Transcript John-Alternate Version

Pharmacologic Treatments of Pain
PMRC Nursing Module
Kim Chapman RN, MSc(N), CON(C)
Clinical Nurse Specialist, Oncology
October 2, 2009
1
Learning Objectives
• Understand the spectrum of pain pharmacology
• Choose pharmacologic treatment options in
chronic and cancer pain
• Identify the more common side effects and
strategies to manage those side effects
2
Mr. Pain’s Story
• 57 yr. old male diagnosed with small cell
lung cancer. Has a lg. mass in his LUL
along with mediastinal & (lt.) hilar
adenopathy, extensive liver mets.
• MI in 2002 - takes ASA daily; peptic ulcer
disease - takes losec daily
• Active until about 1 mos. ago. Lost ~10
lbs. in the last 2-3 mos. Poor nutritional
intake. Constipated. ++ ascites.
Enlarged liver. Jaundiced.
• Arrived for day 1 of his 1st chemotherapy
(etoposide & cisplatin) with c/o abdominal
pain.
3
Mechanistic Approach to Pain
Somatic
NOCICEPTIVE
PAIN
MIXED
Superficial
Deep
Visceral
Central
Peripheral
NEUROPATHIC
PAIN
Others
Ashby MA et al. 1992 51:153-161
4
Nociceptive: Somatic pain
• skin, muscle, connective tissue or bone
• dull, sharp, aching, stabbing, throbbing, or pressure
• well-localized
• usually associated with tissue damage as well as
inflammatory processes
• eg. bone mets., pressure ulcer, infiltrated IV, incision
Nociceptive: Visceral pain
• organs or tissue
• gnawing, cramping, aching, sharp, colicky, dull, or sharp
• localized or referred
• eg. hepatomegaly, bladder spasms
5
Neuropathic pain
• nerve involvement centrally or peripherally
• may arise as a direct consequence of a lesion or
disease affecting the somatosensory system (IASP
2007)
• sharp, tingling, burning, shooting, pins & needles,
allodynia, burning, or lancinating
6
Pain Assessment Findings
• P – Provocation & Palliation – lying, hiccups; certain positioning, heat,
medication, relief of hiccups, relief of anxiety, sleep (BPI)
• Q – Quality of Pain - Classic neuropathic pain both anterior thigh areas
with the usual burning, stinging, & sharp pain along with allodynia possibly due to femoral nerve obstruction or paraneoplastic syndrome.
(LANSS). Dull, achy pain in abdominal area - nociceptive pain (BPI)
• R – Region & Radiation - Pain moves from place to place; always
persistent (BPI)
• S – Severity (on a 0-10 scale) - Pain score of 8-9 at rest and 10 + with
activity (ESAS & BPI)
• T – Timing – constant unless using pain medication; time of day does
not appear to influence pain experience (BPI)
BPI – Brief Pain Inventory; LANSSESAS - Edmonton Symptom Assessment System
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Key Patient Outcomes
• Mr. Pain verbalizes that pain is reduced or
relieved to his satisfaction.
• Mr. Pain uses pharmacologic and nonpharmacologic interventions.
• Mr. Pain participates in activities of daily living
with appropriate medications.
8
What pharmacologic
approach would you use?
9
Your Selection
Opioids
Non-Opioid Analgesics
Adjuvant Medications (Co-analgesics)
10
Pharmacological: Opioids
• *Codeine
• *Hydrocodone
• **Tramadol
• Morphine
• Hydromorphone
• Oxycodone
• Methadone
• Fentanyl
• Sufentanyl
• Levorphanol
• Meperidine
• Naloxone/Pentazocine
Codeine combination products (>7 million prescriptions/yr)
Oxycodone combination products (>1 million prescriptions/yr)
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Pharmacological: Non-Opioid
• Analgesics
– Acetaminophen
– NSAIDS (Antiinflammatory
medications)
• Adjuvant Medications
(Co-analgesics)
– Anticonvulsants (carbamazepine,
phenytoin, gabapentin,
pregabalin)
– Antidepressants (amitriptyline,
nortriptyline, desipramine)
– NMDA blockers
– Corticosteroids (dexamethasone)
– Antispasmodic agents (baclofen)
– Bisphosphonates (pamidronate,
zoledronic acid)
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So, Where’s the roadmap?
13
The Analgesic Stepped Approach
Severe Pain
Moderate
Pain
Codeine
Oxycodone
Tramadol
Fentanyl
Hydromorphone
Methadone
Morphine
Oxycodone
(+/- nonopioid)
(+/- adjuvants)
(+/- nonopioid)
(+/- adjuvants)
Mild
Pain
Acetaminophen
ASA
NSAIDs/COXIBs
(+/- adjuvants)
World Health Organization. Cancer Pain Relief, with a Guide to Opioid
Availability. Geneva, Switzerland: WHO, 1996.
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Leppert W, Luczak J. The role of tramadol in cancer pain management – a review.
Support Care Cancer 2005;13:5-17.
Mr. Pain’s Story
• GP started him on hydromorphone
contin
• ↓ in pain
• developed hives, urticaria & constipation
15
Opioid Therapy: Getting Started
Basic Considerations:
• Patient opioid exposure &
experience
• Patient fears (stigma)
• Caregiver & physician
attitudes, preferences &
biases
• Compliance
• Convenience
• Cost
• Side effects
Pharmaco-clinical Considerations:
• Patient sensitivities/allergies
• Administration & absorption
limitations
• Metabolism & clearance
• Opioid profile
Fine PG. Journal of Pain, Aug. 2001
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Hydromorphone: Key Points
• ~ 5 x more potent than morphine
• Fewer drug interactions
• May be used cautiously in renal failure
• Very soluble - up to 300 mg/ml
• Available in oral liquid, IR tablets, CR capsules, IR
suppositories, & injectable form.
• Less sedation, less pruritis, less constipation &
vomiting than morphine
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Pain & Substance Abuse
Physical Dependence
• pts. are physically acclimatized to
the presence of the drug
• occurs with long-term opioid use
• pts will experience withdrawal if drug
is withheld
• if opiod withdrawn quickly then
withdrawal
• Predictable
Tolerance
• Given dose that relieved pain no
longer produces the same degree
and duration of relief
Addiction
• both physical & psychological
components
• continuous craving & need for
effects other than originally
intended
• results in compulsive drug
seeking behaviours
• the 4 C’s: impaired control
over drug use, compulsive
use, craving, continued use
despite harm (consequences)
(Victoria House, 1998; Wickham, 2001)
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Screening for Addiction/Misuse
Risk
• Previous history of substance abuse/addiction
• Family history of drug abuse &/or addiction
• Previous “chemical coping” with life stresses
• Significant psychiatric history
• Previous high risk behaviours (esp. criminal activity)
• High risk home environment
19
Which opioid(s) would you use
with Mr. Pain?
20
Opioid Therapy: Which Approach?
• Start with an IR opioid & titrate to effect
When dose stable  CR opioid
– fastest method for pain relief
• Start with CR opioid & titrate dose q 1-3 days
(or when side effects stable)
– for stable, chronic pain
• Start with CR opioid baseline dose & use
IR opioid to titrate
– once weekly (may be as soon as q2-4 days in patients with
cancer), add the total daily dose of IR to the CR dose and
repeat weekly until dose stable
21
IR vs. CR Oral Opioids
IR ORAL OPIOIDS
CR ORAL OPIOIDS
~ 2 hours
Onset of action
30 to 45 minutes
Oxycodone has 45
minute onset
Peak effect
60 minutes
---
Serum
half-life
2 to 3 hours
---
Duration of action
4 hours
12 to 24 hours
Comments
Q6h dosing causes
sub-therapeutic
intervals
Monitor for end-of-dose
failure
Note: These studies were conducted in healthy volunteers, or post-op
22
IR vs. CR Oral Opioids
IR Oral Opioids
• Quick onset
Advantages
Disadvantages
CR Oral Opioids
• Convenience and
compliance
• Allows for quick
titration (as early as
• Uninterrupted sleep
every 24 hours)
• Frequent dosing
• Interrupted sleep
• Slower titration
(48 to 72 hours)
• Slower elimination in
event of severe side
effects
23
Mr. Pain’s Story
• GP switched to an equianalgesic dose of
morphine i.e. 100mg BID.
• Uticaria disappeared. No change in hives or
constipation.
• c/o mild, infrequent nausea.
• Started to become agitated & experienced
hallucinations.
24
Opioid Rotation
• Changing one opioid to another
• When: if pain is or has been relieved
with original opioid, but toxicity limits
further dose titration
• Approximate dose ratio of two opioids
required to produce a similar degree of
analgesia
– “equianalgesic tables”
25
Opioid Equianalgesic Doses
Opioid
Oral
Parenteral
30 mg q3-4h around the
clock OR 60mg q3-4h
single or prn dosing
10 mg q3-4h
codeine
130 mg q3-4h
75 mg q3-4 h
hydromorphone
7.5 mg q3-4h
1.5 mg q3-4h
meperidine
300mg q 2-3h
100 mg q3h
oxycodone
30mg q 3-4h
N/A in Canada
morphine
60-134mg oral morphine /day = 25 ug/hr td fentanyl1
Jovey R. et al. Managing Pain. p. 109
1
Health Cnada, 2009
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Morphine
• “Natural” drug derived from opium poppy.
• It’s the old standard NOT the gold standard.
• Very effective orally (first pass through liver).
• Duration of action for oral IR is ~ 4 hrs. & parenteral is ~ 3-4 hrs.
• Active metabolites may accumulate in renal insufficiency leading
to toxicity; not recommended in renal failure.
• Fluctuating plasma levels can lead to variable efficacy & side
effects. In the elderly bioavailability can be as low as 30%.
• More sedating & GI s.e. than the semi-synthetic opioids.
• More CNS effects in elderly (sedation, confusion, hallucinations)
• •Histamine release (pruritis)
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What next?
29
Codeine
• 10% of the overall population lacks the enzyme
(CYP450 2D6) required to metabolize codeine to
active drug morphine
• 2-5% of the population have relatively high amounts of
the converting enzyme
• Ceiling dose is 600 mg/day
• Most constipating of all opioids
• Some SSIs (Paxil, Prozac, Cymbalta) inhibit the
conversion of codeine to morphine
IR: 15mg, 30mg, 60mg tablets
CR: 50, 100, 150, 200mg tablets
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Oxycodone Hydrochloride
• Strong semisynthetic opioid; potency 2x > morphine
• Conversion to oxymorphone may be inhibited by
drugs such as fluoxetine
• CR form is OxyContin®.
• Dose initiation: 10mg q12h for opioid naïve
• No pharmacological dose ceiling for pure opioid
agonists.
• Can be used with close monitoring in renal failure
IR: 5, 10, 15mg tablets
CR: 10, 20, 40, 80mg
Jovey, R. et al Managing Pain 2008 , Pg 96
31
Methadone
• Powder, capsule, liquid, suppositories
• Long half-life (q8h). Half-life variable making it unpredictable with
repeated doses  sudden severe toxicity.
• Variable equianalgesic dose to other opioids
• Individual titration with close monitoring is extremely important
• Special authorization from Health Canada
• Many drug interactions with CYP450 3A4
• Less constipating; does not cause metabolite accumulation; less
expensive
• A good option in neuropathic pain
32
Cytochrome P450 Drug
Interaction Table
University of Indiana
Department of Medicine
www.drug-interactions.com
33
Fentanyl
• Use if difficulty with oral meds; compliance issue;
intractable side-effects
• 25ug. of Fentanyl range is 60 - 134 mg oral
morphine equivalents1
• 60mg of morphine or equivalent before switching
to the 25ug. patch; 45mg if 12.5ug. patch.
• When applying 1st patch continue with other pain
medication x 24 hrs.
• Rate of absorption can be affected by: fever, soap,
oils, alcohol, shaving skin
Duragesic patch: 12.5, 25, 50, 75, 100 ug.
1Health
Canada, January 2009
34
Sufentanil (sufenta)
• Approximately 5 to 10 times more potent than fentanyl
• Relieves pain by stimulating opiate receptors in
CNS25-50 mcg SL/buccal.
• Good choice for use just before activity.
• Pt. teaching re: taking it.
35
Tylenol # 3
• 300mg acetaminophen + 30mg of
codeine in each tablet
• 12 x Tylenol #3 (usual daily dose) = 3.6g
total daily dose of acetaminophen &
360mg of codeine – this exceeds what is
safely recommended for chronic use in
healthy patients
36
Acetaminophen*Suggested Dose Ceilings
• 4 gm/day > 10 days in healthy, well-nourished
patients – short-term use in healthy patients
• 3.2 gm / day for chronic use in healthy
patients
• 2.6 gm / day chronically in at risk patients
• *Daily alcohol consumption, warfarin, fasting,
a low protein diet, cardiac or renal disease
increase the risk of hepatotoxicity
Latta, 2000 http://pain.mc.duke.edu/mild_pain.cfm
37
Tramadol
• An opioid analgesic with a dual mechanism of action
(weak affinity to the Mu receptor + inhibits the
reuptake of serotonin & norepinephrine)
• Recommended for the tx. of moderate - moderately
severe pain.
• CR tramadol can be initiated in opioid naïve at lowest
dose
• Less constipating then codeine
• Maximum 400mg/day
38
Tramadol Dosing
• Immediate release
(Tramacet)
• Extended release (Zytram XL1,
Ralivia, Tridural)
– One tablet is 37.5mg
Tramadol HCL/ 325mg
of acetaminophen
– Doses 100mg, 150mg,
200mg, 300mg, and
400mg
– Maximum dose is 8
tablets per 24hours
– If on IR tramadol calculate
24 hr. dose & initiate total
daily dose rounded down
to nearest 100 mg, titrate
up to max. of 400mg/day
– Beneficial for acute pain
39
What is the appropriate intervention
for Pain’s opioid therapy?
1. Discontinue morphine and initiate tramadol.
2. Switch from MS Contin to OxyContin
3. Administer MS Contin once a day, rather
than every 12 hours
4. Change dose of morphine and add a coanalgesic.
40
Drug Selected:
Oxycodone
• Oxycontin 60mg (40mg & 20mg)
BID
• Oxy-IR 10mg q1hr. prn for BTP
41
Breakthrough Pain
• Always have BTP ordered: ensure it is
adjusted if regular dose is adjusted.
• 30-50% of regular dose q4hrs. (you may want
to use 1/10 to 1/6 of the total daily dose
usually q1hr.)
• Same drug is usually used; may use other
drugs.
• >/= 3 doses BTP/24 hours add to regular dose
• If pain is not improved after 1-2 BTP
increments re-evaluate cause of pain.
42
Based on Mr. Pain’s description of
his pain, would you consider a coanalgesic?
43
What co-analgesic would you
add to Mr. Pain’s pain
management plan?
1. Baclofen
2. Neurontin
3. Zoledronic acid
4. Nortiptyline
44
What was Prescribed?
• Neurontin (gabapentin)
– 100mg BID x 2 days
– 100mg TID x 2 days
– 200mg TID daily
• Baclofen 5mg q8hr
• Senokot-S 2 tabs. at hs
45
Which of the following side effects
will you need to monitor when
neurontin is initiated?
1. Constipation, nausea, itching, tremors,
and hallucinations
2. Sedation, dizziness, nausea, confusion,
and lower extremity edema
3. Ataxia, nausea, alterations in liver
enzymes, and weight gain
4. Ataxia, nausea, vomiting, and diarrhea
46
Neurontin
• Proven indications: postherpetic neuralgia (PHN)
& diabetic neuropathy
• Widely considered to be first-line (co-analgesic)
agent for neuropathic pain despite off label status
• Fewest drug interactions of all AEDs
• Common adverse effects: somnolence, dizziness,
fatigue, ataxia, S & S of CNS depression
47
Neurontin
• 100-300mg mg qhs; PHN initiate at 300mg day 1,
600mg day 2 in divided dose, 900mg day 3 in
divided dose, & titrated further as needed up to
1800-3600mg
• Supplied in 100mg, 300mg, 400mg, 600mg, 800mg
capsules
• Dose reduction needed in renal compromise
• Morphine increases the neurontin concentration in
the blood
48
What Other Coanalgesics are there?
49
Antiepileptic Drugs
• Neurontin
• Pregablin (lyrica)
• Lamotrigine
– Well-tolerated with proven efficacy in neuropathic
pain caused by neurotoxic anti-retroviral therapy
in HIV-positive patients
• Carbamazepine 100-200mg BID
• Valproate 250mg daily to TID
50
Pregablin (Lyrica)
– Indicated for the management of:
• Neuropathic pain associated with diabetic peripheral
neuropathy
• Postherpetic neuralgia PHN)
– Side Effects:
• dizziness, somnolence, dry mouth, edema, blurred
vision, weight gain, constipation, euphoric mood, balance
disorder, increased appetite, and thinking abnormal
(primarily difficulty with concentration/attention)
51
Pregablin (Lyrica)
– Available: 25mg, 50mg, 75mg,150mg, 300mg
– Recommended dose/day: 150mg, 300mg, 600mg
• PHN patients who tolerate LYRICA may benefit
from up to 600 mg/day after 2 to 4 weeks of
treatment with 300 mg/day
– May take up to a week to receive benefit.
– May exacerbate the effects of oxycodone,
lorazepam, or ethanol on cognitive & gross motor
functioning.
– Discontinue gradually over a minimum of 1 week.
52
Cyclic Antidepressants
• Amitriptyline
– Best-established efficacy; most widely used for pain
– Highest anticholinergic s.e. profile of all cyclic
antidepressants
– Common s.e.: sedation, constipation, dry mouth, blurred
vision, urinary retention
– 10-25mg mg qhs
• Nortriptyline
– Less sedation & anticholinergic side effects than
amitriptyline
– Common adverse effects include sedation, dry mouth,
constipation
– 10-25mg qhs
• Desipramine
– Tolerability & efficacy similar to that of nortriptyline
– Less anticholinergic side effects than amitriptyline
25mg qhs
53
Non-Opioid Analgesics:
Acetaminophen
• Used for mild-moderate nociceptive pain
• Dose ceiling
• 2 key side effects: renal toxicity & risk for
hepatotoxicity
• Usual dose: 325mg 1-2 tabs q4-6h
Case, 2003; Zimmerman, 1995, 2000; Bromer, 2003; Perneger, 1994; Garcia Rodriguez, 2001;
FDA Sept. 2002; Health Canada Feb. 2003; Curhan 2002.
54
NSAIDS
• # & diversity have increased over the
past 20 yrs.
• Evidence detailing effectiveness is
contradictory – COX I & COX II
• Analgesic & anti-inflammatory effects
• Routes: Oral preferred, IV faster onset
• Ceiling Dose
55
NSAIDs/COXIBs
• Increase risk of exacerbation of underlying renal
insufficiency
• Increase risk of fluid retention
• Increase risk of cardiovascular complications
• Increase risk of GI bleeds (especially NSAIDs in
patients requiring concomitant ASA for cardiovascular
prophylaxis)
56
NSAIDs
• Side effects
• GI distress
• Bleeding 2° to platelet
dysfunction
• Renal failure
• Bronchoconstriction
• Contraindications • ? Delay in bone healing
57
Which one?
• Ketoprofen (Orudis) – 150-200mg daily (RA & OA); 50mg TIDQID (menstrual cramps & mild-to-moderate pain)
• Indomethacin (Indocid) – 25mg BID - TID
•
Ibuprofen (Motrin) – 200-800mg TID
•
Toradol (Ketorolac) – 10mg q4-6hr
•
Naproxen (Naprosyn) – 250-500mg BID
•
Diclofenac (Voltaren) – 25-50mg TID or 75mg SR daily
(maximum dose 150mg)
•
ASA – 325-650mg QID/q4hr
•
Rofecoxib (Vioxx)
•
Celecoxib (Celebrex) – 100-200mgQD-BID
- Sept. 2004 removed from market
*Taking ASA nullifies the GI protective effect of COXIBs
58
Toradol
• Suggested for moderate pain.
• Recommended as an alternative to lowdose opioids.
• Suggested to limit oral use x 7 days or
parenteral to 2 days.
• Major s.e. are GI; need something for GI
side-effect prevention.
59
Cytoprotective Agents
•
Sucralfate (1gm Qid)
•
misoprostol (200ug Qid) * not best
choice
•
H2 receptor antagonists eg. Cimetidine,
ranitidine
•
Omperazole 20-40mg/day
60
Is an NSAID a good choice for
Mr. Pain?
• History of ulcer complications
• Multiple NSAIDS
• High-dose NSAIDS
• Concomitant anticoagulant use
• Age >/= 60yrs.
• Concomitant corticosteroid use
• History of cardiovascular disease
61
Other Medications for Pain
• Muscle relaxants
– Cyclobenzaprine, Baclofen
• Local anesthetic congeners
– IV Lidocaine, oral Mexiletine
• NMDA (N-methyl D-aspartate) blockers
– Dextromethorphine, ketamine
• Alpha-2 agonists
– Clonidine, Tizanidine
• Botulinum Toxin
62
Mr. Pain has already experienced
uticaria, rash, constipation,
agitation, & hallucinations from
his opioid therapy. What other
side effects might you anticipate
with ongoing opioid therapy?
63
Side Effects of Opioids
COMMON
Side effect
• Nausea and
vomiting
• Constipation
• Sedation and
drowsiness
LESS COMMON
RARE
• Confusion
• Pruritus
• Myoclonus
• Respiratory
depression (very
rare in properly
titrated patients)
• Dry mouth
• Urinary retention
• Sweats
• GE reflux
64
Treatment of Common
Opioid Side Effects
TREATMENT
• Ondansetron 8mg q8hr prn
Nausea and
vomiting
•Haloperidol 0.5-1.0 mg od-tid
•Phenothiazine 5-10 mg PO q4-6h prn
• Dimenhydrinate often too sedating
• If motility is an issue
– Metoclopramide 10-20 mg qid
• Use dietary measures first (bran, flax, prunes)
– Osmotics-MOM, lactulose
Constipation
– Stool softeners - docusate
– Stimulants-senna, bisacodyl
– Suppositories-dulcolax
– Enemas
65
Opioid Neurotoxicity
• Presents as agitation, confusion, myoclonus,
hallucinations & rarely seizures
• Possible precipitants
– Infection/Sepsis
– Dehydration
– Decreased renal clearance
– Rapid dose escalation
• Management: ↓ dose or hold medication until
sensorium clears, Opioid rotation, Consider hydration
with both options
66
Mr. Pain’s Story
• Presented for his 2nd chemotherapy tx.
with well controlled pain.
• Reported taking fewer BTP medication,
once or twice q3-4 days.
• Oncologist decreased his pain
medication.
67
Opioid Dose Reduction
• Careful reduction to decrease opioid
toxicity – monitor pain control
• Dose reduction may include the
concurrent addition of adjuvant
analgesics
68
Putting it Altogether
Susan has been receiving hydromorphone 2 mg s/c.
She is now able to tolerate oral medication. The best
option for the oral dose would be:
A. 1 mg
B. 2 mg
C. 4 mg
D. 8 mg
69
Putting it Altogether
Jane has been taking 10 mg. of morphine by mouth
q4hr with good relief. A decision has been made to
switch her to a sustained release morphine. The
starting dose should be:
A. 15 mg BID
B. 30 mg BID
C. 45 mg BID
D. 60 mg BID
70
Take Home Pearls
• Assessment is key.
• Goal is to reduce pain to an acceptable level.
• Involve the patient in goal setting & negotiating analgesic
strategies.
• Do not delay treating pain – avoid chronic pain.
• A multi-modal approach is recommended (pharm & non-pharm).
• Prevention is better than treatment – give meds regularly.
• Use least invasive route possible & avoid IM injections.
• Anticipate & manage side effects
• www.painCare.ca
71
THANK YOU
72