Oxycodone - PluralWeB

Oxycodone for Cancer Pain Management
Joseph V. Pergolizzi, Jr, MD
Johns Hopkins University and Temple University Schools of Medicine
Rio de Janeiro
April 9, 2016
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The sponsor does not recommend any use of its
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Principle for Safe & Effective Opioid Use
Great variation in the dose of opioid required by individual patients
Modified from www.medicine.ox.ac.uk/bandolier;
World Health Organization: Cancer Pain Relief With a Guide to OpioidAvailability. Geneva, Switzerland 1996
NCCN Adult Cancer Pain Management Guidelines 2015
Advantages of Sustained Release Opioid
Formulations
• Simplified regimen, improved compliance
• Durable analgesic effect
• Prolonged DOA for day long pain
• Circumvents analgesic gaps
• Less focus on pain & clock-watching
• Steady dose
• Slow progression of tolerance
• Greater patient satisfaction, preference
Dr. Joseph Pergolizzi
Long-Term Pain Relief: Oral SR Opioids
Noble M. et al. Cochrane Database Syst Rev. 2010 Jan 20;(1)
Morphine - naturally occurring opioid
- Sulfate or hydrochloride
Formulations
- Syrups, tablets, capsules, suppositories and injectables
- Immediate and controlled release (oral) with 20-30% oral
bioavailability
Indication
Moderate to severe pain
- M6G: potent analgesic – contributes to analgesia
Metabolites1
- M3G: may antagonise analgesic action of morphine and cause
neurotoxic symptoms (eg, delirium)
- Both can accumulate in patients with renal impairment
Renal impairment2
- Use an alternative opioid or reduce dose if
CrCl < 50mL/min and use with caution
- Avoid chronic use if CrCl < 10mL/min
M6G=morphine-6-glucuronide; M3G=morphine-3-glucuronide
1. McMahon SB, Koltzenburg M, eds. Wall and Melzack's Textbook of Pain. 5th ed.
2006
SR Morphine have effective pain control
and improve sleeping quality
A Randomized, Double-Blind, Double-Dummy, Two 7 days Cross- over study 85 cancer
patients received MXL® follow by MST®Continus or vice versa according to a
randomization schedule.
60mg QD oral morphine
30mg Q12H oral morphine
-25% of patients claim pain free
-75% of patients claim mild pain (BS11 <3)
74% of patients claim no night
woken during sleep on the
treatment of these 2 opioids
Palliative Medicine 1997; 11: 475-482
Oxycodone SR Overview
Oxycodone for cancer-related pain
• 17 studies which enrolled/ randomised 1390 patients with 1110 of
these analyzed for efficacy and 1170 for safety.
• Overall, the data included within this review suggest that oxycodone
offers similar levels of pain relief and adverse events to other strong
opioids including morphine, which is commonly considered the gold
standard strong opioid.
• Conclusions are consistent with other recent reviews and suggest that
while the reliability of the evidence base is low, given the absence of
important differences within this analysis it seems unlikely that larger
head to head studies of oxycodone versus morphine will be justified.
• This means that for clinical purposes oxycodone or morphine can be
used as first line oral opioids for relief of cancer pain.
Schmidt-HansenM, BennettMI, Arnold S, Bromham N,Hilgart JS.Oxycodone for cancer-related pain. Cochrane Database of Systematic Reviews
2015, Issue 2. Art. No.: CD003870. DOI: 10.1002/14651858.CD003870.pub5. Schmidt-HansenM, BennettMI, Arnold S, Bromham N,Hilgart
JS.Oxycodone for cancer-related pain. Cochrane Database of Systematic Reviews 2015, Issue 2. Art. No.: CD003870. DOI:
10.1002/14651858.CD003870.pub5.
EAPC Guideline: Step II Opioids
Caraceni A, Hanks G, Kaasa S, et al. Use of opioid analgesics in the treatment of cancer pain: evidence-based
recommendations from the EAPC. Lancet Oncol. Feb 2012;13(2):e58-68.
Oxycodone’s Pharmacological Properties
Analgesic potency twice
that of morphine4
Some possible κ-agonist
activity1
No ceiling dose2
Predictable PK profile2
Effective in a
broad range of
moderate-tosevere 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.
Oxycodone - Semi-Synthetic opioid
Formulations
Oral controlled release tablet
Indication
Moderate to severe pain
Metabolites
Noroxycodone and oxymorphone
- Do not contribute significantly to analgesia1
• Suitable in renal impairment and the elderly2
Renal impairment
• Renal impairment does not result in significant levels of
active metabolites, but plasma concentration of oxycodone
may increase2
• If CrCl <60mL/min: Reduce dose to ⅓ to ½ usual dose2
1. Riley J, et al. Curr Med Res Opin 2008;24:175; 2. OxyContin® tablets - Medsafe, January 2014. 3. The Royal Australasian College of
Physicians. Prescription Opioid Policy, 2009
Oxycodone transporter toward BBB to
CNS
Brain
Blood
Oxycodone
(Cu, ng/mL)
1000
100
10
1
0
60
120
Time (min)
180
240
Okura T et al., Involvement of the pyrilamine transporter, a putative organic cation transporter, in blood-brain barrier transport of oxycodone.
Drug Metab Dispos. 2008 Oct;36(10):2005-2013.
PK of SR v.s. IR Oxycodone*
Benziger DP, Thomas G, Miotto J, et al. Bioavailability and pharmacokinetics of controlled-release oxycodone (OxyContin®) tablets vs. oxycodone
oral liquid. Am Pain Soc Program Book 1994;A-121 #94732 (abstract); 2. Mandema JW, Kaiko RF, Oshlack B, et al. Characterization and validation
of a pharmacokinetic model for controlled-release oxycodone. Br J Clin Pharmacol 1996; 42:747-756.
*Oxycodone IR is not available in BR
Systematic Reviews :
Oxycodone SR use in Cancer Pain
Article
Oxycodone
Studies
Identified
Author Remarks
Koyyalagunta
2012
1
•(RCT) Oxycodone showed efficacy in pain relief at 4 weeks with a
drop in pain score from 7.19 to 3.15; no difference in pain relief and
AEs compared to morphine in pancreatic cancer patients
King 2011A
29
•In patients with moderate to severe cancer-related pain, no
significant difference between the efficacy and tolerability of
oxycodone and other step III opioids, in particular morphine and
hydromorphone.
King 2011B
1
•(Prospective Observational) Nine patients, with renal impairment
switch to oxycodone resulted in ‘high adequate pain control’ (authors’
description with no additional information)
Reid 2006
4
•No difference in mean pain scores between oxycodone and control
drugs (morphine/hydromorphone)
•The efficacy and tolerability of oxycodone are similar to morphine,
supporting its use as an opioid for cancer-related pain.
AKing
et al. Palliative Medicine. 2011; 25(5) 454–470
et al. Palliative Medicine. 2011; 25(5) 525–552
Kovyalagunta et al. Pain Physician. 2012; 15:ES39-ES58
Reid et al. Arch Intern Med. 2006; 166(8):837-43
BKing
* Not studied with immediate release formulation.
Efficacy of SR Oxycodone in the
Treatment of Cancer Pain Patients
% of patients
Rapid onset of analgesic action occurred within 1 hour in 198 cases
(91.7%) of patients following administration of oxycodone controlled1
release tablets
Time of onset
1. Pan H et al. Clin Drug Invest 2007;27(4):259-267.
1
7
Long-term Administration of SR Oxycodone for
the Treatment of Cancer Pain
% Patients reporting adverse drug reactions
• Sustained-released oxycodone is effective for long-term therapy of
chronic cancer pain1
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.
SR Oxycodone:
Quality of Life improvement in cancer pain
Pan H, et al. Clin Drug Invest 2007;27:259
SR Oxycodone:
Effective in Severe Cancer Pain
•
Oxycodone sustained-release tablets and morphine prolonged
release are similarly effective in cancer pain1
Patients achieving
stable pain (%)
1. Mucci-LoRusso P, et al. Eur J Pain 1998;2(3):239-249.
Patients rating therapy as
good or excellent (%)
SR Oxycodone v.s. Morphine in Cancer Pain:
Weekly Rescue Analgesic Consumption
Mean daily number of
rescue analgesic (IRM
10
mg)
for
breakthrough pain at
the end of each week
The weekly rescue medication consumption was 38% higher in patients receiving
sustained-release morphine compared to patients having sustained-release oxycodone1
1. Lauretti GR, Oliveira GM, Pereira NL. Br J Cancer 2003; 89:2027-203
Efficacy of SR Oxycodone in Managing
Neuropathic Pain
Non-malignant
neuropathic pain (n=35)
Malignant neuropathic
pain (n=32)
VAS 8-10/10
(100%; n=35)
VAS 10/10
(100%; n=32)
Baseline
Initiation of oxycodone
(SR)
Follow-up 2-4 weeks
VAS 1-2/10
VAS 4-8/10
(94%; n=33)
(6%; n=2)
VAS 2-4/10
(100%; n=32)
Oxycodone sustained-release tablets may be effective in neuropathic pain arising
from diverse a etiologies
Ong EC. Oncology 2008;74(Suppl.1):72-75.
*†
*†
*†
Pressure pain tolerance threshold
changes (kPa)
Pressure pain tolerance threshold
changes (kPa)
Efficacy of SR Oxycodone in Managing
Visceral Pain – studies in pancreatitis
Placebo (n=24)
Oxycodone (IR) 15 mg p.o. (n=24)
Morphine 30 mg p.o. (n=24)
*
*
Time (minutes)
Time (minutes)
Healthy individuals1
Patients with pancreatitis2
* significantly different from placebo
† significantly different from morphine
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.
*
Oral SR Oxycodone: Ease of Titration
• Dose titration is achieved quickly
• Predictable and reliable pharmacokinetic profile, with
steady-state plasma levels reached within 24 hours
• The wide choice of doses decreases the number of pills to
be taken and increases compliance
• Colour coding of tablets allows easy identification
1. Benziger D et al. Pharmacotherapy 1995;15(8):391.
Easy up titration can improve patient
adherence
- oral SR oxycodone & IR morphine as example for Breakthrough Pain
Pain Severity
Management
40-80mg
30-60mg *
Allow
IR Morphine
dose of 10%~20%
24hr
Allow
IR Oxicodone
doses ofof10~20%
15-50mg *
oral dose1
1
of 24hr oral dose
10-25mg *
10-20mg *
10-15mg *
10mg *
5-10mg *
5mg
*
5mg
*
5mg
*
Morphine IR*
SR
Cancer Progression
1.
2.
NCCN Guidelines, Adult cancer pain, version 1. 2014, p PAIN-E 3 of 9
World Health Organization. Adherence to Long-Term Therapies: Evidence for Action. Geneva: WHO; 2003. Available from:
http://www.who.int/chp/knowledge/publications/adherence_full_report.pdf. Accessed April 2014
SR oxycodone every 12 hours in
managing moderate to severe cancerrelated pain: Side Effects
NOTE. Reported by - 5% of patients and considered by the investigator to
be possibly, probably, or definitely related to study medication.
*Fewer patients reported headache with CR oxycodone (P = .029).
Kaplan R, et al. J Clin Oncol 16:3230-3237
Oxycodone Adverse Events
Oxycodone Prescribing Information.
Tolerability of Opioids in Moderate-Severe Pain:
Adverse Events
OXYCODONE
Fentanyl
Morphine
Tramadol
Dermatology (Pruritus)
<%3
%3-%10
>%8
%3-%11,9
GIS (Constipation)
>%3
>%10
>%9
%10-%29,7
GIS (Nausea)
>%3
>%10
>%7
%13-%26,2
GIS (Vomitting)
>%3
>%10
>%10
%3-%9,4
Neurologic (Astenia)
>%3
>%9,7
Neurologic (Somnolance)
>%3
>%9,7
>%9
%4-%20,3
Neurologic (Headache)
>%3
>%10
%3-%15,8
%5-%10
%1-%5 (Dispnea)
Psychiatric (Anxiety)
Psychiatric (Halucination)
Respiratory (Apnea, Respiratory
Arrest, Respiratory Depression)
%3-%10
%3-%10
%3-%10
%3-%10
Renal (Urinary Retention)
Micromedex®
http://www.fda.gov/Safety/MedWatch/default.htm FAERS
<%5
Drawbacks of Opioid Analgesics
Limitations
Special
Issues

Respiratory depression

Constipation, nausea, and vomiting

Sedation and cognitive impairment

Histamine release (urticaria, sweating, vasodilation,
pruritus)

Urinary retention

Drug-to-drug interactions

Physical dependence and tolerance with chronic use

Inability to sufficiently control pain on post-op mobilization

Withdrawal syndrome with abrupt cessation

Short-acting single and combination opioid agents require
multiple daily doses

Costs associated with adverse events

Risk of misuse, abuse, addiction, and diversion
Moreland LW, et al. Rheum Dis Clin North Am. 1999;25:153-191. Power I, et al. Surg Clin North Am. 1999;79:275-295.
Miyoshi HR. Bonica’s Management of Pain. 2001:1682-1709.
Question
• What is the primary reason for opioid
rotation in your opinion?
A. Development of tolerance
B. Worsening of pain
C. Intolerable side effects
D. Lack of availability
E. Preference in route of administration
Question
• How Often do you rotate opioids?
A. Eventually for all patients
B. Only when there’s a need
C. Hardly ever
D. I don’t rotate as I have limited options
Indications for Opioid Rotation
Gregory TB. Clin Ther. 2013;35(12):2007-27.
Incomplete cross tolerance!! Why
Quang-Cantagrel ND, Wallace MS, Magnuson SK. Anesth Analg. 2000 ;90(4):933-7.
Genetic factors
• Increasing recognition of genetic variations in
humans in terms of
• Expression of pain (eg Sodium channel pathologies)
• Response to analgesics (eg Cytochrome P450 slow
or fast metabolisers; genetic mutations of opioid
receptors and catecholamine metabolism)
Klepstad P. et al. The 118 A > G polymorphism in the human mu-opioid receptor gene may increase morphine
requirements in patients with pain caused by malignant disease. Acta Anaesthesiol Scand. 2004 Nov;48(10):1232-9
The 118 A > G polymorphism in the Human muopioid Receptor Gene may Increase Morphine
Requirements in Patients with Pain Caused by
Malignant Disease.
Klepstad P. et al. The 118 A > G polymorphism in the human mu-opioid receptor gene may increase morphine
requirements in patients with pain caused by malignant disease. Acta Anaesthesiol Scand. 2004 Nov;48(10):1232-9
Opioid Rotation Considerations
• Relative potency
• Use 25% to 50% of equianalgesic dose
• Consider starting at the lowest dose again or due to
incomplete cross-tolerance by reducing the
equianalgesic dose of the new opioid by 50%.
• Review potential exacerbating factors for pain
that might affect effectiveness or adverse effects
• Think of each opioid rotation as a “discrete
clinical trial”
Nalamachu SR. Opioid rotation in clinical practice. Adv Ther 2012; 29(10):849-863.
A Real Balancing Act
Dr. Joseph Pergolizzi
Balancing Treatment Consideration
With Risk Management
• Opioids play an important role in the treatment of cancer pain and CNCP. 1
• Despite barriers, there is a need to balance effective pain management with the
appropriate use of opioids2
• The goal of pain treatment is to decrease pain and improve functioning while
monitoring for adverse effects or aberrant behaviors2
• To do this, HCP’s should incorporate risk-management strategies into their
practice, such as Universal Precautions2
Trescot AM, et.al. Pain Physician. 2008; 11(suppl): S5-S62.
Gourlay DL, et.al. Pain Med. 2005; 6(2): 107-112.
What Are Universal Precautions?
1.
Diagnosis With Appropriate Differential
2.
Psychological Assessment, Including Risk of Addictive Disorders
3.
Informed Consent
4.
Treatment Agreement
5.
Pre- and Post-Intervention Assessment of Pain Level and Function
6.
Appropriate Trial of Opioid Therapy With/Without Adjunctive Medication
7.
Reassessment of Pain Score and Level of Function
8.
Regularly Assess the “4 As” of Pain Medicine
9.
Periodically Review Pain Diagnosis and Comorbid Conditions, Including Addictive
Disorders
10.
Documentation
Gourlay DL, et.al. Pain Med. 2005; 6(2): 107-112
Mundipharma Pursued Multiple Technologies to
Reformulate OxyContin® to Mitigate Abuse and
Misuse
September 2009
• Second Advisory
March 2009
• NDA
October 2008
• FDA Complete
May 2008
• First
November 2007
• Initial NDA
submitted
Early 2000s
• Mundipharma • 10-40 mg
began
reformulation
efforts
OxyContin®: é uma marca registrada
Advisory
Committee
Response
Letter
resubmitted
• 10-80 mg
• In vitro study
program
Committee
Reformulated OxyContin® (ORF)
What’s coming…………..?
Physiochemical Barrier and Retains CR Properties
 ORF is harder to cut, chew, break, or crush
 Contains polyethylene Oxide, non-ionic hydrophilic polymer that is insoluble in
alcohols serves as an abuse deterrent.
 Upon contact with water it forms a viscous gel
 Attempts to dissolve the tablets in liquid result in a gummy substance that cannot
be injected or snorted.
 The tablets either do not break, or break into pieces that retain some controlled
release functionality.
 However, ORF is bioequivalent to the original OxyContin®
OxyContin®: é uma marca registrada
Summary: Efficacy
• Efficacy & tolerability of oxycodone are superior to those of other strong
opioids, supporting its use as an opioid for moderate-to-severe cancerrelated pain.
• Proven efficacy in neuropathic and visceral pain (reduction in pain scale,
improvement in functions, QOL indicators such as sleep).
• The new formulation OxyContin® ORF starts within one hour and allows
simple, 12-hourly dosing with sustained pain control.
• Completed formulation choices and no ceiling dose (proven efficacy with
high dose) offer optimal individualised pain control.
• Oxycodone has important clinical, pharmacokinetic and pharmacodynamic
aspects with steady-state plasma levels reached within 24 hours which
make it a reasonable alternative to other opioids.
1. Mandema JW et al. Br J Clin Pharmacol 1996;42(6):747-756.
Summary: Safety
• The lack of clinically significant metabolite activity
contributes to favourable adverse event profile
• 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
1. Citron M L et al. Cancer Invest 1998;16(6):562-571.
Summary
Need for early recognition and treatment of moderate to
severe pain is essential
• “Oligoanalgesia” (inadequate treatment of pain) exists and patients want to
avoid it.
• We must aggressively assess our patients pain
• Opioids are the mainstay of treatment for moderate to severe cancer pain
but do have side effects which can limit their effectiveness
• There is no one golden that works in 100% of the patients 100% of time and
we need options; Opioids are an option that has proven safety and efficacy
in the appropriate patient populations.
Dr. Joseph Pergolizzi
Obrigado!
Questions?
Mundipharma Brasil Produtos Médicos e Farmacêuticos Ltda
Rua Verbo Divino 2001 – 16 andar – Cj162
São Paulo – SP – 04719-002
Abril 2016
OxyContin®
(cloridrato de oxicodona) - APRESENTAÇÃO: Comprimidos revestidos de liberação controlada de 10 mg, 20
mg e 40 mg. Embalagens com 12 e 30 comprimidos. USO ORAL. USO ADULTO. – INDICAÇÕES: tratamento de dor moderada a
severa, quando necessária a administração contínua de analgésico, 24 horas/dia, por período prolongado; tratamento
individualizado para manejo da dor, iniciando a terapia com oxicodona depois da utilização de analgésicos não opioides, como
antiinflamatórios não esteroides, e acetaminofeno; uso pós-operatório apenas se o paciente tiver recebido a droga antes do
procedimento cirúrgico, ou quando se prevê que a dor pós-operatória será moderada a severa e perdurará por período prolongado.
Não deve ser utilizado como analgésico condicionado à dor. CONTRAINDICAÇÕES: hipersensibilidade à oxicodona; situações nas
quais os opioides são contraindicados, incluindo depressão respiratória, asma brônquica ou na hipercapnia aguda ou severa,
presença ou suspeita de íleo paralítico. Categoria B: Este medicamento não deve ser utilizado por mulheres grávidas sem
orientação médica. PRECAUÇÕES E ADVERTÊNCIAS: Risco de depressão respiratória ou sintomas de abstinência. Pode
causar hipotensão severa e hipotensão ortostática. Usar com cautela em: alcoolismo, insuficiência adrenocortical, depressão do
SNC ou coma, delirium tremens, pacientes debilitados, cifoscoliose associada com depressão respiratória, mixedema ou
hipotireoidismo, hiperplasia prostática ou obstrução uretral, insuficiência hepática grave, pulmonar ou renal, psicose tóxica, em
pacientes com choque circulatório ou abdômen agudo, em doenças do trato biliar, inclusive pancreatite aguda. A oxicodona afeta
as respostas das pupilas e da consciência. Pode agravar as convulsões em pacientes com transtornos convulsivos.
REAÇÕES ADVERSAS: constipação intestinal, náuseas, sonolência, vertigem, vômitos, prurido, cefaleia, secura na boca,
sudorese e astenia, depressão respiratória, apneia, depressão circulatória, parada respiratória, hipotensão ou choque.
INTERAÇÕES MEDICAMENTOSAS E COM EXAMES LABORATORIAIS: Efeitos aditivos com álcool, outros opioides, drogas
ilícitas e bloqueadores neuromuscular. Possível interação com medicamentos que bloqueiem a via de metabolização da CYP2D6 e
CYP3A4. Pode elevar o nível de amilase sérica.
POSOLOGIA: OXYCONTIN® é administrado a cada 12 horas, alguns poderão beneficiar-se de uma dosagem assimétrica (com
a dose da manhã diferindo da dose da tarde). Alimentos não têm efeito significativo sobre a absorção da oxicodona em
OXYCONTIN® comprimidos.
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