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 drugs 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

Opioid Induced Hyperalgesia

Enhanced pain response to a noxious

stimulus
Evidence for changes/ source in spinal
cord and brain
AKA: Opioid Neurotoxicity

Types of OIH

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 1970s
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
ratsits 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

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
CPP/
EP

MM 43%

MM 74%

No change
MM 15%
MM 34%
MM 76%
No change
No change

OIH: MW

Surgery pts, volunteer

High vs. low/no opioid dose intraop
Increased postop pain, opioid use in pts
received high dose
C/S*

TAH

Col

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

Gyn

Angst Anesth 2006

Chronic Pain Patients

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

Human volunteers
Capsaicin-heat for
mechanical pain
Pain remifentanil
Pain & allodynia
after infusion

Wood, Anesth Analg

Clinical significance of MW

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

Animal studies opioid 1000x lower

normal dose: OIH to mechanical &
thermal
Locally injected LDhyperalgesia
Normal doseantinociceptic
Both reversed with antagonist
Theory: LD opioid trigger excitatory
signaling cascade

OIH: LD in Humans

1940s 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

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

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

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

*Morphine is most common

most used opioid

*Dilaudid
Oxycodone
Less often fentanyl or methadone
* I have seen clinically this year

Mechanism HD

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

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

Pain controlled/ mild: opioid dose

Uncontrolled pain: dose + adjuvant
OR rotate to non-phenantrene opioid
Benzodiazapines
Fluids
Educate
Davis M, Walsh D

Bottom Line

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 (contd)

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?

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