Transcript Opioid Induced Hyperalgesia

Pain Management:
Dennis Q. McManus, MD
Long Term Use of Opioids
• Opioid Induced Hyperalgesia
– Increased pain as body becomes tolerant
– Easy to start and hard to stop
• Develops quickly (two weeks)
• Slowly resolves (six months to a year)
• Frontal Lobe Effects
– Reduced anxiety – Main effect!
– Increased apathy
– Frontal lobe inactivity and atrophy
– Depression
Definition Basics
• Acute pain
• Chronic and acute cancer/palliative pain
• Chronic non-cancer pain
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Chronic back pain
Fibromyalgia
Chronic migraines
Chronic joint pain
Clinical Approach
Guiding Principals
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Stabilize opioid use
Change to long acting opioid
Slow taper off of opioid medications
No “break through” medications
– For stable condition
– Treat acute exacerbation as for non-tolerant
patients
• Dental extractions
• Postop
Clinical Examples
• Chronic migraine Headaches
– 36 yo with increasing headaches. Frequent
ER visits now referred for treatment. MRI
negative times three. Exam normal except for
photophobia, marked distress, requesting a
“pain shot”.
– Using twelve hydrocodone 10 mg/ APAP 325
mg per day.
What is happening?
• Drug seeker? ER thinks so.
• I posit drug effect.
– Opioid induced hyperalgesia:
• Initial doses of opioid very effective (most prescribed
treatment in some states)
• Body responds to peak doses of repeated opioid use
by increasing sensitivity to pain. (animal experiments)
• Tolerance can be overcome by increasing the dose of
opioid. (AKA honeymoon effect)
What is happening?
– Opioid induced hyperalgesia:
• Younger patients understand this quite well and
will frequently rob Peter to pay Paul.
– Leads to Friday night calls when Peter is hurting
– Results in the frequently asked question: “what have you
done for me lately?”
– Non-pain example: tardive dyskinesia
• A consequence of opioid use
Approach to Treatment
– Changed to methadone 5 mg PO BID
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Minimize roller coaster effect of short acting opiates
Eliminate acetaminophen
Checked EKG for QTc prolongation
Added magnesium oxide 500 mg daily
– Can reduce prolonged QTc
– Anecdotal evidence will help with headaches
– Used hydroxyzine and promethazine to help sleep
through severe headaches
– Tizanidine nightly to help with chronic daily
headaches.
“Roller Coaster” Effect
ok
not ok
Approach to Treatment
• Once stabilized on opioid
– Slowly tapered off of methadone
– Monitored on a monthly basis
• Once off opioid
– Headaches resolved.
– Tizanidine tapered off one year later.
Learning Points
• Roller coaster effect
– Leads to opioid withdrawal
– Increased pain during withdrawal
– Higher tolerance develops with ever
increasing doses of opioids to cover pain
(usually initiated in the ER)
Learning Points
• Opioid Induced Hyperalgesia
– Peak dose dependent
– Peak doses accelerated degree of tolerance
and subsequent duration of slow taper off of
opiates. The higher you go the longer the fall.
• Tolerance takes two to four weeks to develop
• The pronociceptive response takes up to six
months to a year to resolve (IMHO).
Learning Points
• Always encouraging avoiding triggers to
pain. (No head banging!)
• Use sleep as a “rescue” treatment.
• Avoid medication associated with
tolerance or sleep deprevation
(benzodiazepines and stimulants)
Clinical Examples
• 72 yo lady with chronic low back pain. OA
on the MRI LS spine with no nerve or
spinal cord compromise. Exam mild
kyphosis, and SBT 4 errors out of 28.
• On fentanyl 25 mcg/ hr changed every 72
hours. Oxycodone 5 mg PO every six
hours as needed. Using four tablets a day
and needs more medication to get her
work done.
Approach to Treatment
• Changed oxycodone to one half tablet
every six hours while awake.
• Trazodone 50 mg nightly to help sleep.
• Long discussion about not hurting her
back.
– Prior PT no help and does not do her HEP
because it hurts.
– Still sweeping floor, doing dishes and laundry.
Approach to Treatment
• If you have a headache and are banging
your head every day, what should you
stop doing?
• Listen to your pain
• Lose “no pain, no gain” idea.
• Dirty Harry said it best.
Approach to Treatment
• Older we are the slower we are to heal.
• Pacing, pacing and more pacing.
• I am not Harry Potter. I do not have a
magic wand.
• Pain level decreased from 6/10 to 2/10
with gentle PT and minimizing sources of
pain producing behaviors at home.
Learning Points
• Break through medications leads to
– More tolerance and need for more medication
– Reliance of medication instead of common
sense to manage pain producing behaviors.
– Again no head banging if you have a
headache.
• Medication side effects include memory
loss and frontal lobe dysfunction including
apathy, depression and anxiety.
Clinical Examples
• 45 yo lady with FMS in bed 12 to 16 hours
a day. Will have a good day every 10 to
16 days. Exam consistent with FMS.
• On fentanyl 100 mcg/24 hr TOP Q72
hours.
• Hydrocodone 7.5 mg/ APAP 500 mg every
six hours up to four times a day as
needed.
Approaches to Treatment
• Change break through medications to
scheduled every three hours while awake.
• Discussion about pacing.
• Baclofen 10 mg nightly.
• PT for gentle stretching while in bed
initially.
Approaches to Treatment
• Once opioids stabilized slow reduction
was initiated and patient was tapered off of
fentanyl.
• Daily activities were slowly increase to
where she is no longer in bed.
Learning Points
• Eliminate break through pain medications
• Use break through behavior and home
exercise/stretches instead of more
medication.
• Synchronize sleep wake cycle.
• Involve family members in process.
Summary
• Chronic opioids may cause more pain than
they relieve.
• Break through medications accelerates
tolerance and development of OIH.
• Listening to pain and changing pain
producing behaviors
• Long term use of opiates is associated
with frontal lobe atrophy.
History of Opioids
•Friedrich Wilhelm Adam Sertürner (1783-1841)
– First to discover an extractable material from plants to be used as
a drug.
– Named Morphine from Ovid’s (43 BC to 17 AD) Latin name for
the god of dreams, Morpheus, who was the son of Somnus, the
god of sleep.
Opioids
A Brief History
Dennis Q. McManus, MD
Those who cannot remember the past
are condemned to repeat it.
-George Santayana, The Life of Reason [1905-1906], Volume I, Reason in
Common Sense, Chapter 12, 1906
History of Opioids
• Opium
– Sumerians use opium in 5000 B.C.
• Ideogram for opium is “HUL” meaning joy or
rejoicing
• 1500 years before the Egyptians record alcohol
production
– The Greek naturalist, Theophrastus (371- 287
B.C.), record is the earliest undisputed use of
poppy juice
– By 1000 A.D. opium is widely
used in China
History of Opioids
– Paracelsus (1493-1541 A.D.)
introduces Laudanum in 1500 A.D.
• Born in Switzerland and named
Theophrastus Philppus Aureolus
Bombastus von Hohenheim
• His arrogant manner gave rise to the
word bombastic
• “The dose makes the poison” auf
Deutsch “Alle Ding’ sind Gift und nicht
ohn’ Gift; allein die Dosis macht, das
ein Ding kein Gift ist.”
History of Opioids
• "Among the remedies
which it has pleased
the Almighty God to
give to man to relieve
his sufferings, none is
so universal and
efficacious as opium."
Thomas Sydenham
(1625-89 A.D.)
History of Opioids
• Chinese imperial government prohibited
smoking and trading of opium in 1729.
• Punishment for opium shop owners was
strangulation.
History of Opioids
• Friedrich Wilhelm Adam Sertürner (1783-1841)
– Isolates Morphine from Opium 1803-1806
– Conducts first human experiments 1817
• Sertürner and three teenagers none older than 17
• Over 45 minutes three doses of 30mg of the free base
(180mg salt)
• In a stupor took an emetic and gave to his volunteers much
vomiting ensued
• Several days for the head and body pain to resolve
• Speculates that morphine in small doses is a strong poison
• Deduces important medical properties of opium is from
morphine and leaves to the physicians to test.
History of Opioids
• Opium Wars
– Dutch traded opium 16501773
– British East India Company
1773-1833
• Exported tea to America and
conspired to tax the commodity
• Imported opium from India into
China
– 1838 imported 1400 tons of
opium
– 1839 Len Zexu appointed drug
“Czar”
History of Opioids
• Opium Wars
– Lin Zexu
• Incorruptible
• Letter to Queen Victoria not to trade in unbeneficial goods
• Confiscated and destroyed 3 million pounds of opium on
June 3rd
• England sends war ships in response in 1839
• Continued conflict culminates in second western invasion
and unequal treaty 1856-1860
• China today celebrates Anti-smoking day on June 3rd
History of Opioids
• Hyperdermic syringe is invented
1853
– Doctor Alexander Wood article 'A
New Method of treating Neuralgia
by the direct application of Opiates
to the Painful Points'
– First to produce a needle fine
enough to pierce skin
– Infusion and intravenous injection
reported as early as 1670
History of Opioids
• American Civil War and late 1800’s
– The North
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Uses 10 million opium pills
2.8 million ounces other opium preparation
Veterans used opium for war wounds
Surveys in late 1800’s in Midwest majority of
opium users were women for neuralgia, morning
sickness and menstrual pain.
• Soldier’s disease was a term for opiate addiction
History of Opioids
• Late 1800’s increased
availability of morphine
and no regulation
– Morphine injection kits
– Opium containing patent
medicines
– Cures for opium and
morphine addiction
common
– Sigmund Freud extols the
virtues of cocaine to cure
morphine addiction
History of Opioids
• 1898 Heroin marketed for cough and later
lauded as a cure for morphine addiction
• 1890 Increased concern about the unsavory use
of opiates and cocaine lead to extensive
condemnation in Hearst newspapers
• 1890 opium and morphine are taxed in the U.S.
• 1905 patent medicine manufacturers required to
label contents of their products
• 1909 importation of opium in U.S. made illegal
and users begin to snort Heroin ($6.50/ounce)
History of Opioids
• 1914 Harrison Narcotics Acts effectively illegalizes
Heroin and Cocaine
• After the passage of the Act Heroin street prices
increases to $100/ounce
• 1956 Heroin is outlawed for any purpose in the U.S.
• 1967 Mixed agonist/antagonist drugs are developed to
maintain the pain killing effect of opiates and reduce the
addictive potential (Talwin/pentazocine)
• 1970s Talwin with antihistamine tripelennamine
becomes a abused combination leading to Talwin NX
• 1990 Butorpanol and buprenorphine introduced
History of Opioids
• Summary
– Opioids initially viewed with favor
– Increased use leading to abnormal behaviors
– Repeated attempts to synthetically modify
opiates to produce safer and effective
analgesics with continued addiction liability
– Why?
Pain: Definition
• An unpleasant sensation occurring in
varying degrees of severity as a
consequence of injury, disease, or
emotional disorder.
• Multiple levels of input from tissue damage
to brain interpretation
• Affective component of pain
Pain Imaging
• Hand place in cold or warm water
• PET scan before and during pain
• Effects of suggestion on brain activation
Frontal Lobes
• Decreased gray matter density in opiatedependent subjects
– Frontal lobes
– Temporal cortex
• Reduced phosphocreatine in frontal cortex
• Orbital frontal activation in abstinent opiate
users under craving recalls
Frontal Lobe
• Varying levels of opioids effects
– Dole experiments with methadone and heroin
– Air force dexterity test
– Normal performance by methadone
maintained opiate users
Frontal Lobes
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Opioids main effect
is in the frontal brain
or the affective
component of pain
Functional imaging
of pain locates
frontal lobe
activation
Frontal Lobes
• Phineas Gage
– Unpleasantness in Vermont
– September 13, 1848
– Explosion with tamping iron
Frontal Lobes
• Prior to the accident
– He was known as a shrewd and smart business man
– Very energetic and persistent in executing all his
plans of operation
• Gage survived his ordeal
– Fully able to walk and talk
– He became irreverent, indulged in the grossest
profanities and impatient of restraint or advice
– Friends noted he was no longer Gage
Frontal lobes
• 38 yo man with anterior cerebral artery
aneurysm
• After repair subtle damage to the frontal
white matter tracts.
• Lost his employment
• Maintained a high I.Q. (138)
• Unable to make decisions soon lost his
family and his financial assests
Descartes’ Error
• Intact temporal and frontal areas for
decision making
• Cold calculated decisions need emotional
weighting
• Example of young executive in the
gambling paradigm
Frontal Lobe Dysfunction
• Depression
• Disorganization
• Apathy
Opiate Use
– Acute pain
– Cancer pain both chronic and acute
– Chronic non cancer pain
Objectives
• Noncancer chronic pain
– Short acting opiates
• Accelerates opioid induced hyperalgesia
• Has episodic euphoria/dysphoria (mood swings)
– Long acting opiates
• Moderates mood swings
• Reduces peak effect of short acting opiates
• Useful in stabilizing and tapering off opioids
– Opiates contraindicated because of opioid induced
hyperalgesia
Opiate Properties
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Euphoria (short acting opioids)
Affective component of pain (anxiety)
Bodies response is to increase sensitivity
of pain (opioid induced hyperalgesia)
Opioid Euphoria
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Only associated with increasing blood
levels
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Heroin vs morphines example
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Active metabolite is morphine
Acetylation accelerated penetration of the BBB
Oxycontin example ($634,500,000 fine)
Steady state levels not euphoric
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Peak levels not associated with increased
function
Hydrocodone example
Short Acting Opioid:
A Graph
ok
not ok
How Opioids Work
• Stops response to pain
– Pain is still perceived
– Acutely the pain does not bother the patient
– Doses to stop nociceptive signals in the spinal
cord is ten times higher than the doses to stop
breathing.
How Opioids Work
• Frontal lobe effect
– Anxiety important to planning and daily
function
– Anxiety effect separated from increased pain
effect
– Long term use of opioids associated with
frontal lobe atrophy
– High dose opioids similar to frontal lobotomy
Frontal Lobes
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Opioids main effect
is in the frontal brain
or the affective
component of pain
Functional imaging
of pain locates
frontal lobe
activation
Opioid Induced Hyperalgesia
• Methadone maintained addicts
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Compton P, Charuvastra VC, Ling W. Pain intolerance in opioid-maintained former opiate addicts: effect of
long-acting maintenance agent. Drug Alcohol Depend. 2001 Jul 1;63(2):139-46
– Subjects
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18-55 yo
18 subjects in each group (methadone, buprenorphine, control)
In good general health
Excluded
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Actively using illicit drugs
Using Anticonvulsants
Neuroleptics
Analgesics
Chronic or acute pain patients
Neurologic or Psychiatric diagnosis (e.g. peripheral neuropathy or schizophrenia)
• Methadone and buprenorphine maintained former addicts
• All methadone and buprenorphine subjects met FDA criteria for methadone
maintenance.
• Controls age matched and drug naïve
• Testing used cold-pressor latency
– Withdrawal latency in seconds to cold noxious stimulus
– Good reliability and validity (Walsh NE, Schoenfeld L, Ramamurthy
S, Hoffman J. Normative model for cold pressor test. Am J Phys Med Rehabil.
1989 Feb;68(1):6-11. )
Opioid Induced Hyperalgesia
– Subjects
• Methadone or buprenorphine maintained former
addicts
• Excluded
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Actively using illicit drugs
Using Anticonvulsants
Neuroleptics
Analgesics
Chronic or acute pain patients
Neurologic or Psychiatric diagnosis (e.g. peripheral
neuropathy or schizophrenia)
Opioid Induced Hyperalgesia
– Subjects
• All methadone and buprenorphine subjects
met FDA criteria for methadone
maintenance.
• Controls age matched and drug naïve
• Testing used cold-pressor latency
– Withdrawal latency in seconds to cold noxious
stimulus
– Good reliability and validity (Walsh NE, Schoenfeld L,
Ramamurthy S, Hoffman J. Normative model for
cold pressor test. Am J Phys Med Rehabil.
1989 Feb;68(1):6-11. )
Opioid Induced Hyperalgesia
• Chronic opioid maintained subjects
Opioid Induced Hyperalgesia
• Summary of Studies
– Anesthesiology 2006; 104:570-87
Opioid Induced Hyperalgesia
• Summary of Studies
– Anesthesiology 2006; 104:570-87
Opioid Induced Hyperalgesia
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Animal studies
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Hyperalgesia during withdrawal
Time coarse
Nervous system sites of effect
Opioid Induced Hyperalgesia
• Animal Studies
Opioid Induced Hyperalgesia
• Time coarse
– Continuous (pellet or infusion)
• Dectected effect 1 to 2 days
• Resolved typically in time to develop
– Intermittant Bolus
• 2-5 days
• Usually resolved in 2-5 days
– Recovered animals from OIH had robust response to
second round of opioid administration Celerier E, Laulin J, Larcher
A, Le Moal M, Simonnet G: Evidence foropiate-activated NMDA processes masking opiate analgesia in rats.
Brain Res1999; 847:18–25
Learned OIH
• A suggested model
– Anesthesiology 2006; 104:570-87
Opioid Induced Hyperalgesia
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Clinical implication in chronic pain
management
– Pain state may worsen
– Tolerance impedes dose reduction
Opioid Induced Hyperalgesia
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Clinical implication in chronic pain
management
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Frontal lobe dysfunction may lead to social
dysfunction
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Loss of employment
Disability
Domestic instability