Title: Opioids for Pain: Giving the Right Drug at the Right Dose at the Right Time
1Opioids for Pain Giving the Right Drug at the
Right Dose at the Right Time
- Curt Gedney, M.D.
- Diplomate, American Board of Hospice and
Palliative Medicine - Palliative Care Physician, St. Lukes RMC
Boise/Meridian - Primary reference http//www.eperc.mcw.edu/EPERC
/FastFactsIndex
2Opioids for PainPart One
- Types of Pain
- Opioid Receptors
- Types of Analgesics
- The WHO Ladder of Pain Management
- Dose Escalations
- Dose Conversions
3Opioids for PainPart Two
- Opioids Special Considerations
- Sublingual Morphine
- Transdermal Fentanyl
- Transmucosal Fentanyl
- Methadone
- Opioid Infusions
- Opioid Side Effects Delirium Neurotoxicity
4Major Categories of Pain
- 1. Nociceptive CNS and peripheral afferent
pathways modulated via spinal cord (dorsal horn) - Somatic aching, constant, localized, e.g.
musculoskeletal - Visceral sharp, crescendo/decrescendo, e.g.
cholecystitis, renal stones, intestinal
obstruction, MI - 2. Neuropathic ischemia, destruction or
encroachment of nerve by disease or tumor - paroxysmal shooting or shock-like pain on a
background of burning, aching sensation
5Major Categories of Pain
- 3. Inflammatory response to tissue damage that
potentiates pain - 4. Soft tissue pain pressure ulcers, burns
- 5. Intracranial pressure pain brain tumor edema
and hemorrhage
6Types of Neuropathic Pain
- Deafferentation phantom-type pain, usually
localized numbness, tingling or burning sensation - Allodynia pain resulting from a non-noxious
stimulus to normal skin, e.g. pain on light touch
or placement of clothing - Dysesthesia (continuous) an unpleasant abnormal
sensation produced by a normal stimulus, e.g.
constant burning of the hand due to malignant
brachial plexopathy
7Types of Episodic Pain
- 1. End of dose failure
- Dose of medication does not last the desired or
prescribed time parameters - 2. Incident pain
- Pain on movement or with activity
- 3. Breakthrough pain
- Crescendo (escalating) pain superimposed over
stable or managed chronic pain - Coluzzi, PH, Cancer Pain Management Newer
Perspective on Opioids and Episodic Pain. Am J
Hospice and Palliative Care. 199813-22.
8Opioid PharmacologyReceptor Site Theory
- Opioid Narcotic or opiate-like drugs includes
natural, synthetic and endogenous substances - Receptor sites There are several opioid receptor
sites mu (beta-endorphins), kappa (dynorphins)
and delta (met- leu-enkephalins).
9Mu Receptors 1 2
- Effect Location
- 1. Analgesia (robust) 1. Mid-brain/SC
- 2. Respiratory depression 2. Medulla
- 3. Inhibits GI motility 3. Intestines
-
- 4. Euphoria 4. Limbic system
-
10Kappa Receptors 1,2 3
- Effect Location
- Analgesia (mild) Spinal cord
- Inhibits GI motility Intestines
- Diuresis Pituitary gland
11Delta Receptors 1 2
- Effect Location
- 1. Analgesia (minor) 1. Spinal cord
- 2. Tolerance 2. Unknown
- 3. Seizures 3. Striatum/cortex
12Drugs and Receptor Activation
- There are three opioid receptor subtypes mu,
kappa and delta. - The opioid receptor subtypes location helps
explain its function - The mu opioid receptor subtype produces the
strongest analgesic response. - Major anesthetics like fentanyl, morphine,
oxycodone, hydromorphone, and tramadol
predominantly activate the mu opioid receptor.
13Receptor Affinity of Opioid Analgesics
- Receptor mu delta kappa NMDA
- Morphine A
- Fentanyl A
- Hydromorphone A
- Oxycodone A A?
- Methadone A A A
- Pentazocine A
- Stadol, Nubain A
- Ketamine A? A? A
- Dextromethorphan A? A? A
- A strong agonist
14N-Methyl D-Aspartate Antagonists/Inhibitors
- NMDA Antagonists block amino acid glutamate from
binding to NMDA receptors, reducing the
depolarization of spinal cord neurons. The
continued firing of these neurons causes
hyperalgesia. This hypersensitivity to a painful
stimulus causes a windup phenomenon, a
progressive increase in depolarization spikes
that causes a single summation spike and the
spontaneous firing of neurons that can persist
for minutes.
15NMDA Inhibitors
- Reduce the occurrence of windup and decrease
morphine tolerance at the mu receptor site. These
drugs work the same way as tricyclics for
neuropathic pain by preventing the uptake of
serotonin and norepinephrine. - Methadone oral, IV/SC
- Ketamine- IV/SC and oral,using parenteral
solution - Dextromethorphan
- Memantine HCl (Namenda)
- Venlafaxine and Duloxetine
16Types of Analgesics
- 1. Non-opioid or non-steroidal anti-inflammatory
drugs (NSAIDS)work primarily at the peripheral
nervous system level - A. OTC ASA, acetaminophen, ibuprofen
- B. Prescription ibuprofen, naproxen,
indomethacin, etc. - 2. Opioids work primarily at the CNS level
- A. Opioid agonists morphine, meperidine,
hydromorphone, fentanyl (Duragesic), levorphanol
(Levo-Dromoran), oxymorphone (Numorphan),
oxycodone, tramadol, codeine - B. Opioid agonist-antagonists pentazocine
(Talwin), nalbuphine (Nubain), butorphanol
(Stadol), buprenorphine (Buprenex)
17Types of Analgesics-2
- 3. Adjuvant analgesics-- various actions
- A. Anticonvulsants, e.g. phenytoin,
carbamazepine, valproate, gabapentin, pregabalin - B. Antidepressants, e.g. tricyclicsamitriptyline,
desipramine SNRIsvenlafaxine , duloxetine - C. Others steroids, Baclofen, eutetic mixture of
local anesthetics (EMLA, lidocaine, lidoderm), IV
Lidocaine, dextromethorphan, bisphosphonates - Peralta A Pain Management in the Elderly.
International Jour of Pharmaceutical Compounding,
May/June 2004 8(3)187-192.
18WHO Analgesic Ladder
- MILD (1-3) NSAID mild analgesics COX 12,
propoxyphene, APAP, ASA - MODERATE (4-7) Opioids, NSAIDS /- adjuvants
oxycodone, codeine, tramadol, COX 12 - SEVERE (8-10) Opioid, NSAID Adjuvants
morphine, meperidine, methadone, fentanyl,
oxycodone - World Health Organization. Cancer Pain Relief
(2nd ed.), 1996
19Oral Opioid Dosing Intervals
- Short-acting agents (morphine, oxycodone,
hydromorphone, codeine) have a peak analgesic
effect in 60-90 min. with a total duration of
analgesia of 2-4 hr. - AHCPR Clinical Practice Guidelines (1994)
recommends dosing intervals of 3-4 hrs. - These agents may be dosed as often as every 2 hrs
in pts with normal renal function. - If agents are combined with APAP and given every
4 hrs, a long-acting opioid should be prescribed.
20Use of Opioids in Pain Management
- Since opioids like morphine have a short
half-life (t1/2) of 60 to 90 minutes, they reach
steady state within 4-5 half-lives. Once steady
state is achieved, you can titrate the dose up by
50-100 within 24-48 hours. Once the patients
pain is controlled, i.e. pain rating of 0-2, you
can convert the immediate release opioid to long
acting opioid for pain. - Note It is imperative to initiate a bowel
regimen when starting opioid therapy.
21Oral Opioid OrdersGood and Bad Examples
- Tylenol 3 1-2 po q4-6 hr prn mod pain, and
Percoset 1-2 po q4-6 prn severe pain - 1. Short-acting opioids rarely last 6 hrs.
- 2. only one opioid/non-opioid combo should be
ordered at a time, assess for response, then
change if needed - 3. Subjective ratings of pain by nurses are
inaccurate only the pt knows the truth - 4. Be careful not to exceed 4 gm/d APAP
- Preferred order Percoset 1 po q4 hr prn pain
22Oral Opioid Orders-2
- MS Contin 60 mg q6 hr and Duragesic patch 25
mcg/hr q72 hr - None of the oral long-acting products should be
prescribed less than q8 hr, and q12 hr dosing is
preferred - Dont use two different long-acting products at
the same time. Instead, always order a
short-acting product for breakthrough pain. - Duragesic is a poor choice for poorly controlled
pain. It can be safely dose escalated only every
2-3 days. - Preferred order MS Contin 90 mg q12 hr and MSIR
15 mg 1-2 q4 hr prn pain
23Opioid Dose Escalation
- Ms. B is on a morphine drip at 5 mg/hr for cancer
pain. Her physician has written an order to
increase drip by 1 mg/hr, titrate to comfort.
Her nurse increases the drip to 6 mg/hr when she
complains of pain. Thirty minutes later she still
has no relief. Whats the problem?
24Opioid Dose Escalation-2
- Opioids, like other drugs, should be dose
escalated on the basis of a percentage increase.
Going from 5 to 6 mg is only a 20 increase. - Pts generally do not notice a change in analgesia
when dose increases are less than 25 - For mod to severe pain, increase by 50-100
- For mild to mod pain, increase by 25-50
- Do not increase basal infusion rate (or
long-acting oral opioids) more than 100 at a
time or more often than every 6-8 hrs.
25Opioid Equianalgesic Table
- Morphine 30 mg po 10 mg IV
- Hydrocodone 30 mg
- Oxycodone 20 mg
- Hydromorphone 7.5 mg 1.5 mg IV
- Meperidine 75 mg IM/IV
- Fentanyl 15 mcg/hr IV/TD
- Methadone see Methadone table
26Calculating Opioid Dose Conversions
- Morphine 10 mg IV 30 mg oral Hydromorphone
7.5 mg oral 1.5 mg IV - 1. Change route, keeping drug the same Change 90
mg q12 ER Morphine to Morphine IV by continuous
infusion - 24-hr oral Morphine dose 180 mg po
- Convert to IV 180/3 60 mg IV
- Hourly infusion rate 60/24 2.5 mg/hr
- Rec if a new drug, start at 50 of calculated
dose to account for variation in first pass
clearance and incomplete cross-tolerance.
27Calculating Conversions-2
- 2. Change drug, keep same route
- Change 90 mg q12 ER Morphine to oral
hydromorphone - 24-hr oral Morphine dose 180 mg po
- Hydromorphone dose 180/4 45 mg po
- Rec start new opioid at 50 of calculated
equianalgesic dose for possible incomplete
cross-tolerance - Reduce dose 50 22 mg/24 hr 4 mg q4
28Calculating Conversions-3
- 3. Changing drug and route
- Change 90 mg q12 ER Morphine to IV hydromorphone
as continuous infusion - 24-hr Morphine dose 180 mg po
- IV Morphine dose 180/3 60 mg IV
- Morphine 60 mg IV 60/10 X 1.5 9 mg
hydromorphone IV/24 hr - Reduce dose 50 for cross-tolerance 9/2 4.5
mg/24 hr 0.2 mg/hr IV
29Part One Summary
- Oral short-acting opioids are the mainstay of
pain management for the majority of patients.
They can be dose escalated as much as 50-100 per
day because of rapid upregulation of receptors
and short half-life. When dose requirements are
high, long-acting opioids are more useful in
controlling pain. Opioids are readily
interconvertible according to established
conversion ratios.
30Opioids for PainPart Two
- Opioids Special Considerations
- Sublingual Morphine
- Transdermal Fentanyl
- Transmucosal Fentanyl
- Methadone
- Opioid Infusions
- Opioid Side Effects Delirium Neurotoxicity
31Sublingual Morphine
- Advantage Longer duration of action (4 hr) vs.
IV (1-2 hr) - Disadvantages
- 1. Data do not support more rapid absorption
through sublingual mucosa than by oral route - 2. Mean time to maximum concentration is shorter
with PO than with SL morphine - Bioavailability of SL morphine is only 9 vs.
23.8 with an oral solution - Absorption through oral mucosa is best with
potent, non-ionized and lipid soluble drugs. SL
morphine has low potency, is highly ionized and
one of the least lipid soluble opioids, making it
a poor choice as a SL med.
32Fentanyl Dose Conversions
- Mr. L is an 80 year-old man with cancer who has
been on a morphine drip in the hospital at 3
mg/hr. Upon discharge back to the nursing home
the drip is dcd and he is placed on a 50mcg/hr
Fentanyl patch. The next day he is found in pain,
nauseous, jittery and diaphoretic. What happened
to Mr. L?
33Dosage Conversion Oral Morphine to Transdermal
Fentanyl
- PO Morphine Transdermal fentanyl
- (mg/24 hr) (mcg/hr)
- 45-134 25
- 135-224 50
- 225-314 75
- 315-404 100
- 1035-1124 300
- Source Janssen Pharmaceutica
34Dosage Conversion Oral Morphine to Transdermal
Fentanyl
- Mcg/hr dose of Duragesic ½ X mg/day dose of
oral morphine - Example
- Duragesic 100 mcg/hr dose Q72 hrs Oral Morphine
SA 100 mg Q12 hrs or - Duragesic 2400 mcg or 2.4 mg/day MS 200 mg/day
(ratio 180) - Levy, MH. Pain Management Center, Fox Chase
Cancer Center at NHO Annual Meeting, Oct., 1992
35Fentanyl Conversion-2
- In PDR, conversion of morphine to fentanyl is
135-224 mg of morphine 50 mcg/hr fentanyl
patch. The patient was receiving 3 X 24 72 mg
IV morphine X 3 216 mg oral morphine/24 hrs.
So, according to PDR, the appropriate conversion
dose is 50 mcg/hr fentanyl.
36Fentanyl Conversion-3
- An Alternate Formula, published by Breitbart et
al (2000) uses a fixed dose conversion ratio - 2 mg oral morphine 1 mcg/hr transdermal
fentanyl - So 216 mg oral morphine is approximately
equianalgesic to 100 mcg/hr fentanyl - So the patient was underdosed on discharge from
the hospital, so was in pain
37Fentanyl Conversion-4
- Therapeutic blood levels of fentanyl are not
reached for 13-24 hours after patch is applied. - So the patient was having withdrawal symptoms.
Other breakthrough meds should have been used
until the fentanyl had reached therapeutic
levels. - Note also Drug will continue to be released into
the blood for at least 24 hrs after patch
removal, so when replacing the patch, the new
drug should be titrated up accordingly. - Upward titrations of fentanyl should be done no
more often than every 48-72 hours.
38Oral Transmucosal Fentanyl Citrate
- OTFC- a solid formulation of fentanyl, a lozenge
on a handle - Lipid soluble and 80 non-ionized, so very
suitable for transmucosal absorption - Bioavailability higher if absorbed through oral
mucosa than if swallowed - Rapid onset of analgesia (3-5 min), with peak
effect at 20-40 minutes, short half-life
39OTFC-2
- Available in 200, 400, 600, 800, 1200 1600 mcg
dosage strengths - Place between cheek and gum, move gently side to
side for 15 min. - Always start at 200 mcg and titrate up
- If first dose inadequate, take a second dose 30
min later. If that is effective, switch to 400
mcg doses. - Pt should take no more than two units per pain
period during initial titration period.
40Methadone for Pain Why?
- Acts as both a mu receptor agonist and an NMDA
receptor antagonist. Its NMDA action makes it
very useful in the treatment of neuropathic pain. - Methadone is sometimes effective for refractory
pain when morphine or hydromorphone are not. - A special license to prescribe methadone is not
required, except for those treating addiction.
41Methadone Unique Qualities
- Has an extended half-life, up to 190 hours, yet
duration of analgesia is 6-12 hours after steady
state is achieved. - Rapid titration guidelines do not apply to
methadone. Dose should not be increased more
frequently than every 5-7 days. It is not
indicated in poorly controlled pain where rapid
dose adjustments are needed. - Patients with a prolonged QT interval, or who
have other risk factors for Torsades, may need
EKG monitoring.
42Starting Methadone
- After a single dose, there is a short
distribution phase (with acute pain relief) with
a half-life of 2-3 hrs and a slow elimination
phase (half-life 15-60 hrs). - Dosing must account for accumulation of the drug
over days. - No dose reduction is required with renal failure.
- Drug interactions Rifampin, phenytoin,
carbamazepine, and several antiretroviral meds
decrease methadone levels. Amitriptyline,
fluconazole, erythromycin, metronidazole,
fluoxetine and grapefruit juice increase levels.
43Starting-2
- 1. Begin methadone 5 or 10 mg po bid or tid for
5-7 days. With elderly, begin at 2.5 mg QD/BID
and titrate up more slowly. - 2. If pain persists, increase dose by 50,
continue for 5-7 days, and increase dose every
5-7 days until pain controlled. - 3. Use short-acting opioid with short half-life
(e.g. morphine 10 mg) every 1-2 hrs prn for
breakthrough pain and to provide relief during
titration phase.
44Conversion to Methadone
- Conversion Ratio of oral Morphine to oral
Methadone - 31, 3mg morphine to 1 mg methadone
- for doses of morphine up to 100 mg/day
- 101-300 mg 51
- 301-600 mg 101
- 601-800 mg 121
- 801-1000 mg 151
- gt1001 mg 201
45Conversion to Methadone-2
- Calculate equianalgesic dose of methadone from
total current opioid dose. - Day 1 Replace 1/3 of opioid dose with oral
methadone on bid or tid schedule. - Day 2 Replace next 1/3 of opioid dose.
- Day 3 Complete change to methadone.
- Reference J Pall Med 2002 5127-138.
46Opioid Infusions in the Imminently Dying Patient
- 1. Calculate an equianalgesic dose of currently
used opioids. E.g. 60 mg q12 po 120 mg/24 hr
40 mg IV/24 hr 2 mg/hr basal rate - 2. If the current opioid dose is ineffective,
escalate the basal dose by 25-100 - 3. Give a loading dose when starting the infusion
if equianalgesic dose is being escalated or if pt
is opioid naïve (4-10 mg loading dose prior to
starting 2 mg/hr infusion) - 4. Choose a bolus rescue or PCA dose. A dose
50-150 of the hourly rate is a place to start.
In this example, bolus at 1-3 mg.
47Opioid Infusions-2
- 5. Choose a dosing interval. Peak effect from an
IV bolus is 5-10 min, so dosing interval should
be 10-20 min. - 6. Reassess for desired effect vs. side effects
every 10-15 min. until stable. Adjust bolus dose
every 30-60 min. until desired effect is
achieved. - 7. Reassess need for a change in basal rate no
sooner than every 6-8 hrs. Take total bolus doses
into account, but never increase basal rate by
more than 100 at one time. Be sure to give a
loading dose to rapidly achieve steady-state
blood levels. - When pts become anuric close to death, d/c
continuous dosing in favor of bolus dosing to
prevent metabolite accumulation and delirium.
48Opioid Infusion Titration Orders
- Bad example MS 2-10 mg/hr, titrate to pain
relief - Places full responsibility for dose titration on
the nurse - Provides no guidance re how fast to titrate (q
hr, q shift?) or dose titration intervals (should
the dose be raised from 2 to 3 mg or 2 to 10 mg?) - Sets up potential for overdosage by too zealous
dose escalation - Provides only one option for poorly controlled
painincreasing basal rate - Makes no sense to dose escalate more frequently
than every 8 hrs, since it takes that long to
achieve steady-state blood levels after a basal
dose change - Preferred MS 2 mg/hr and MS 2 mg q15 min prn
breakthrough pain (or 2 mg via PCA dose) and RN
may dose escalate the prn dose to a maximum of 4
mg within 30 minutes for poorly controlled pain.
49Opioid Side Effects Delirium
- Occurs in as many as 80 of inpatients on
opioids often goes undiagnosed and untreated. - Manifests as confusion or hallucinations
- Risk is highest in late-stage or actively dying
cancer pts who have become dehydrated and whose
renal clearance is compromised.
50Delirium Treatment
- Fluids to correct dehydration
- You may try decreasing opioid dose, but not at
the expense of pain control. - A better way is to switch to an equianalgesic
dose of a different opioid. - Use antipsychotics such as haldol or
chlorpromazine. Avoid benzodiazepines, as pts may
have a paradoxical reaction.
51Opioid Side Effects Myoclonus and Neurotoxicity
- More risk as pt gets closer to death
- Manifests as muscle twitching or psychomotor
agitation - May try reducing opioid dose, but not at expense
of pain control - Opioid switch
- Benzodiazepines such as lorazepam or clonazepam
can be effective.
52Opioid Toxicity
- Occurs as opioid dose is increased in response to
perception that pt is still in pain - If myoclonus occurs, the appropriate opioid dose
has been exceeded. - Or toxicity presents as generalized, rather than
localized, painthe opioid overwhelms the CNS
53Opioid Toxicity Treatment
- DO NOT increase opioid dose, even though the pt
has generalized pain. - Try a reduction in dosage of 25. If this is
effective you may further reduce the dose until
symptoms are resolved. - If pain increases on the lesser dose, either
restore the previous dose and add benzos or
switch to an equianalgesic dose of a different
opioid.
54Part Two- Summary
- Sublingual morphine, while easy to use, appears
to have less effectiveness than oral forms.
Transmucosal fentanyl, though more expensive, can
provide long-term pain relief. - Transdermal fentanyl is helpful for patients with
chronic pain who cannot tolerate oral medication
with its side effects, but is not useful for
acute or uncontrolled pain. - Methadone is cheap and particularly useful for
neuropathic pain. It must be used cautiously with
respect to its long half-life.
55Summary (cont.)
- Opioid infusions, both IV and subcutaneous, are
very useful for hospitalized patients with severe
pain, as well as for patients who are imminently
dying. - Delirium and neurotoxicity are common side
effects of opioids, and can be treated with dose
reduction, opioid switching, and administration
of IV fluids and antipsychotics (delirium) or
benzodiazepines (myoclonus).