Download Pain Control at the End of Life: Balancing Efficacy and

Jennifer Good MD
Hospice Medical Director, Home Nursing Agency
Altoona, Pennsylvania
Mary Mihalyo BS, PharmD, RPh
Duquesne University
Pittsburgh , Pennsylvania
Objectives
 To understand the concept of “total pain” and how
treating physical pain is foundational to treating total
pain.
 To understand the difference between nociceptive and
neuropathic pain and how treatment differs.
 To understand basic principles in starting and
maintaining narcotic therapy for pain.
 To recognize that there are “preferred agents” for pain
control in patients at the end of life based on their
clinical condition and comorbidities.
Mary Q.
 Mary Q. is a 91 year old woman referred to hospice with end
stage dementia. She is nonverbal and requires assistance with all
ADLs. She requires hand-feeding and is eating about 25% of her
meals. She has lost 20 lbs over the past 3 months and currently
weighs 90 lbs (41 kg). She has had a recent UTI which was
treated in her nursing facility and has a Stage 2 decubitus ulcer.
Lab evaluation is essentially normal except her creatinine is 1.0
mg/dl and albumin is 2.6 g/dl. She has been increasingly
withdrawn and cries and grimaces with any cares or movement.
 Is Mary in pain?
 What should be done about it?
Pain at the end of life
 Extremely common symptom
 Children: 62 – 90% have pain at the end of life1
 Adults with non-cancer diagnoses: 40% have pain
within days of death2
 Adults with advanced cancer: 64% have pain (and 1/3 of
these patients report pain as severe)3
1
American Pain Society. Guidelines for the Management of Cancer Pain
in Adults and Children. Glenview IL 2003.
2 Lynn et al. Ann Intern Med 1997; 126(2): 97 – 106
3 Van Den Beuken et al. Ann of Oncol 2007; 18:1437 – 1449.
Total Pain
 4 Components
 Physical pain (usually from multiple sources)
 Emotional or psychic pain
 Social or interpersonal pain
 Spiritual or existential pain
Three main steps to treating pain
1.
Thorough assessment of all types of pain, and
assessment of the risks and benefits of treatment
2. Treat each type of pain with individualized, etiology-
specific interventions
3. Continuous reassessment of treatment goals (pain
levels, functional status) and tolerability/adverse
effects of prescribed treatments.
Pain Assessment
 Gold standard is patient report
 Some patients unable to provide verbal report
 Children
 Adults with advanced dementia
 Patients with neurological impairment or critically ill
 Pain assessment tools
 Used in research settings to objectify responses

Should use the same tool consistently
 Used in patient populations in whom verbal description
of pain difficult
Wong-Baker FACES pain scale
Pain Processes
 Four Steps
1. Transduction (NSAIDs, Local Anesthetics &
Anticonvulsants)
2. Transmission (Opioids, NMDA Antagonists)
3. Perception (Distraction, Relaxation, Imagery)
4. Modulation (Tricyclic Antidepressants, Opioids,
GABA Agonists)
Nociceptive Pain
 Pain caused by stimulation of nociceptive receptors on
peripheral afferent nerves – generally 2 main types:
 Visceral—pain that originates in the thoracic,
abdominal or pelvic viscera
 Somatic—activation of nociceptive receptors on body
surface or musculoskeletal tissue
 Deep—stimulation of nociceptors in bones, ligaments,
muscles.
 Superficial—stimulation of nociceptors in skin and
superficial tissues
Neuropathic Pain
 Pain resulting from direct injury or dysfunction of
peripheral or CNS tissue. Two main types:
 Peripheral
 Central
Common causes of pain at the End
of Life
 Pain from pre-existing medical conditions
 Arthritis
 Migraines
 Muscle strain
 Neuropathy
 Pain related to underlying malignancy
 Tumor effects
 Paraneoplastic
 Bone metastases
 Bladder spasm
 Contractures/poor positioning
 Constipation
 Pressure ulcers
Clearing up opioid misconceptions
 Opioids rarely cause significant respiratory depression
 Opioids rarely cause addiction in this patient
population
 Opioids are rarely associated with significant tolerance
 Opioids rarely cause death
 Opioids rarely cause nausea that requires their
discontinuation
Goals of Pain and Symptom
Management
 Improve quality of life
 Use of medication efficiently
 Minimize side effects
 Use appropriate routes of administration
 Keep medication dosage schedules simple
 Anticipate disease progression
 Give patient and care givers information and
choices
Master: Rules for Rational Drug
Therapy
 Minimize number of drugs used
 Alternatives should be considered
 Start low and go slow
 Titrate to effect
 Educate patient/caregivers
 Review regularly
Pain management “Rights”
 Right (Opioid) for
Patient
 Right dose of drug
 Right route of
administration
 Right time of
administration
(around the clock)
Pain management is all about….
 Age
 Renal function
 Hepatic function
 Etiology of pain
 Environment of care
 Ambulation status
Renal
Function
Renal Function
CrCl > 40
CrCl = 30-40
Preferred agents
Oxymorphone
Morphine
Oxycodone
Hydromorphone
Methadone
Oxycodone
Hydromorphone
Methadone
CrCl = 10-30
Oxycodone
Methadone
CrCl < 10
Oxycodone
Methadone
Cockcroft Gault:
CrCl (mg/min)=
[(140- age) x IBW]/(SCr x 72)
For women multiply by 0.85
Opioids to Avoid in Renal Failure
 Morphine
 Oxymorphone
 Hydromorphone
 Meperidine
 Propoxyphene
Opioid Cost Comparison/Day
 MS Contin® 400 mg/day
$20.02
 Avinza® 400 mg/day
$27.59
 OxyContin® 320 mg/day
$34.36
 Duragesic® 200 mcg/hr
$30.82
 Methadone 40 mg/day soln
$ 3.00
 Methadone 40 mg/day tabs
$ 0.60
 Methadone 40 mg diskette
$ 0.36
Why use Morphine?
 Morphine is WHO’s strong opioid of choice for
cancer pain management
 Orally, no other strong opioid has a clear
advantage over morphine
 Exception—renal failure; worry about accumulation of
morphine 6-glucuronide
 Orally available in immediate release and long acting
formulations
 Can also be given rectally, IV, SC, epidural, IT
Pharmacokinetics of Morphine
 Onset of action:
 IV = 5 – 10 minutes
 SC/IM= 30 minutes
 PO= 1 hour
 Half-life :
 3 – 4 hours (PO/PR/SC/IM)
 Steady state after 4 – 5 half lives (≈ 24 hours)
 Duration of effect with “immediate release”
preparations – 3 – 4 hours, less with IV administration
Principles Governing Morphine Use
 Address psychological, social and spiritual needs
in addition to physical needs
 Use morphine when weak opioid plus NSAID are
not effective
 Continue NSAIDs unless contraindicated
 Use oral route unless NPO
 Administer around the clock with rescue doses as
needed
Starting Morphine in patients with
poorly controlled pain
 Use current opioid use as guideline (calculate
equivalent morphine dose using equianalgesic tables)
 Decrease total equivalent oral daily morphine dose by
approximately 25% - 50% to allow for incomplete
cross-tolerance
 Divide calculated dose in half and give as SR every
twelve hours
 Use immediate release morphine for incident or
breakthrough pain
Opioid Equivalents
Drug
Oral/Rectal (mg)
IV/SC (mg)
Morphine
30
10
Oxycodone
20
N/A
Hydromorphone
7.5
1.5
Codeine
200
120 (IM only)
Hydrocodone
30
N/A
Oxymorphone
10
1
Fentanyl
N/A
100 mcg
John H.
 John H. is a 75 y/o with metastatic renal cell cancer
with multiple bone metastases. His renal function is
normal. His pain is poorly controlled in spite of
Percocet 5/325 one to two tablets every four hours and
ibuprofen.
 How would you transition Mr. H to morphine?
Calculating Mr. H’s morphine dose:
 Mr. H has taken an average of 8 percocet daily over the
past several days: 40 mg of oxycodone/day
 Using the equianalgesic table this is approximately 60
mg of morphine/day
 Normally, dose should be decreased approximately
25% - 50% (to be “on the safe side” and allow for
incomplete cross tolerance)
 New dose of morphine SR 15 – 30 mg PO q12 hours
 Breakthrough dosing immediate release morphine 5 –
10 mg every 2 - 3 hours
Titrating morphine dose for poorly
controlled pain
 Mild to moderate pain—increase dose by 25 – 50%
 Moderate to severe pain—increase dose by 50 – 100%
 How quickly dose can be escalated depends on drug
half-life:
 Immediate release can be safely increased every 2 – 4
hours
 Sustained release morphine can be safely increased
every 24 hours
 Fentanyl (transdermal)can be safely increased every 72
hours
 Methadone can be safely increased every 4 – 5 days
Is Oral Morphine Really Effective?
 Yes
 Median max dose is 15-20 mg Q4 hours
 Equivalent to 60 mg SR BID
 Few patients require more than 200 mg Q4 hours
 Equivalent to 600 mg SR BID
 SR tabs are equally effective as IR tabs
 If pain does not respond to oral morphine, SQ or
IV will not work either
What if Pain Seems Morphine Resistant?
 Unresolved spiritual or social issues?
 May require psychotherapy plus an anxiolytic or
antidepressant
 Morphine poorly-responsive pain
 Bone
 Liver
 Neuropathic pain
 Crampy musculoskeletal pain
Using SC or IV morphine
 Consider when patient no longer able to take PO
 Add up total 24 hour morphine dose and divide by 3—
this is total 24 hour IV/SC dose
 Divide total 24 hour IV/SC dose by 24 in order to
determine hourly dose
 Can also allow demand dosing for breakthrough
pain—usually 50 – 100% of the hourly dose every 15
minutes
John H.
 Mr. H’s illness has progressed considerably over the
past 8 weeks. He is spending almost all his time in bed
and is eating very poorly. He is now using MS Contin
100 mg q12 and uses MSIR 15 mg every 3 hours as
needed (average 5 doses daily). His pain is relatively
well controlled but his hospice nurse has noticed that
some of his medications are missing.
 What do you do now?
John H.
 Consider initiating SC morphine infusion
 Total oral morphine dose in 24 hours: 275 mg
 Equivalent IV morphine dose in 24 hours: 275 mg /3 or
91.6 mg
 Hourly IV dose: 91.6 mg/24 or 3.8 mg/hour
 Start IV morphine at 3 mg/hr
 Breakthrough dosing 1 mg SC q15 minutes PRN
 Be very careful about using continuous opioid
infusions if opioid naïve.
Ask “Why Not Use Morphine?”
 We should do all we can to use morphine!
 If a patient is inappropriate to receive morphine
then ask “ Why Not Use Methadone?”
 Oxycodone should be reserved for patients who
are inappropriate for morphine AND methadone
 Fentanyl should be reserved for patients who are
NPO or those with poor environment of care
If we can’t use morphine—Ask
“Why not use methadone?”
 Methadone becomes opioid of choice if morphine
is inappropriate because:
 No active metabolites
 Less N/V
 Less constipation
 NMDA receptor blockade
 Decreases pill burden
 Cost effective
Advantages of methadone for pain
at the end of life
 Lipophilicity allows for mucosal membrane absorption





(oral, rectal, vaginal, sublingual)
Only long acting opioid available in liquid formulation
Most efficacious opioid for neuropathic pain due to its
action at NMDA receptor
Long half life but rapid onset of action (30 – 60
minutes)
Safe in both renal and hepatic dysfunction (generally
no dose reduction)
Cheap
Concerns about methadone
 Respiratory depression
 Arrhythmias (due to QT prolongation/torsade de pointes)
 Concomitant cardiac disease
 Concomitant use of other medications that prolong QT
interval



Atypical antipsychotics
Antiarrhythmics
Fluoroquinolone antibiotics
 Multiple drug interactions
 Conversion from other drugs is complicated
 Reports of deaths in community
Traditional Myths Regarding
Methadone
 It requires special licensure to prescribe and dispense
methadone.
 FALSE!
 Methadone is only used in drug addiction.
 FALSE!
 Methadone is NEVER appropriate in hospice patients
because:
 Half-life is too long
 Difficult to titrate
 Too many drug interactions
 Patients don’t like it
 FALSE!
Dosing the opioid naïve patient
 Methadone 2.5 mg po qd hs or BID
 Increase total daily dose no more frequently than
every 5 days
 Daily monitoring x initial 7 days
Methadone Equianalgesic
Dosing Ratio
24 Hour Oral Morphine Morphine:Methadone
Ratio per 24 Hours
Equivalent
<30 mg/24 hrs
30 – 99 mg/24 hrs
100-299 mg/24 hrs
300-499 mg/24 hrs
500-999 mg/24 hrs
>1000 mg/24 hrs
2:1
4:1
8:1
10:1
15:1
20:1
Storey P, Primer of Palliative Care 3rd ed AAHPM 2004
Methadone Conversion Protocols
 UK (Morley-Makin):
1.
2.
3.
Stop previous opioid
Start 1/10 of calculated morphine equivalent up to 30 mg every 3
hrs PRN for 5 days.
On day 6 use last 48 hrs to calculate bid or tid dose.
 Edmonton Palliative Care (Bruera):
1.
2.
3.
4.
Reduce current opioid by 1/3 each day for 3 days.
Start methadone using a 10:1 conversion, dosed every 8 hrs.
Replace deleted opioid with methadone, increasing the dose each
day for 3 days.
Use short acting opioid for BTP.
Mihalyo Method
 Determine starting dose using Morley-Makin Method
 Give starting dose q12h ATC
 Breakthrough dose = scheduled dose
q3h prn, max 2 doses per day
OR
Consider alternative short-acting opioid to
manage BTP
 Adjust q12h scheduled dose on day 6 based on total
amount given on day 5
 Breakthrough dose =10% of 24hr dose q3hprn
Suggested Guidelines for
Considering Methadone Therapy
 Patient has:
 > 200mg oral morphine equivalent a day
 Neuropathic pain
 Side effects from other opioids
 Renal / liver failure
 True allergy to morphine
Nursing Considerations

Consult with “methadone champion” physician,
nurse or pharmacist
 Instruct caregiver to call if pain not controlled or
patient excessively sedated
 Call patient approximately 2 hours after 1st dose
and 12 hours later
 Daily phone calls/visits until dose is stabilized
(7-10 days)
Methadone Side Effects

Similar to other opioids except:




Myoclonus is rare
Less xerostomia
Less constipation and nausea
Hallucinations are uncommon

Possible risk of Torsades de pointes – especially at
higher doses (literature suggests that < 200 mg/d
is safe)

Less sedation however, sedation may be more
problematic because of long half life.
Methadone Advantages in Summary
 Long half life reduces need for frequent dosing
 1 to 3 doses/day
 Effective for neuropathic pain
 Reduced opioid tolerance
 Fewer side effects
 Inexpensive
 Does not accumulate in renal failure
 Safe for morphine allergic patients
Oxycodone
 Advantages
 Available in immediate release formulation (±
acetaminophen) and sustained release
 Better in renal failure than morphine (although not as
safe as methadone or fentanyl)
 Generally accepted by both patients and physicians
 Disadvantages
 High risk for diversion
 Cost
 No parenteral formulation
Indications for oxycodone
 Contraindications or intolerance to morphine or
methadone
 Renal dysfunction
Fentanyl
 Transdermal (Duragesic®)
 Use lowest dose in opioid naïve patient
 Therapeutic levels not reached for 12 – 24 hours after
patch applied, drug continues in blood stream for up to
24 hours after patch is removed
 Some patients may require patch every 48 hours
 Cachexia does not clearly impact drug absorption
 Useful in certain patients—renal failure, poor
compliance, caregiver concerns
Fentanyl
 Transmucosal (Actiq)
 Lozenge on a stick
 Available in 200, 400, 600, 800, 1200, 1600 mcg
 Only for patient receiving opioids (equivalent to 60 mg
morphine daily)—not for opioid naïve
 Swallowed fentanyl only partially bioavailable (approx.
75% of dose)
 Ridiculously expensive (> $40 per 200 mcg lozenge; >
$120 per 1600 mcg lozenge)
Kadian® and Avinza®
 Kadian®
 Longest acting morphine preparation (q24 hour dosing)
 Bioequivalent with ER morphine products
 Morphine granules
 Capsules can be opened and given through PEG/NGT or
sprinkled in food
 $$$$
 Avinza®
 Mixture of immediate and timed released granules
 High doses risk fumarate toxicity
 Cannot use with alcohol (granules dissolve)
 Capsules can be opened and given through PEG/NGT
 $$$$
Not recommended
 Mixed agonist-antagonists
 pentazocine, butorphanol, nalbuphine,
buprenorphine
 compete with agonists  withdrawal
 analgesic ceiling effect
 high risk of psychotomimetic adverse effects
with pentazocine, butorphanol
Not recommended
 Meperidine (Demerol®)
 poor oral absorption
 normeperidine is a toxic metabolite




longer half-life (6 hours), no analgesia
psychotomimetic adverse effects, myoclonus, seizures
if dosing q 3 h for analgesia, normeperidine builds up
accumulates with renal failure
 Propoxyphene (Darvon® and Darvocet®)
 no better than placebo

low efficacy at commercially available doses
 toxic metabolite at high doses
 OFF THE MARKET IN U.S. 2010
Bone/nerve compression pain
 NSAIDS
 Cox 1&2 mixed



Ibuprofen (Motrin®,Advil®)
Naproxen (Naprosyn®)
Choline Mg Salsalycilate (Trilisate®)
• Cox 2 Inhibitors
 Celecoxib (Celebrex®) Limited Use
 Corticosteroids
 Prednisone (Deltasone®)
 Dexamethasone (Decadron®)
Neuropathic Pain
 Tricyclic Antidepressants
(First line for non-stabbing pain)
 Desipramine (Norpramin®)
 Nortriptyline (Pamelor®)
 Doxepin (Sinequan®)
 Amitriptyline (Elavil®)
Tricyclic Antidepressant SE’s
DRUG
AntiCholinergic
Sedation
Orthostatic
Hypotension
Seizures
Conduction
Abnormalities
Amitriptyline
++++
++++
+++
+++
+++
Desipramine
++
++
++
++
++
++
++
++
++
++
++
+++
++
++
++
Nortriptyline
Doxipen
Neuropathic Pain
 Anticonvulsants
(First line for stabbing pain)
 Gabapentin (Neurontin®) 300mg TID
 Carbamazepine (Tegretol®) 200mg QID
 Divalproex Na (Depakote®) 1gm qd
Mary Q.
 Appears to have persistent pain
 Age and renal function are important considerations
(CrCl ≈23 ml/min by Cockcroft-Gault equation)
 Renal function is contraindication to NSAIDs
 Treatment options:
 Scheduled acetaminophen
 Methadone 2.5 mg PO qhs
 Fentanyl 12 mcg/hr (second line but reasonable in renal
failure).
Jennifer Good, MD
[email protected]
Mary Mihalyo, BS, PharmD
[email protected]