efforts before and after treatment with oxycodone controlled-release tablets in a double-blind placebo controlled study.

• After two weeks, patients receiving oxycodone controlled-release tablets reported:– Significant reductions in pain– Improvements in coping efficacy– Reductions in helplessness and passive coping compared

with placebo

• Oxycodone controlled-release tablets may be beneficial to osteoarthritis patients when incorporated as part of a multidisciplinary approach to pain management

Zautra AJ, et al. Clin J Pain 2005;21:471-477. 66

Oxycodone controlled-release tablets provide improvement in coping with osteoarthritic pain

Üeberall MA, Mueller-Schwefe G. Abstract no. 681-P287 11th World Congress on Pain; 21–26 August 2005,. Sydney, Australia.

67

• Compared with standard treatment*, oxycodone prolonged release tablets provided significantly better rates of pain relief and employability

*Standard treatment = analgesia any drug except oxycodone and physiotherapy as determined by investigator

Oxycodone prolonged release tablets – effective in back pain

• Double-blind, randomised, crossover study1

– 57 patients with moderate-to-severe chronic low back pain– Treatment started with oxycodone controlled-release tablets

(10mg, 12-hourly) or IR oxycodone tablets 5mg, q.i.d.

• Oxycodone controlled-release tablets are as effective as immediate-release oxycodone tablets:– 91% of patients achieved stable pain control– Pain intensity reduced to ‘slight’ and maintained at this level

• Pain relief with oxycodone controlled-release tablets was maintained for 12 hours.

1. Hale ME et al. Clin J Pain 1999;15(3): 79-183. 68

Oxycodone controlled-release and immediate-release tablets – efficacy in moderate-to-severe low back pain

• Costs and resource utilisation were assessed in a 5-year retrospective study of a database of German physicians1

• Transdermal fentanyl was associated with higher 6-month costs than oxycodone tablets or controlled-release morphine

• Costs for additional medications were lowest in patients receiving oxycodone tablets

• Patients receiving oxycodone tablets required significantly fewer consultations compared with fentanyl and morphine

1. Bruggenjurgen B et al. Gesundheitswesen 2007;69(6):353-8. 69

Healthcare costs in patients with musculoskeletal pain

1. Curtis GB et al. Eur J Clin Pharmacol 1999;55(6):425-429. 70

• Oxycodone controlled-release tablets were effective in controlling moderate-to-severe post-operative pain, when compared with morphine prolonged release tablets1

* Calculated by adding up all the pain relief scores recorded over 12 hours. Pain relief scores were recorded using a categorical scale where 0 = none, 1 = a little, 2 = moderate, 3 = a lot and 4 = complete.

Relative potency of oxycodone controlled-release tablets and morphine in post-operative pain

1. Cheville A et al. J Bone Joint Surg 2001;83-A(4):572-576. 71

• Double-blind, randomised study in 59 patients admitted for in-patient rehabilitation following knee arthroplasty1

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Efficacy of oxycodone controlled-release tablets in unilateral total knee arthroplasty

Cheville A et al. J Bone Joint Surg 2001;83-A(4):572-576. 72

• Use of oxycodone controlled-release tablets during rehabilitation after knee arthroplasty leads to improved pain control, more rapid functional recovery and earlier discharge from hospital, compared with placebo1

Efficacy of oxycodone controlled-release tablets in unilateral total knee arthroplasty

• Objective:Open-label study designed to assess the efficacy and safety of oxycodone controlled-release tablets in 126 patients who had been receiving PCA opioids

• Conclusion: Oxycodone controlled-release tablets provide adequate analgesia and are generally well tolerated by most patients who are transferred from PCA opioids

McCroskery E et al. Abstract no.348 - p.606. Proceedings of the 9th World Congress on Pain; 1999 Aug 22 -27; Vienna, Austria.

73

Clinical study of oxycodone controlled-release tablets in patients with post-operative pain

Efficacy in visceral painOxycodone tablets

74

• Visceral pain presents a common clinical challenge that is difficult to diagnose– Pain in upper abdomen– Pain in lower abdomen

• Visceral pain is typically referred to other areas of the body1

• Visceral pain is less understood than other pain types – often confounded by its symptomology1

1. IASP, Clinical Update Vol XIII 2005. 75

Visceral pain: a common clinical challenge

• Modulation of peripheral sensory processing– K-opioid agonists– Surgical differentiation

• Modulation of central sensory processing– N.B. nociception vs drug-induced hyperalgesia– NMDA receptor antagonists

1. Staahl C et al. Basic Clin. Pharmacol Toxicol 2006;98(2):201-211. 76

Chronic visceral pain: therapeutic approaches

Ross FB, Smith MT. Pain 1997;73(2):151-157.

Baseline nociception (tail flick latency) – similar but earlieronset with oxycodone

The µ-selective antagonist effects morphine

Colorectal distension in rats intrathecal administration

Time (m)

Time (m)

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Analgesic effect of oxycodone immediate release injection is mediated by the к – opioid receptor

Staahl C et al. Pain 2006;123(1-2):28-36.

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80

100

120

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* Different from placebo# Different from morphine

78

Oxycodone immediate release oral solution (К and µ agonist) has a significant effect on mechanically evoked visceral pain than morphine (µ - agonist)

Mechanical activation – studies in human volunteers

1. Staahl C et al. Pain 2006;123(1-2):28-36; 2. Staahl C et al. Scand J Gastroenterol 2007;42(3):383-390. 79

Time (minutes)

Healthy individuals1Patients with pancreatitis2

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Visceral pain – studies in pancreatitis

Proven efficacy in severe cancer painOxycodone tablets

80

• Improved life expectancy of patients with cancer has unfortunately led to significant increases in the number of patients experiencing chronic, intractable pain (in particular, neuropathic pain). Half of all patients with advanced cancer experience moderate-to-severe pain.

• It has been suggested that cancer pain can be effectively managed in most patients by the appropriate use of the World Health Organization (WHO) guidelines, but it continues to be under-treated in many patients.

• Opioids remain the mainstay of cancer pain therapy, however there is no standard dose. The WHO suggests that the ‘right’ dose is that needed to relieve a patient’s pain.

81

Cancer pain and its challenges

1. Citron ML et al, Cancer Invest 1998;16(8):562-571. 82

• Oxycodone controlled-release tablets are effective for long-term therapy of chronic cancer pain1

Patients’ mean pain intensity remained between slight-to-moderate throughout the study and the acceptability of therapy was fair to good throughout the study.

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Long-term administration of oxycodone controlled-release tablets for the treatment of cancer pain

1. Mucci-LoRusso P, et al. Eur J Pain 1998;2(3):239-249. 83

• Oxycodone controlled-release tablets and morphine prolonged release are similarly effective in cancer pain1

Patients rating therapy asgood or excellent (%)

Patients achievingstable pain (%)

Oxycodone controlled-release tablets – effective in severe cancer pain

%

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Time of onset

1. Pan H et al. Clin Drug Invest 2007;27(4):259-267. 84

• Rapid onset of analgesic action occurred within 1 hour in 198 cases (91.7%) of patients following administration of oxycodone controlled-release tablets1

Efficacy of oxycodone controlled-release tablets in the treatment of cancer pain in Chinese patients

1. Pan H et al. Clin Drug Invest 2007;27(4):259–267.

• Within 4 weeks, oxycodone controlled-release tablets significantly improved all Quality of Life scores in patients with moderate-to-severe cancer pain (p<0.01)1

85

Oxycodone controlled-release tablets maximise the Quality of Life of patients with cancer pain

86

A preferred choice to morphine? Oxycodone tablets

• The coefficients of variation for morphine controlled-release tablets were approximately 33% higher than those for oxycodone controlled-release tablets

• The absorption of oxycodone from oxycodone controlled-release tablet is significantly more consistent than the absorption of morphine from morphine controlled-release tablets

1. Colucci RD et al. Am J Ther 2001;8(4):231-236. 87

Oxycodone controlled-release tablets – more consistent compared to morphine

• AUC values for controlled-release oxycodone and its metabolites (oxymorphone and noroxycodone) in the four groups:

• Age does not have a significant impact on the pharmacokinetics of oxycodone from noroxycodone tablets; hence dose adjustments are not necessarily required for elderly patients.

*Oxymorphone below measurable concentration (<0.2ng.ml-1) in six of the seven volunteers.

1. Kaiko RF et al. Clin Pharmacol Ther 1996;59(1):52-61. 88

Pharmacokinetic – pharmacodynamic relationships of oxycodone controlled-release tablets

• The main difference between oxycodone controlled-release tablet and morphine controlled-release is in the oral bioavailability: >60% for oxycodone and 20% for morphine (various other values for morphine bioavailability have been quoted in the literature).

• The pharmacokinetics of oxycodone controlled-release tablet is altered in renal impairment, hepatic impairment and, to a lesser extent, by gender and age

1. Biancofiore G. Ther Clin Risk Manage 2006;2(3):229-234. 89

Oxycodone controlled-release tablet is more bioavailable compared to morphine controlled-release

1. Mucci-LoRusso P et al. Eur J Pain 1998;2(3):239-249. 90

• Oxycodone controlled-release tablets have comparable efficacy to morphine controlled-release tablets in controlling cancer pain1

* Categorical scale: 0 = no pain, 1 = slight, 2 = moderate, 3 = severe; † Significant decrease (P≤0.005); + Categorical scale: 1 = very poor, 2 = poor, 3 = fair, 4 = good, 5 = excellent; ‡ Significant increase (P = 0.0001); § Significant increase (P = 0.0061)

Oxycodone controlled-release tablets and morphine controlled-release tablets have comparable efficacy

• Proactive identification and management of patients who require opioid switching significantly improves pain control and is reproducible across different clinical settings

• Switching to oxycodone significantly improves pain control in patients who experience uncontrolled pain or intolerable side effects with morphine1

911. Riley J et al. Support Care Cancer. 2006;14(1):56–64.

Switching from morphine

• The risk and impact of switching were compared in patients receiving long-acting analgesics1

• Rates of switching at 6 months were:– Patients without cancer: 11% (oxycodone tablets), 19%

(fentanyl), 26% (morphine)– Compared with morphine, patients receiving oxycodone

tablets or fentanyl were significantly less likely to switch treatment

• Total healthcare charges were significantly higher for patients who switched therapy than those who did not

921. Riley J et al. Supp Care Cancer 2006;14(1):56-64.

Switching therapy when receiving opioids

RileyJ et al. Supp Care Cancer 2006;14(1):56-64. 93

• Overall, successful pain control was achieved in 179 (96%) of the 186 patients enrolled in the study

Need to switch to an alternative opioid in cancer patients

“Oxycodone represents a valid alternative to morphine in the management of moderate-to-severe cancer pain, also as first-line treatment” 1

A preferred choice to morphine

941. Biancofiore G. Ther Clin Risk Manage 2006;2(3):229-234.

Common side effectsOxycodone tablets

95

• The adverse event (AE) profile of oxycodone tablets is qualitatively similar to other strong opioids

• Most frequently reported AEs during clinical trials in cancer and chronic non-malignant pain include constipation, nausea, vomiting, sedation, dizziness and pruritus1-5

• WHO recommends all patients receiving strong opioids are treated for constipation with an adjuvant medication6

• Respiratory depression is a potentially serious side effect with all opioid analgesics

– Appropriate monitoring and careful prescribing should minimise the risk

• Oxycodone tablets must never be crushed, chewed or broken as this could lead to a potentially fatal overdose

96

1. Mucci-LoRusso P et al. Eur J Pain 1998;2(3): 239-249; 2. Watson C, et al. Neurol 1998;50(6):1837-1841; 3. Watson CP et al. Pain 2003;105:71-78; 4. McCroskery E et al. Proceedings of EFIC; 2000 Sep 26-29; Nice, France; 5. Roth SH et al. Arch Intern Med 2000;160(6):853-860.;6. World Health Organization. 2nd ed. Geneva: The Organization; 1996.

Adverse event profile

SummaryOxycodone tablets

97

• Treatment of severe chronic pain is an important unmet need – Chronic pain has a substantial impact both on patients and

on society

• Severe chronic pain often requires treatment with strong opioids

• Oxycodone tablets are a prolonged-release or controlled release formulation of oxycodone that has advantages over controlled-release morphine in terms of metabolism, receptor binding, etc.

• Oxycodone tablets are effective for severe chronic pain, including:– Neuropathic– Somatic

• Oxycodone tablets are also effective for experimental models of visceral pain1

1. Staahl C et al. Pain 2006;123(1-2):28-36. 98

Summary

• Neuropathic pain is the result of injury or malfunction in the central or peripheral nervous system– The efficacy of oxycodone tablets has been demonstrated in

several conditions associated with neuropathic pain:• Postherpetic neuralgia1

• Diabetic neuropathy2

• Somatic pain occurs at pain receptors at the body surface or in musculoskeletal tissue– Oxycodone tablets are highly effective in the treatment of

severe osteoarthritis pain3 and moderate-to-severe low back pain4

1. Watson C et al. Neurology.1998;50(6):1837-1841; 2. Watson CP et al. Pain 2003;105(1-2):71-78; 3. Markenson J et al, Clin J Pain 2005;21(6): 524-535; 4. Richards P et al. Pain Med 2002;3:176. 99

Summary

• Visceral pain is caused by activation of pain receptors in internal areas of the body, such as thoracic or abdominal cavities– A number of models have been developed to assess

analgesia in visceral pain where oxycodone has proven efficacy1

• Cancer may be associated with all pain types– The efficacy and tolerability of oxycodone in cancer pain

has been clearly demonstrated in a number of studies2-11

1. Staahl C et al. Pain 2006; 123:28-36. 2. Mucci-LoRusso P et al. Eur J Pain 1998;2: 239-249. 3. Citron et al. Cancer Invest 1998, 16: 562-571. 4. Parris WC-V et al. J Pain Symptom Manage 1998;16:205-211. 5. Hagen NA et al. Cancer 1997;79:1428-1437. 6. Kalso E et al. Clin Pharmacol Ther 990;47:639-646; 7. Kalso E et al. Pharmacol Toxicol 1990;67:322 -328. 8. Maddocks I et al. J Pain Symptom Manage 1996;12 :182-189. 9. Gagnon B et al. Support Care Cancer 1999;7:265-270. 10. Riley J et al. Supp Care Cancer 2006;14:56-64. 11. Pan H et al. Clin Drug Invest 2007; 27 (4): 259-267.

100

Summary

• The biphasic ACROCONTIN® delivery system starts within one hour and allows simple, 12-hourly dosing with sustained pain control

• Proven efficacy in neuropathic, somatic and visceral pain (reduction in pain scale, improvement in functions, QOL indicators such as sleep)

• No ceiling dose (proven efficacy with high dose)

• Predictable pharmacodynamic profile

• Predictable and reliable pharmacokinetic profile, with steady-state plasma levels reached within 24 hours

1. Mandema JW et al. Br J Clin Pharmacol 1996;42(6):747-756.

101

Oxycodone tablets: efficacy

• The lack of clinically significant metabolite activity contributes to favourable adverse event profile (hallucinations and itching)

• Majority of adverse events diminish over time

• Allows conservative administration in patients with mild renal or hepatic impairment

• No dose adjustment even among elderly patients

• Decrease the risk of drug interaction in cases of concomitant therapy

1. Citron M L et al. Cancer Invest 1998;16(6):562-571. 102

Oxycodone tablets: safety

• Dose titration is achieved quickly (predictable and reliable pharmacokinetic profile, with steady-state plasma levels reached within 24 hours)

• Choice of formulations increases flexibility and allows tailored individual pain relief

• The wide choice of doses decreases the number of pills to be taken and increases compliance

• Colour coding of tablets allows easy identification

• Immediate release formulation available for breakthrough pain in cancer pain management

1. Benziger D et al. Pharmacotherapy 1995;15(8):391. 103

Oxycodone tablets: ease of titration

• Oxycodone prolonged release and controlled-release tablets are an effective treatment in moderate-to-severe pain

• Oxycodone tablets provide an effective analgesia with rapid onset and sustained control of pain

• Oxycodone tablets exhibit improved adverse effect profile

• Oxycodone tablets offer optimal individualised pain control

104For detailed information, please refer to the full Prescribing Information of OxyContin® tablets.

Oxycodone: summary

105

Oxycodone tablets can be used effectively to treat severe chronic

pain1,2,3

Oxycodone tablets can be used as an alternative

treatment to morphine4

1. McCroskery E et al. Proceedings of EFIC; 2000 Sep 26-29; Nice, France; 2. Roth SH et al. Arch Intern Med 2000;160(6):853-860; 3. Richards P et al. Pain Med 2002;3:176; 4. Riley J et al. Supp Care Cancer 2006;14(1):56-64.

Conclusions

• A multidisciplinary group of specialists across Asia Pacific convened to form the Regional Chronic Pain Communications Council (RCPC).

• Aim of the RCPC: to address the mounting problem of chronic pain in the region

• The RCPC has developed the first Asia Pacific Declaration for Chronic Pain Relief:– A call to action to improve management and outcomes for

people affected by this devastating condition.

106Asia Pacific Declaration for Chronic Pain Relief. Backgrounder. 1st Congress of the Association of Southeast Asian Pain Societies 2006; (http://www.masp.org.my/index.cfm?menuid=19&parentid=12).

Expert opinion


• The primary aims of the RCPC Declaration:

1. To raise awareness and elevate the profile of chronic pain as a condition in its own right Establishing chronic pain as a priority health issue in the minds

of governments, healthcare professionals and the general public

2. To improve awareness and knowledge of chronic pain management among healthcare professionals to help sufferers find relief across the Asia Pacific region.

107Asia Pacific Declaration for Chronic Pain Relief. Backgrounder. 1st Congress of the Association of Southeast Asian Pain Societies 2006; (http://www.masp.org.my/index.cfm?menuid=19&parentid=12).

Asia Pacific Declaration for Chronic Pain Relief

®: OXYCONTIN and ACROCONTIN are Registered Trademarks

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