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OXYCODONE

SLIDE SET

OXYCODONE IN PAIN MANAGEMENT


Achieving an effective and tolerable approach to the treatment of different types of moderate-to-severe chronic pain

Section I
INTRODUCTION AND DESCRIPTION OF PAIN Pain: introduction Pain: assessment Pain: a multifactorial syndrome Pain: aetiology Pain: prevalence

Introduction to pain
Pain is "an unpleasant sensory and emotional experience associated with actual or potential tissue damage1 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

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

Assessment of 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

Assessment of pain
Descriptions of the Categorical Pain Relief Scale, Visual Analogue Pain Scale, and Pain Relief Scale
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 0100 No pain relief Complete pain relief

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

Categorical scale

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

Numerical scale
Basic requirement: measure amount of pain Have you experienced unusual or ongoing pain recently? Yes____ NO_____ Numeric rating scale (NRS) No pain 0 Worst possible pain 10 Location of pain____ (Provide body figure drawing if necessary)

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 No relief Level of pain relief (with current medication and other treatment)
Adapted from http://stahlonline.cambridge.org/content/ep/images/85702c15_tbl11.gif

Complete relief

Visual analogue scale

UNIVERSAL PAIN ASSESSMENT TOOL


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

NO HURT 0

HURTS LITTLE BIT 2

HURTS LITTLE MORE 4

HURTS EVEN MORE 6

HURTS WHOLE LOT 8

HURTS WORST 10

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

Pain a multifactorial syndrome


Pain analysis Pain management Analgesic medication Specialist involvement

Anxiety

Housing

Physical factors
Panic Low mood Psychological factors Financial status

TOTAL PAIN

Social factors

Employment Family Friends

Depression
Irritation Philosophical factors

Why?

Judgement

Religion

Values

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

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Pain aetiology

Skeletal system,other,16%

Spine back, 28%

Symptomatic pain, 9%

Ischemic Heart Diseases, 5% Injuries, 5%

Arthritic conditions, 20% Medical interventions, 4%


Tumors, 2%

Neurological conditions, 4%

Siegel, der Klinikarzt, 2001;4.

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Pain treatment and aetiology

Spine/Back Arthrosis Other Ischaemic heart disease Symptomatic pain Injuries Neurological conditions Medical interventions Tumours

Siegel, der Klinikarzt, 2001;4.

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Prevalence of pain

Chronic non-malignant pain

19% of the population1 (up to 40%)2

Post-operative pain

47- 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.

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Prevalence of pain
Chronic pain is a major healthcare problem worldwide1 Each year, acute pain affects 1520%, 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. Bonicas Management of Pain. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:316.

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Section II
PAIN: AN UNMET CLINICAL NEED Risk of under-treatment of pain Under-treatment of pain Barriers to pain management Pain an unmet clinical need in Europe Cancer pain an unmet need Pain an unmet need in Asia Pacific
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Risk of pain under-treatment is high


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

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Impact on Quality of Life and physician shift

The under-treatment of pain has a tremendous impact on an individuals Quality of Life

Almost

50%

of chronic pain sufferers have changed physicians at least once

while

29%

of severe pain sufferers have switched three times or more

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/ 17

Barriers to pain management


Failure to adopt a specific assessment tool Limited time for optimal pain management

Physician related

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

Failure to report pain to the physician

Thinking one can see pain through


Underestimating the level of pain

Patient related

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

SMA News June 2007;39(6).

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Pain an unmet clinical need


Outcomes of attitudinal analysis (n=4839)

Pain

66% had moderate pain

34% had severe pain

Employment

61% less able or unable to work

19% had lost their job

13% had changed their job

Clinical intervention

Only 2% had been managed by pain specialist

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

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

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Duration of pain
On average, sufferers lived with chronic pain for a mean of 5.9 years One-fifth had suffered pain for >20 years

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

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Pain perceptions
64% feel treatment is inadequate Most patients prescribed NSAIDS (44%)

28% believe healthcare professionals (HCPs) do not know how to treat pain Only 5% receive strong opioids

Only 23% referred to pain specialist

PAIN
43% believe HCPs focus on illness not pain

40% do not have adequate pain relief

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

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Pain an unmet clinical need in cancer


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)

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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].

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Patient perceptions in cancer pain

11% of patients (NRS>5) receiving no analgesia

36% left in intolerable pain

38% felt only cancer treated, not pain

63% had breakthrough pain

PAIN
Most common side effect constipation 37% 22% never asked about their pain by HCPs

50% believe HCP does not consider QoL important

Only 33% of HCPs use pain scales

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

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Summary

Pain is widespread

More than half of patients reported pain within the previous month

Pain is undertreated

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

Treatment is often sub-optimal Breakthrough pain is under-treated

Treatment side-effects such as constipation are often not addressed

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

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

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Pain a burden in Asia Pacific region


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

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).

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Section III
GOAL OF PAIN MANAGEMENT Principles of pain management WHO ladder of pain intervention Challenging the WHO 3 step ladder The need of the hour: a two step analgesic approach

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Goal of pain management

Minimise pain and Improve Quality of Life

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Pain management principles and options


Alternate therapy

Psycho-social support

Coanalgesics

Non-Opioid analgesics

Opioids for mild pain

Opioids for severe pain

PAIN

Treatment for side effects

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.

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WHO 3 step ladder

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

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Challenging the WHO 3 step


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

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

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

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A two step analgesic approach


35 30 25 20 15 10 5 0
Percentage of days with pain intensity > 5 %

28.6

* 22.8
11.2

** 8.6

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

Percentage of patients dissatisfied with treatment

100

85.7 86.2

50 12.1 8.5 0 Conventional treatment

Fewer patients receiving Step 3 opioids early were dissatisfied with therapy
Innovative treatment
*p<0.001, **p=0.023

Conventional treatment: treated according to WHO 3 step ladder Innovative treatment: direct move to Step 3 after Step 1
Maltoni M et al. Support Cancer Care 2005;13(11):888-894.

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Oxycodone
AN OVERVIEW

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Oxycodone hydrochloride - formulations


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)

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

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Characteristics of oxycodone

Some -agonist activity1

Analgesic potency twice that of morphine4

No ceiling dose2

Predictable PK profile2

Effective in a broad range of moderateto-severe chronic pain1

>60% oral bioavailability3

Metabolised by CYP3A4 / CYP2D6

Negligible clinical impact of metabolites2

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.

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Innovative delivery system


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.

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Oxycodone proven analgesic efficacy in moderate-to-severe pain


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

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Section IV
EFFICACY OF OXYCODONE TABLETS IN PAIN MANAGEMENT Neuropathic pain Somatic pain Visceral pain Cancer pain

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Oxycodone tablets
Proven efficacy in neuropathic pain

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Neuropathic pain: an unmet clinical need in Asia Pacific region


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

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).

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Asia Pacific declaration for neuropathic pain


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

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).

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Neuropathic pain conditions


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.

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Treatment of neuropathic pain with opioids


In a meta-analysis of RCTs, intermediate-term studies demonstrate significant efficacy of opioids over placebo for neuropathic pain1
Post treatment Pain Intensity (Mean [SD]) Type of pain condition: Diabetic neuropathy* Phantom limb** Mixed neuropathic Post-herpetic neuralgia Post-herpetic neuralgia* 41.0 [27.0] (n=82) 33.0 [16.0] (n=12) 60.0 [40.0] (n=19) 44.0 [24.0] (n=76) 35.0 [25.0] (n=38) 26.3 [24.7] (n=36) 53.0 [26.0] (n=77) 40.0 [12.0] (n=12) 64.0 [19.0] (n=19) 60.0 [20.0] (n=76) 54.0 [25.0] (n=38) 46.7 [26.9] (n=36) Opioid (n =263) Placebo (n=258)
Favours Opioid Favours Control

Diabetic neuropathy*

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

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

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Efficacy of oxycodone controlled-release tablets in managing neuropathic pain


Non-malignant neuropathic pain (n=35) VAS 8-10/10 (100%; n=35) Malignant neuropathic pain (n=32) VAS 10/10 (100%; n=32)

Baseline

Initiation of oxycodone
(CR)
VAS 1-2/10 (94%; n=33) VAS 4-8/10 (6%; n=2) VAS 2-4/10 (100%; n=100)

Follow-up 2-4 weeks

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

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

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Efficacy of oxycodone controlled-release tablets in postherpetic neuralgia


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

Mean pain VAS pain score (mm)

Mean daily pain intensity

Steady pain

Brief pain

Skin pain

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

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Efficacy of oxycodone controlled-release tablets in painful diabetic neuropathy

Mean pain VAS pain score (mm)

Mean daily pain intensity

Steady pain

Brief pain

Skin pain

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

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

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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

Least square means BS-11 pain scores (boxes)

Baseline

Days 1-27

Days 28-42

When first-line therapies are inadequate, oxycodone controlled-release tablets are effective in low doses in controlling severe painful diabetic neuropathy
Gimbel JS et al. Neurology 2003;60(6):927-934.

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Gabapentin plus morphine provides pain control superior to either agent alone
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/morphine P=0.01 morphine vs. placebo P=0.04 morphine vs. GBT/morphine

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

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Oxycodone prolonged release tablets with gabapentin optimise pain relief in PDN
Co-administration of oxycodone prolonged release tablets and existing gabapentin (GBT) therapy has a clinically meaningful effect in painful diabetic neuropathy (PDN)
Mean BS-11 pain scores (boxes)

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

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

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

NRS average score

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

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

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

Study end

Mean dose (mg/day)

Study end Study start Study start

Monotherapy

Combined therapy

(Oxycodone tablets(CR) n=106; (Oxycodone tablets (CR)+ pregabalin n=134) pregabalin n=169)

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

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Analgesic therapy in postherpetic neuralgia


Intervention Oxycodone prolonged release tablets NNT (95% CI) 2.50 (1.74 - 4.41)

Tricyclic antidepressants
Combined opioids Gabapentin Tramadol Pregabalin

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)

Tricyclic antidepressants, opioids, gabapentin, tramadol and pregabalin can be considered effective treatments for postherpetic neuralgia
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Hempenstall K et al. Analgesic therapy in postherpetic neuralgia: a quantitative systematic review. PLoS Med 2005;2:e164.

Oxycodone prolonged release tablets - an effective treatment in postherpetic neuralgia

NNT to obtain one patient with >50% pain relief

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

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

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

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Oxycodone prolonged release tablets - an effective treatment in postherpetic neuralgia

NNT to obtain one patient with >50% pain relief

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

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

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

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Oxycodone prolonged release tablets - an effective treatment in postherpetic neuralgia

NNT to obtain one patient with >50% pain relief

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

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Oxycodone tablets
Proven efficacy in somatic pain

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Challenges of somatic pain


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

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Oxycodone prolonged release tablets efficacy in osteoarthritis


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
Adjusted mean change (mm) in WOMAC score from baseline at day 60 Pain Stiffness Physical function Composite

0 -5 -10 -15 -20 -25


Oxycodone tablets (PR)
Placebo (n=51)

* *

* p< 0.001

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

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Oxycodone prolonged release tablets efficacy in osteoarthritis


Randomised, double-blind, 3-month placebo-controlled study in patients with osteoarthritis Oxycodone prolonged release tablets led to a significant improvement in 1 patients function compared with placebo
P=0.001

Interference Composite

P=0.012

Enjoyment of Life

P<0.001

Sleep

P=0.006

Normal Work

P=0.018

Mood

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

Change in LS Mean BPI Interference score from baseline at Day 90

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


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

Mean dose (mg/day)

Mean pain intensity

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

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

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

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

Pain interference score

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

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


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 12hourly were effective for the treatment of persistent moderate-tosevere back pain, when compared with placebo.

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

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

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

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Oxycodone prolonged release tablets effective in back pain


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 eberall MA, Mueller-Schwefe G. Abstract no. 681-P287 11th World Congress on Pain; 2126 August 2005,. Sydney, Australia.

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Oxycodone controlled-release and immediaterelease tablets efficacy in moderate-to-severe low 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, 12hourly) or IR oxycodone tablets 5mg, q.i.d.

Oxycodone controlled-release tablets are as effective as immediaterelease 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.

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Healthcare costs in patients with musculoskeletal 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.

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


Oxycodone controlled-release tablets were effective in controlling moderateto-severe post-operative pain, when compared with morphine prolonged 1 release tablets

* 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.

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

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


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

VAS pain score

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

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


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

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

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


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.

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Oxycodone tablets
Efficacy in visceral pain

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Visceral pain: a common clinical challenge


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.

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Chronic visceral pain: therapeutic approaches


Modulation of peripheral sensory processing
agonists Surgical differentiation
K-opioid

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.

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Analgesic effect of oxycodone immediate release injection is mediated by the opioid receptor
The -selective antagonist effects morphine

% of peak effect

+ Nalz

Baseline nociception (tail flick latency) similar but earlier onset with oxycodone

% of peak effect

Time (m) Colorectal distension in rats intrathecal administration +nor-BNI 0.33nmol

Time (m)

% of peak effect

Time (m)

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

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Mechanical activation studies in human volunteers


Placebo (n=24)

Oxycodone (IR) (n=24)


Morphine (n=24) 140

* Different from placebo


# Different from morphine

120
Threshold changes

**

**

**

**

**

**

* #* * * * *

100 80 60

40
20 0 0 30 60 90
Min Pinch pain tolerance threshold (skin)

Oxycodone immediate release oral solution ( and agonist) has a significant effect on mechanically evoked visceral pain than morphine ( - agonist)
Staahl C et al. Pain 2006;123(1-2):28-36.

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Visceral pain studies in pancreatitis

Pressure pain tolerance threshold changes (kPa)

Pressure pain tolerance threshold changes (kPa)

* *

Time (minutes)

Time (minutes)

Patients with pancreatitis2


* significantly different from placebo significantly different from morphine

Healthy individuals1

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.

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Oxycodone tablets
Proven efficacy in severe cancer pain

80

Cancer pain and its challenges


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 patients pain.

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Long-term administration of oxycodone controlledrelease tablets for the treatment of cancer pain
Oxycodone controlled-release tablets are effective for long-term therapy of chronic cancer pain1
% Patients reporting adverse drug reactions

Patients mean pain intensity remained between slight-tomoderate throughout the study and the acceptability of therapy was fair to good throughout the study.
Related common opioid adverse events

Study week

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

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Oxycodone controlled-release tablets effective in severe cancer pain


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

Patients achieving stable pain (%)

Patients rating therapy as good or excellent (%)

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

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Efficacy of oxycodone controlled-release tablets in the treatment of cancer pain in Chinese patients
Rapid onset of analgesic action occurred within 1 hour in 198 cases (91.7%) of patients following administration of oxycodone controlled-release tablets1

% of patients

Time of onset

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

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

1. Pan H et al. Clin Drug Invest 2007;27(4):259267.

85

Oxycodone tablets
A preferred choice to morphine?

86

Oxycodone controlled-release tablets more consistent compared to morphine

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.

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Pharmacokinetic pharmacodynamic relationships of oxycodone controlled-release tablets


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.

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


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.

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Oxycodone controlled-release tablets and morphine controlled-release tablets have comparable efficacy
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 (P0.005); +

Categorical scale: 1 = very poor, 2 = poor, 3 = fair, 4 = good, 5 = excellent; Significant increase (P = 0.0001); Significant increase (P = 0.0061)

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

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Switching from morphine


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

1. Riley J et al. Support Care Cancer. 2006;14(1):5664.

91

Switching therapy when receiving opioids


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

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

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Need to switch to an alternative opioid in cancer patients


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

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

93

A preferred choice to morphine


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

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

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Oxycodone tablets
Common side effects

95

Adverse event profile


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

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.

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Oxycodone tablets
Summary

97

Summary
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 controlledrelease 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 100 2006;14:56-64. 11. Pan H et al. Clin Drug Invest 2007; 27 (4): 259-267.

Oxycodone tablets: efficacy


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.

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Oxycodone tablets: safety


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.

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Oxycodone tablets: ease of titration


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.

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Oxycodone: summary
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

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

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Conclusions

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.

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Expert opinion
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.

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).

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Asia Pacific Declaration for Chronic Pain Relief


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.

: OXYCONTIN and ACROCONTIN are Registered Trademarks

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).

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RM-OXYC-0072-V1-0310