Opioid Induced
Hyperalgesia
Jill Mosby, MD
June 18th 2008
History OIH

1880: Rossbach “When
dependence on opioids
finally becomes an
illness of itself, opposite
effects like restlessness,
sleep disturbance,
hyperesthesia,
neuralgia, and irritability
become manifest” 2
History OIH
Six decades later
Himmelsbach
described opioid
abstinence syndrome:
“aching in bones,
joints, muscles is
probably the most
common withdrawal
symptom” 2
Definitions
Analgesia
 absence of sense of pain
Nociceptive
 Causing pain
Agonist
 a chemical substance capable of activating
a receptor to induce a full or partial
pharmacological response
Antagonist
 a drug that counteracts the effects of
another drug
More definitions
TOLERANCE
 Exposure to a drug induces changes that
cause decreased response to drug’s effects
over time
 Can develop quickly or slowly
 Cross tolerance can occur (ie: with opioids)
SENSITIZATION
 A form of nonassociative learning
characterized by an increase in
responsiveness upon repeated exposure to
a stimulus
Standard Risks of Opioid

Physical dependence
Tolerance
Addiction
Overdose
Typical side effects

? Opioid Induced Hyperalgesia
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Opioid Induced Hyperalgesia

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Enhanced pain response to a noxious
stimulus
Evidence for changes/ source in spinal
cord and brain
AKA: Opioid Neurotoxicity
Types of OIH


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Maintenance therapy and withdrawal
(MW)
Very high dose, or escalating dose
(HD)
Ultra-low dose (LD)
Early evidence OIH: MW
Rodent Studies Summery
 Rodents: mice, rats, guinea pigs
 > 75 studies since 1970’s
 Multiple opioids (Morphine, Fentanyl,
Heroin, experimental)
 Multiple routes (IT/SQ/IV/PO/IP)
 Time frame of OIH: hours, days, or
longer
 Pain threshold measured:
Mechanical, Electrical or Thermal stimuli
This must not be one
of the experimental
rats…it’s too happy!
Rat studies:
during opioid
exposure
Vanderah et al, J Neurosc 2001
Angst (chart)
Rats: Persistent hyperalgesia
Celerier et al, J Neurosc 2001
Angst (chart)
Rats: Persistent hyperalgesia
Celerier et al, J Neurosc 2001
Angst (chart)
Celerier et al, J Neurosc 2001
Acute hyperalgesia after isolated
exposure
Celerier et al, Anes 2000
Mechanisms studied OIH-MW
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Opioid receptors: Mu receptor
NMDA antagonist (ketamine, MK-801)
NMDA activation
PKC inhibition
IT glutamate/ substance P
Spinal EAA (increase in chronic opioid use)
IT Cyclooxygenase inhibitors (NSAID)
Spinal dynophin
Spinal cytokines
IT GM1 ganglioside
Dorsal horn Fos-C
Hemoxygenase & nitric oxide synthase inhibitors
↑
↓
↑
↓
↑
↑
↓
↑
↑
?
?
↓
Evidence for MW in humans
 Human studies
former opioid
addicts
 Maintained on
methadone vs.
no maintenance
 Show increased
sensitivity to
some types of
pain
Test
Threshold
CPP
----
Tolerance
MM 42% ↓
PP
No change
----
EP
No change
----
CPP
----
MM 53% ↓
CPP
----
MM 56% ↓
CPP/
EP
MM 43% ↓
No change
MM 74% ↓
MM 15% ↓
CPP/
EP
MM 34% ↓
No change
MM 76% ↓
No change
OIH: MW
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Surgery pts, volunteer
High vs. low/no opioid dose intraop
Increased postop pain, opioid use in pts
received high dose
C/S*
TAH
Col
Gyn
Opioid use HD 60%↑ HD
vs. LD/None
120% ↑
HD
85% ↑ HD
ND
Postop Pain
HD vs.
LD/None
30% ↑ HD
50% ↑ HD
ND
ND
Angst Anesth 2006
Chronic Pain Patients
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6 Pts chronic back
pain >6 months
Started on LA
morphine
↓ Tolerance &
Threshold of CPP
Pain scores ↓ 30%
Secondary
outcomes not
changed
Angst J Pain 2006
OIH: MW
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Human volunteers
Capsaicin-heat for
mechanical pain
Pain ↓ remifentanil
Pain & allodynia ↑
after infusion
Wood, Anesth Analg
Clinical significance of MW
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Argues acute & chronic opioid use
may have new risk: OIH (MW)
Opioids may worsen initial pain & ↑
sensitivity to other sources of pain
Query NMDA antagonists future role
help prevent OIH
OIH: LD
Animal Studies
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Animal studies opioid 1000x lower
normal dose: OIH to mechanical &
thermal
Locally injected LD→hyperalgesia
Normal dose→antinociceptic
Both reversed with antagonist
Theory: LD opioid trigger excitatory
signaling cascade
OIH: LD in Humans
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1940’s study biphasic response to
morphine in 7/57 former addicts. Mild
hyperalgesia to heat at low dose,
analgesia at high dose.
1979 study showed LD opioid & antagonist
had improved post op pain, but was not
confirmed repeat studies
No controlled studies in humans
OIH: HD in Animal studies
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IT morphine 10x normal: scratching/ biting/
aversion to touch, not resolved with
naloxone
IT strychnine: allodynic/ hyperalgesic
Spinal cord EP studies: HD opioids act similar
to IT Strychnine
IT injected Glycine: attenuates allodynia
OIH: HD in Animal Studies
 33 opioid related structures studied,
characteristic of chemicals produce
allodynia/ hyperalgesia:
• Phenantrene structure
•
•
•
•
Hydrogen at position 14
Ether bond
One or no methyl group on nitrogen
Free 3-OH position ro glucuronide/sulfate conjugate
OIH: HD in humans
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Nine case reports pts with allodynia
22 pts, 8 had myoclonus
Most patients morphine
Routes: PO, IV, IT
Reducing dose opioid or rotation resolved/
reduced sx in 21/22 pts
This is the OIH that is seen clinically
in palliative care, ? Rad-Onc
OIH: HD Clinical Picture
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Severe allodynia
Intractable, escalating pain on HD/ED
opioid
< 50% myoclonus (?), more at rest
Delirium, mental status changes
Increased doses caused ↑ pain
Can lead to sz, coma, death
Reducing dose or rotating opioid
reversed sx in almost all patients
Culprit Medications
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*Morphine is most common
• most used opioid
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*Dilaudid
Oxycodone
Less often fentanyl or methadone
* I have seen clinically this year
Mechanism HD
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Phenantrene structure linked
NMDA linked, with effects on
excitatory signals in CNS
? Metabolites of opioid (Morphine-3glucuronide), this is less discussed in
literature
Phenantrene ring
Barriers to Treatment
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Clinicians often do not know about,
recognize, or understand OIH
Family/ patients understanding: How
can my Morphine do harm?
Both groups need education
Management of HD
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Pain controlled/ mild: ↓ opioid dose
Uncontrolled pain: ↓ dose + adjuvant
OR rotate to non-phenantrene opioid
Benzodiazapines
Fluids
Educate
Davis M, Walsh D
Bottom Line
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Future of pain control will be greatly
influenced by this area of research
Peripheral nerves, spinal cord & CNS all
involved in OIH
Chronic pain could be worsened by
acute and ongoing opioid therapy
Bottom Line (cont’d)
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For Patients with resistant/ escalating
pain, hyperalgesia should be considered
OIH (HD) treat with decreased opioid dose
or rotation to another opioid
I hope this has given some insight into
some of the challenges in treating pain
I hope this helps you recognize OIH (HD)
Questions to ponder
 Opioid tolerance & hyperalgesia linked?
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Worsening chronic non-malignant pain?
Are there genetic differences that cause OIH
MW & HD?
What is on horizon to help HD OIH?
Ketamine like medication?
Bibliography
1)
2)
3)
4)
Angst MA, Clark JD: Opioid induced
hyperalgesia. Anesth 2006; 104: 570-87
Mercandante S, Ferrera P, et al:
Hyperalgesia: an emerging Iatrogenic
Syndrome. J Pain and Sympt
Management 2003; 2: 769-775
Davis MP, Shaiova LA, Angst MS: When
opioids cause pain. 2007; 25: 44974498
Chang G, Chen L, Mao J: Opioid tolerance
and hyperalgesia. 2007; 91: 199-211
Bibliography
5)
6)
7)
8)
9)
Ballantyne JC, et all: Opioid Induced Hyperalgesia. Pain:
Clinical Updates 2008; 16: 1-4
Celerier E, Rivat C, et al: Long-lasting Hyperalgesia
Induced by Fentanyl in Rats. Anesth 2001; 92: 465-72
Celerier E, Laulin JP, et al: Progressive Enhancement of
Delayed Hyperalgesia Induced by Repeated Heroin
Administration: a Sensitization Process. J Neurosc 2001;
21: 4074-80
Chu LF, Clark DJ, et al: Opioid Tolerance and Hyperalgesia
in Chronic Pain Patients after one month of oral morphine
therapy: a preliminary prospective study. J Pain 2006;
7:43-48
Hood DD, Curry R, Eisenach JC: Intravenous remifentanyl
produces withdrawal hyperalgesia in volunteers with
capsaicin-induced hyperalgesia. Anesth Analg 2003; 97:
810-5