1. SL Fentanyl and Methadone- Are 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

2. Disclosure: Unrestricted educational grant

3. Learning Objectives At the end of the session the participant will:
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

4. At the end of the day the participant will be able to:
Identify my husband, Nathanael Anderson

5. Opioids 101 Opioids: Originally derived from opium
Natural and synthetic
Narcotic (Greek work for stupor) –
dependence /addiction

6. Classification of Opioid Receptor Sites Adapted from Medical care of the Dying, 4th Ed.
Effect
Mu (OP3)
Kappa (OP2)
Delta(OP1)
Pain
Analgesia
Respiratory rate
Depression
Heart Rate
Bradycardia GI
Nausea
Reduced motility
Constipation
Affect
Sedation
Indifference
?euphoria
Psychotomimetic
Dysphoria

7. Opioids 101 Different Opioids: Codeine Butrans Tramadol Morphine
Nucynta
Oxycodone
Hydromorphone
Fentanyl
Methadone

8. Opioid Equivalency DRUG PO DOSE SC/IV DOSE FORM COMMENTS Morphine 10mg
Tab (IR,SR)
Inj
Supp
Codeine
100mg
50mg
Tramadol
N/A
Tab (IR, SR)
Oxycodone
Tab
(IR,SR)
Hydromorphone
2mg
1mg
Methadone
Special
PO/PR/SL
Duration & half-life increase with repeated use (cumulative effect)
Fentanyl
25 mcg/hr ~ 100mg PO morphine/
24h
Roughly 100mcg/h = morphine
4 mg/h iv
SR Patch
IR SL
Change SR patch q 72 hours
Reservoir takes 12 hours to build

9. 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?

10. 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

11. 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 ( mg IV q 1-2 min until alert; only lasts min)
Physical Dependence
Withdrawal if therapy stopped abruptly
Myoclonus
TX with benzo, or anticonvulsant

12. Adverse Effects & Management
Will the S/Es go away?
Tolerance develops to the respiratory depression, nausea, vomiting and sedation…
…but NOT constipation!

13. 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

14. 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”

15. 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

16. Typical Episode of BT Cancer Pain
BTcP refers to the pain flares that occur beyond the baseline persistent pain

17. 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.

18. 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

19. What is Breakthrough Pain?
A BT dose is an additional dose – it does not replace/delay administration of next regular dose

20. Impact of Breakthrough Pain
Patients with BT pain have higher levels of:
Background pain
Peak pain
Depression
Anxiety
Functional impairment
BT pain has a significant negative effect on quality of life

21. 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

22. 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

23. What we want…..

24. BT Medication
New option – ABSTRAL

25. 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– 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

26. Fentanyl Citrate

27. Oral transmucosal administration
Convenient and easy to use1
Takes advantage of characteristics of the oral mucosa that facilitate rapid absorption:2
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– Simmonds MA. Oncology 1999;13:1103– Weinberg DS et al. Clin Pharmacol Ther 1988:44:335–342

28. 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:
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.

29. 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

30. 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

31. 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 Rauck RL et al. Curr Med Res Opin 2009;25:2877–85

32. Absorption of Abstral across the oral mucosa
Abstral is formulated as rapidly disintegrating sublingual tablets1

33. Abstral pharmacokinetic profile during the first 60 minutes

34. 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)

35. 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)

36. 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
Chewing, sucking or swallowing could result in reduced absorption and low plasma concentrations of fentanyl
Abstral tablets are available in six dosing strengths:

37. 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

38. 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

39. 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

40. 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

41. 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

42. 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

43. Questions?

44. 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!

45. 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, half-life hours
“rapid and extensive distribution phase followed by slow elimination phase”

46. Methadone Pharmacology During Initial Dosing Period (0 to 1 day)
Free fraction in plasma
Drug elimination B
Analgesia
A Majority of drug initially sequestered to tissue binding sites
B Small quantity of methadone available

47. Methadone Pharmacology At Steady State (3 – 5 days +)
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

48. Methadone Elimination
Eliminated mainly via liver metabolism and fecal excretion (renal minor)
Renal and hepatic impairment do not affect methadone clearance
No active metabolites

49. 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 msec from baseline or absolute value greater than 500 is considered significant

50. 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 msec, consider increasing methadone with caution and ECG reassessment
If QT > 500 msec, consider reducing dose of methadone

51. 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

52. Different MEDDs: Edmonton model: 10:1 methadone to morphine
Milan model:
4:1 if mg morphine
6:1 if 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

53. Reasons for Rotating Opioids

54. 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

55. How to rotate opioids Calculate equivalent dose
Reduce by 25-30% for incomplete cross tolerance at the receptors
Stop new opioid and start new

56. 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

57. 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

58. 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 %
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)

59. 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

60. 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

61. 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

62. 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

63. Methadone Overdose Methadone Toxicity Treatment
Nalaxone mg q 2 min until respiratory rate > 8/min and O2 saturation > 90%
Repeat q 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

64. 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

65. 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

66. 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

67. 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!

68. Rotate to methadone

69. Case 1 Hydromorph contin 96 mg/day =~ 500 mg morphine/day
10:1 ratio for MEDD yields a methadone dose of 50 mg/day

70. Case 1
Method:
BT dose:

71. Case 2 Sarah, 45 yo female with metastatic rectal ca
Pain is rectum, radiating down legs
Currently on hydromorphone 8 mg/h in CADD

72. Case 2
Rotate to methadone

73. 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

74. Case 2
Method:
BT dose:

75. 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

76. Case 3
Rotate to methadone

77. Case 3 Duragesic 150 ug/hr = ~600mg morphine/day
10:1 ratio = 60 mg methadone

78. Case 3
Method:
BT dose:

79. 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

80. Case 4
Rotate to methadone

81. Case 4
MS Contin 200 mg/day, 10:1 ratio = Methadone 20 mg

82. Case 4
Method:
BT dose:

83. 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

84. Case 5
Start him on methadone

85. Case 5
Relatively opioid naïve
Methadone starting dose?

86. Case 5
Method:
BT dose:

87. 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 respiratory-arrest threshold
Avoid drug interactions via careful history

88. 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

89. 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!

90. Questions?