Pain Management

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Pain Management
Dennis Q. McManus, MD
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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

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Definition Basics

• Acute pain
• Chronic and acute cancer/palliative pain
• Chronic non-cancer pain
• Chronic back pain
• Fibromyalgia
• Chronic migraines
• Chronic joint pain

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Clinical ApproachGuiding Principals

• 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

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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.

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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)

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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

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Approach to Treatment

• Changed to methadone 5 mg PO BID
• 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.

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Roller Coaster Effect
ok
not ok
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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.

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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)

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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).

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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)

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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 Ovids (43 BC to 17 AD)
  Latin name for the god of dreams, Morpheus, who
  was the son of Somnus, the god of sleep.

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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

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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

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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.

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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.)

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History of Opioids

• Chinese imperial government prohibited smoking
  and trading of opium in 1729.
• Punishment for opium shop owners was
  strangulation.

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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.

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History of Opioids

• Opium Wars
• Dutch traded opium 1650-1773
• 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

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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

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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

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History of Opioids

• American Civil War and late 1800s
• The North
• Uses 10 million opium pills
• 2.8 million ounces other opium preparation
• Veterans used opium for war wounds
• Surveys in late 1800s in Midwest majority of
  opium users were women for neuralgia, morning
  sickness and menstrual pain.
• Soldiers disease was a term for opiate addiction

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History of Opioids

• Late 1800s 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

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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)

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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

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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?

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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

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Pain Imaging

• Hand place in cold or warm water
• PET scan before and during pain
• Effects of suggestion on brain activation

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Frontal Lobes

• Decreased gray matter density in opiate-dependent
  subjects
• Frontal lobes
• Temporal cortex
• Reduced phosphocreatine in frontal cortex
• Orbital frontal activation in abstinent opiate
  users under craving recalls

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Frontal Lobe

• Varying levels of opioids effects
• Dole experiments with methadone and heroin
• Air force dexterity test
• Normal performance by methadone maintained opiate
  users

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Frontal Lobes

• Opioids main effect is in the frontal brain or
  the affective component of pain
• Functional imaging of pain locates frontal lobe
  activation

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Frontal Lobes

• Phineas Gage
• Unpleasantness in Vermont
• September 13, 1848
• Explosion with tamping iron

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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

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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

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Descartes Error

• Intact temporal and frontal areas for decision
  making
• Cold calculated decisions need emotional
  weighting
• Example of young executive in the gambling
  paradigm

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Frontal Lobe Dysfunction

• Depression
• Disorganization
• Apathy

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Opiate Use

• Acute pain
• Cancer pain both chronic and acute
• Chronic non cancer pain

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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

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Opiate Properties

• Euphoria (short acting opioids)
• Affective component of pain (anxiety)
• Bodies response is to increase sensitivity of
  pain (opioid induced hyperalgesia)

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Opioid Euphoria

• Only associated with increasing blood levels
• Heroin vs morphines example
• Active metabolite is morphine
• Acetylation accelerated penetration of the BBB
• Oxycontin example (634,500,000 fine)
• Steady state levels not euphoric
• Peak levels not associated with increased
  function
• Hydrocodone example

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Short Acting OpioidA Graph
ok
not ok
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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.

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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

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Frontal Lobes

• Opioids main effect is in the frontal brain or
  the affective component of pain
• Functional imaging of pain locates frontal lobe
  activation

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Opioid Induced Hyperalgesia

• Methadone maintained addicts
• 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 163(2)139-46
• Subjects
• 18-55 yo
• 18 subjects in each group (methadone,
  buprenorphine, control)
• In good general health
• Excluded
• 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 Feb68(1)6-11. )

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Opioid Induced Hyperalgesia

• Subjects
• Methadone or buprenorphine maintained former
  addicts
• Excluded
• Actively using illicit drugs
• Using Anticonvulsants
• Neuroleptics
• Analgesics
• Chronic or acute pain patients
• Neurologic or Psychiatric diagnosis (e.g.
  peripheral neuropathy or schizophrenia)

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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 Feb68(1)6-11. )

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Opioid Induced Hyperalgesia

• Chronic opioid maintained subjects

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Opioid Induced Hyperalgesia

• Summary of Studies
• Anesthesiology 2006 104570-87

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Opioid Induced Hyperalgesia

• Summary of Studies
• Anesthesiology 2006 104570-87

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Opioid Induced Hyperalgesia

• Animal studies
• Hyperalgesia during withdrawal
• Time coarse
• Nervous system sites of effect

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Opioid Induced Hyperalgesia

• Animal Studies

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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
  8471825

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Learned OIH

• A suggested model
• Anesthesiology 2006 104570-87

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Opioid Induced Hyperalgesia

• Clinical implication in chronic pain management
• Pain state may worsen
• Tolerance impedes dose reduction

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Opioid Induced Hyperalgesia

• Clinical implication in chronic pain management
• Frontal lobe dysfunction may lead to social
  dysfunction
• Loss of employment
• Disability
• Domestic instability