Download Breakthrough Pain

SL Fentanyl and MethadoneAre they friends or enemies?
Pamela Mansfield MD CCFP
Clinical Director of Palliative Care
Moncton Area, Horizon Health Network
Past President of the NBHPCA
President of the Moncton Medical Staff
Lecturer Dalhousie University
April 25, 2013
Disclosure:
Unrestricted educational grant
Learning Objectives
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At the end of the session the participant will:
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Be able to identify the various opioids available to treat pain
Know the potencies of the different opioids
Understand dosing of opioids
Know the principles of breakthrough pain
Know the medications available to treat breakthrough pain
Name the unique properties of methadone and reason for
its use
Understand the specific toxicity unique to methadone and
potential drug interactions
Demonstrate the steps for starting and rotating patients to
methadone
At the end of the day the participant
will be able to:
 Identify my husband, Nathanael Anderson
Opioids 101
 Opioids:
 Originally derived from opium
 Natural and synthetic
 Narcotic (Greek work for stupor) –
dependence /addiction
Classification of Opioid Receptor Sites
Adapted from Medical care of the Dying, 4th Ed.
Effect
Mu (OP3)
Kappa (OP2)
Delta(OP1)
Pain
Analgesia
Analgesia
Analgesia
Respiratory rate
Depression
Heart Rate
Bradycardia
GI
Nausea
Reduced motility
Constipation
Constipation
Affect
Sedation
Indifference
?euphoria
Sedation
Psychotomimetic
Dysphoria
Nausea
Opioids 101
 Different Opioids:
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Codeine
Butrans
Tramadol
Morphine
Nucynta
Oxycodone
Hydromorphone
Fentanyl
Methadone
Opioid Equivalency
DRUG
PO
DOSE
SC/IV
DOSE
Morphine
10mg
5mg
Codeine
100mg
50mg
Tramadol
100mg
N/A
Tab (IR, SR)
Oxycodone
5mg
N/A
Tab
(IR,SR)
1mg
Tab (IR,SR)
Inj
Supp
Hydromorphone
Methadone
Fentanyl
2mg
Special
25 mcg/hr ~
100mg PO
morphine/
24h
Roughly
100mcg/h =
morphine
4 mg/h iv
FORM
COMMENTS
Tab (IR,SR)
Inj
Supp
PO/PR/SL
Duration & half-life
increase with repeated
use (cumulative effect)
SR Patch
IR SL
Change SR patch q 72
hours
Reservoir takes 12
hours to build
Adverse Effects & Management
 Sedation/Drowsiness
 Tend to clear in a few days
 Ritalin?
 Confusion/Delirium
 Associated with sedation
 Usually occurs in titration phase
 Hallucinations/Dysphoria
 Reassurance
 No specific TX – antipsychotics?
Adverse Effects & Management
 Dry mouth: common - Increase fluids, suck on
candy/ice chips
 Puritis – histamine release; Nonsedating
antihistamines
 Nausea/Vomiting/Dyspepsia
 Caused by stimulation of the chemoreceptor
trigger zone
 Occurs in 50-70% of pts
 Usually resolves in a few days
 Antiemetics
Adverse Effects & Management
 Respiratory depression*****see methadone slide!
 In the presence of ongoing pain: RARE
 Occurs primarily when opioid-naive pts are initiated at high doses, or
when dosage increases are made too rapidly
 Naloxone only if severe (0.1-0.2 mg IV q 1-2 min until alert; only lasts 1015 min)
 Physical Dependence
 Withdrawal if therapy stopped abruptly
 Myoclonus
 TX with benzo, or anticonvulsant
Adverse Effects & Management
Will the S/Es go away?
 Tolerance develops to the respiratory depression,
nausea, vomiting and sedation…
…but NOT constipation!
 http://www.youtube.com/watch?v=HEpwXiRoBOs
Principles of Dosing
 Better to schedule medication instead of waiting for
pain – otherwise just chasing pain!
 Short acting (intermediate release) – q 4h
 Steady state plasma level ~ 1 day
 Long acting (sustained release) – q12 h
 Stead state plasma level within 2-4 days
What is Breakthrough Pain?
 1st defined in 1990 by Portenoy and Hagen as
“transient increases in pain in a cancer patient
who has stable, persistent pain treated with
opioids”
 episodic/transient/breakers/inbetween/
interd0se
 International Association of the Study of Pain “a transitory flare of pain that occurs on the
background of relatively controlled baseline
pain”
What is Breakthrough Pain?
 An acute episode of pain superimposed on
constant/ongoing pain
 Frequency and duration varies considerably from
patient to patient
 Few seconds – couple of hours
Typical Episode of BT Cancer Pain
BTcP refers to the pain flares that occur beyond the baseline
persistent pain
Uncontrolled Baseline Pain vs BT Pain
BTcP must be distinguished from uncontrolled background pain, for
successful treatment
1. Portenoy RK and Hagen NA. Prim Care Cancer 1991:27–33.
2. Bennett D et al. P&T 2005;30:296–301.
Not BT Pain
 End of dose failure
 Baseline/Persistent Pain
 Incident Pain – but also only lasts for a short time and
predictable, and baseline pain is controlled
What is Breakthrough Pain?
 A BT dose is an additional dose – it does not
replace/delay administration of next regular dose
Impact of Breakthrough Pain
• Patients with BT pain have higher levels of:
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Background pain
Peak pain
Depression
Anxiety
Functional impairment
• BT pain has a significant negative effect on quality of life
Breakthroughs
 GROT: 10% of total daily dose given q1h (po) or
q30min s/c
Or ½ of q4h dose
 If pain uncontrolled incr dose:
 25-50% mild-moderate pain,
 50-100% for severe to uncontrolled pain
 Or at least equal to amts of BTs used
BT Medication
 Same opioid as long acting opioid – reaches peak
effect in 30 min (sc) or 1 hour (po), lasts 4 hours
 Fentanyl/Sufentanyl SL or SC – faster onset,
inconvienent delivery
What we want…..
BT Medication
 New option – ABSTRAL
Characteristics of fentanyl citrate
 Lipophilic opioid analgesic
with a potency 100 times
that of morphine1
 The most lipophilic of the clinically available
immediate-release opioids2
 Well suited to oral transmucosaldelivery2
 Quickly crosses cellular barriers, providing broad tissue distribution
and rapid onset of action3
 Oral transmucosal fentanyl citrate (OTFC)
 The first rapid-onset opioid to be approved for the treatment of
BTcP4
 Recommended by the European Association of Palliative Care5
1. Abstral™ Product Monograph.
2. Bennett D et al. P&T 2005;30:354–361.
3. Coluzzi PH. Am J Hosp Palliat Care 1998;15:13–22.
4. Actiq® Cephalon 2009
5. Hanks GW et al. Br J Cancer 2001;84:587–593
Fentanyl Citrate
Oral transmucosal administration
 Convenient and easy to use1
 Takes advantage of characteristics of the oral mucosa that
facilitate rapid absorption:2
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large surface area
high permeability
high vascularity
uniform temperature
 Associated with high bioavailability, due to avoidance of
first-pass metabolism3
1. Zeppetella G. Palliat Med 2001;15:323–328.
2. Simmonds MA. Oncology 1999;13:1103–1108.
3. Weinberg DS et al. Clin Pharmacol Ther 1988:44:335–342
Abstral Indication
 For the management of breakthrough pain in cancer
patients who are already receiving, and who are
tolerant to, opioid therapy* for their persistent
baseline cancer pain
 Adults 18 years of age or older
* Patients taking for one week or longer (≥), at least:
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60 mg oral morphine/day;
25 mcg transdermal fentanyl/hour;
30 mg oral oxycodone/day;
8 mg oral hydromorphone/day; or
an equianalgesic dose of another opioid for 1 week or longer.
Abstral Contraindications
 Non-opioid-tolerant patients
 The management of acute or postoperative pain,
including headache/migraine, dental pain, or use
in the emergency room
 Patients with severe respiratory depression or
severe obstructive pulmonary conditions
 Patients with known sensitivity or intolerance to
fentanyl products
Appropriate Patient Selection
for Abstral
Patient must have
persistent baseline pain
Baseline pain must be
adequately controlled
Patient also experiences
transient episodes of
moderate-to-severe pain
Abstral Pharmacological
characteristics
 Fentanyl citrate has a potency approximately 100 times
that of morphine1
 Overall bioavailability of Abstral is estimated to be 54%
mainly through the oral mucosa1
 Pharmacokinetics of Abstral display dose proportionality
over the dose range of 100–800 µg, with single and
multiple dosing1,2
1. Abstral™ Product Monograph 2011
2. Rauck RL et al. Curr Med Res Opin 2009;25:2877–85
Absorption of Abstral across the oral
mucosa
 Abstral is formulated as rapidly disintegrating
sublingual tablets1
Abstral pharmacokinetic profile
during the first 60 minutes
Efficacy of Abstral in patients with cancer:
Phase III primary endpoint
 Abstral gave rise to significant improvements in pain
intensity versus placebo:
 Mean summed pain intensity difference was significantly
greater with Abstral than placebo at both 30 and 60
minutes (p≤0.0005)
Efficacy of Abstral in patients with cancer:
Phase III Secondary endpoint
 Greater improvements in pain intensity difference were observed with Abstral
versus placebo from 10 minutes post-dose
 Significant differences were maintained throughout the 60-minute
assessment period (Abstral versus placebo, p≤0.0055)
 More patients reported ≥30% reduction in pain intensity with Abstral than with
placebo (p<0.0001)
Dosage and administration
 To administer Abstral, one tablet is placed under
the tongue at the deepest part of the sublingual
cavity, where it is allowed to dissolve completely
o Chewing, sucking or swallowing could result in
reduced absorption and low plasma concentrations of
fentanyl
 Abstral tablets are available in six dosing strengths:
Recommended titration schedule
 The initial dose of
Abstral used must
be 100 µg
 Abstral dosing for
a subsequent
episode should be
separated by at
least 2 hours
 No more than four
doses per day
Long-term safety of Abstral
1. Rauck RL et al. Curr Med Res Opin 2009;25:2877–85.
2. Nalamachu S et al. Curr Med Res Opin Vol.27,No.3,2011,519–530
Long-term safety of Abstral:
adverse events
1. Rauck RL et al. Curr Med Res Opin 2009;25:2877–85.
2. Nalamachu S et al. Curr Med Res Opin Vol.27,No.3,2011,519–530
Reminder: Key Safety Messages
 Must not be used in opioid non-tolerant adult
cancer patients
 Abstral – Starting dose is 100mcg S/L; titrate
by 100mcg until 400mcg, then tirate by
200mcg (max dose = 800mcg) separated by
2h; max 4 doses/day
 ABSTRAL contains fentanyl, a controlled
substance with potential for being abused
and sought after by drug abusers/people with
addiction disorders
Reminder: Key Safety Messages
 Fentanyl products, which are designed to
manage breakthrough pain, should not be used
in patients who are receiving partial opioid
agonists such as buprenorphine or agents with
some opioid effects such as tramadol, as the
safety of their concomitant use has not been
established
 Patients and caregivers must follow proper
storage, handling and disposal guidelines
BTP Conclusion
 Uncontrolled Baseline Pain does not equal
Breakthrough Pain
 Breakthrough pain needs to be treated to have good
overall pain control
 Usual choice of breakthrough is 10% of current 24hr
opioid dose
 ABSTRAL are new options:
 has demonstrated rapid onset of action
 Easy-to-administer S/L tab
 Demonstrated favourable safety profile when used in adult
opioid-tolerant cancer patients
 AEs as expected for opioid medications
Questions?
What is Methadone?
 Synthetic opioid
 Similar in binding to mu, kappa receptors; delta?
 Unique from other opioids is NMDA receptor
antagonist, and 5-HT/NE neuronal reuptake
 Invented in Germany during WWII
 1960s - Used to treat heroin addiction
 1980s – renewal of interest for treating pain
 Problem?
 Variable opioid conversion ratio, long half-life, and
drug interactions make it a scary drug!
Methadone is Lipophilic:
 Good: GI tract and cutaneous absorption
 Bad: accumulation in tissues and increased protein
binding → prolonged retention
 Onset of action 30min, peak effect in 3-4 hours, halflife 12-150 hours
 “rapid and extensive distribution phase followed by
slow elimination phase”
Methadone Pharmacology During Initial
Dosing Period (0 to 1 day)
A
Free fraction
Drug
in plasma elimination
B
Analgesia
A Majority of drug initially sequestered
to tissue binding sites
B Small quantity of methadone
available
Methadone Pharmacology
At Steady State (3 – 5 days +)
C
E
D
Analgesia
C Once the reservoir is full, subsequent
doses available to plasma (leading to
reduced requirement)
D Increased dose fraction for analgesia
E In steady state, equilibrium is maintained
– in effect a slow-release reservoir
Methadone Elimination
 Eliminated mainly via liver metabolism and fecal
excretion (renal minor)
 Renal and hepatic impairment do not affect
methadone clearance
 No active metabolites
Methadone and Prolonged QT
 Mechanism not yet fully identified
 Significant QTc prolongation is defined as
> 500 msec
 Risk factors include: low K+ or Mg+ (a side-effect of
cisplatinum therapy), hx of CHF, bradycardia or
baseline long QT, liver disease, concomitant disuse or
use of medications, or a reduction in plasma protein
levels which then increase methadone concentration
 QTc in females normal up to 460 msec and 440 msec
in males
 A change of 40-60 msec from baseline or absolute
value greater than 500 is considered significant
Methadone and Prolonged QT
Suggested Guidelines:
What are the goals of care? Do we “care” if the QT
interval is prolonged?
 ECG if methadone dose > 300 mg/d
 Recheck with methadone dose increases
 Recheck if possible drug interaction that could
increase effective dose
 If QT between 450-500 msec, consider increasing
methadone with caution and ECG reassessment
 If QT > 500 msec, consider reducing dose of
methadone
Methadone Dosing
 In addiction: OD
 For Pain: BID to TID, maybe QID?
 Conversion morphine to methadone: Morphine
Equivalent Drug Dose – MEDD
 Anywhere from 2.5:1 to 15:1
Different MEDDs:
 Edmonton model: 10:1 methadone to morphine
 Milan model:
 4:1 if 30-90 mg morphine
 6:1 if 90-300 mg morphine
 8:1 if > 300 mg morphine
 UK model:
 10:1 if < 300 mg morphine a day
 > 300 mg morphine start with 30 mg/day in divided
doses
 Palermo model:
 5:1 (20%) of previous daily dose of morphine
 NS Cancer Centre:
 10:1 if <500 mg morphine a day
 20:1 if >500 mg morphine a day
Reasons for Rotating Opioids
Reasons for Rotating Opioids
 Inadequate Pain Relief
 Side Effects
 sedation, nausea/vomiting,
confusion/delirium, dry mouth, dizziness,
puritis, urinary retention, opioid-induced
neurotoxicity, myoclonus, mood changes
 Dosage/Volume
 Lose route
 Tolerance
How to rotate opioids
 Calculate equivalent dose
 Reduce by 25-30% for incomplete cross tolerance at
the receptors
 Stop new opioid and start new
Edmonton Model
 Occurs over three days
 Day 1: Decrease 30% of the morphine dose over 24 hours
and replace it with methadone every 8 hours using a
morphine:methadone 10:1
 Breakthrough – use same med as before
 Day 2: If pain control good, decrease the original dose of
morphine by another 30%; increase the dose of methadone
only if the patient experiences moderate to severe pain
 Day 3: Discontinue the last 30% of the original morphine
dose and maintain patient on regular methadone tid
Modified Morley-Makin Model
 Stop current opioid
 Calculate MEDD
 Use 10% of MEDD every 3 hours prn (10:1), not to
exceed 30 mg/dose
 On day 6, divide the total dose of methadone
given in the last 48 hours by 4 and use the dose q
12 h, or divide by 6 and use the dose q 8 h
 BTD is 10% of daily dose q3h prn
Cowboy Method
Mansfield-Horton Model
 Stop opioid
 Start methadone at 5-10 mg tid depending on pain
and previous opioid dose (10:1, max 30 – 45 mg/day)
 Increase every 3-5 days depending on pain
 Mild pain 25%, moderate pain 33%, severe pain 50100%
 If opioid naive, start at 2.5 mg bid
 Use previous breakthrough dose, or once pain stable
change to methadone for breakthrough (10% daily
dose q 3 h prn)
Chicken Method
 Calculate the MEDD
 Decrease current opioid dose by 1/3, start 1/3 of
calculated methadone target dose (bid or tid)
 Wait 3 days, decrease current opioid dose by another
1/3, increase methadone dose by 1/3 or best
judgement
 Wait 3 more days, d/c old opioid dose, increase
methadone to target dose or best judgement
Breakthroughs for other Opioids
 10% of total daily dose or ½ of q4h dose, given po q1h
prn, or s/c q 30 min prn
 If pain uncontrolled, increase dose:
 25-50% mild-moderate pain
 50-100% for severe to uncontrolled pain
 Or at least equal to amts of BTDs used
Breakthrough for Methadone
 10% of total daily dose of previous opioid, or ½ of q4h
dose, given po q1h prn, or s/c q 30 min prn
 OR: 10% of total daily methadone dose given po q 1h
prn or q 3h prn, max 6 doses per day
 If pain uncontrolled increase dose:
 25-50% for mild-moderate pain,
 50-100% for severe to uncontrolled pain
 Or at least equal to amts of BTs used
Methadone Overdose?
 Sedation always proceeds respiratory depression
 Monitor for and concern if:
 Lack of response to tactile or vigorous stimuli
 RR < 10/min
 Systolic BP < 90 mmHg or 20% less than baseline
 O2 saturation levels occasionally helpful but can be
falsely reassuring
 Consider in patients with history of sleep apnea,
obesity or any condition which decreases
ventilation capacity
Methadone Overdose
Methadone Toxicity Treatment
 Nalaxone 0.1-0.2 mg q 2 min until respiratory rate >
8/min and O2 saturation > 90%
 Repeat q 20-30 min until patient stabilized.
 Because of methadone’s long half life, a naloxone
infusion may be required following stabilization
 Start with 50 mcg naloxone (0.1 mcg/ml) per hour
and titrate to effect
Potential methadone drug interactions
There are 2 ways to cause an effect:
1. By starting a medication which will alter the
metabolism, e.g.:
• Starting fluconazole or paroxetine may reduce clearance
resulting in increased serum levels and sedation/toxicity
• Starting retonavir or dilantin may increase clearance
resulting in decreased levels and may reduce analgesia
or ppt withdrawal
Potential methadone drug interactions
By stopping a medication which will alter the
metabolism, e.g.:
• Stopping fluconazole or paroxetine may increase
clearance resulting in decreased serum levels and
reduced analgesia or withdrawal symptoms
• Stopping retonavir or dilantin may decrease clearance
resulting in increased levels and may increase analgesia
or cause sedation/toxicity
Potential methadone drug interactions
CYP3A4 inhibitors – increase methadone levels
CYP3A4 inducers – decrease methadone levels
Fluconazole
Rifampin
Ketoconazole
Phenytoin
Fluoxetine*
Phenobarbitol
Norfluoxetine*
Carbamazepine
Fluvoxamine*
Risperidone
Paroxetine*
Ritonavir
Macrolide antibiotics
Nevirapine
Nifedipine
Glucocorticoids
Verapamil
Fusidic acid
Diltiazem
Grapefruit juice
Sertraline hydrochloride*
Cimetidine
Nafazedone*
*Also inhibits CYP1A2
 See cards
Case 1
 Jackie, 52 yo female with metastatic breast ca to lung,
liver, bone, and brain
 Major pain is in head
 Tried other adjuvants
 On 48 mg hydromorph contin bid now, BT
hydromorphone 12 mg po q1h prn (taking 10/day)
 Still no difference in pain level!
 Rotate to methadone
Case 1
 Hydromorph contin 96 mg/day =~ 500 mg
morphine/day
 10:1 ratio for MEDD yields a methadone dose of 50
mg/day
Case 1
 Method:
 BT dose:
Case 2
 Sarah, 45 yo female with metastatic rectal ca
 Pain is rectum, radiating down legs
 Currently on hydromorphone 8 mg/h in CADD
Case 2
 Rotate to methadone
Case 2
 Hydromorphone 8 mg/h = 192 mg s/c
hydromorphone/day
 Hydromorphone 192mg s/c = 384 hydromorphone
po/day
 Hydromorphone 384 mg = 1920mg morphine
 10:1 MEDD = 192 mg methadone/day
Case 2
 Method:
 BT dose:
Case 3
 Burt, 60 yo male with pancreatic ca
 Pain is epigastric, hard to describe
 Was on hydromorph contin 24 mg po bid, then
rotated to Duragesic, and titrated up to Duragesic 150
ug/h
 Still using hydromorphone 12 mg po q 1 h prn and
showing signs of neurotoxicity
Case 3
 Rotate to methadone
Case 3
 Duragesic 150 ug/hr = ~600mg morphine/day
 10:1 ratio = 60 mg methadone
Case 3
 Method:
 BT dose:
Case 4
 Glenda, 65 yo female multiple myeloma
 Pain in back, admitted with nausea/vomiting, thought
to be related to escalating morphine doses
 MS Contin 100 mg po bid
Case 4
 Rotate to methadone
Case 4
 MS Contin 200 mg/day, 10:1 ratio = Methadone 20 mg
Case 4
 Method:
 BT dose:
Case 5
 Harold, 62 yo male with multiple myeloma and post
herpetic neuropathic pain in the occipital region –
rates as 8/10
 Not using opioids regularly, finds “they don’t work”
 On maximum dose gabapentin, as well as
amitriptyline
Case 5
 Start him on methadone
Case 5
 Relatively opioid naïve
 Methadone starting dose?
Case 5
 Method:
 BT dose:
Key Messages About
Prescribing Methadone for Pain
 Titrate slowly to analgesic effect
 reduces risk of toxicity/sedation/respiratory
arrest
 pain threshold is reached at lower doses
than sedation threshold and respiratoryarrest threshold
 Avoid drug interactions via careful history
Key Messages About
Prescribing Methadone for Pain
 Monitor closely for adverse effects and drug
interactions
 ask about/investigate drug interactions at
every visit
 Educate patients and include them as part of
the care team
 being attentive to/reporting adverse effects
and informing about other drugs being
taken
Key Messages About
Prescribing Methadone for Pain
Methadone is a highly effective
opioid for pain and can and should
be used not just third line, but
second and first line!
Questions?