1. Opioid Induced Hyperalgesia
Jill Mosby, MD
June 18th 2008

2. 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

3. History OIH
Six decades later Himmelsbach described opioid abstinence syndrome: “aching in bones, joints, muscles is probably the most common withdrawal symptom” 2

4. 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

5. 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

6. Standard Risks of Opioid
Physical dependence
Tolerance
Addiction
Overdose
Typical side effects
? Opioid Induced Hyperalgesia

7. Opioid Induced Hyperalgesia
Enhanced pain response to a noxious stimulus
Evidence for changes/ source in spinal cord and brain
AKA: Opioid Neurotoxicity

8. Types of OIH Maintenance therapy and withdrawal (MW)
Very high dose, or escalating dose (HD)
Ultra-low dose (LD)

9. 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!

10. Rat studies: during opioid exposure
Vanderah et al, J Neurosc 2001
Angst (chart)

11. Rats: Persistent hyperalgesia
Celerier et al, J Neurosc 2001
Angst (chart)

12. Rats: Persistent hyperalgesia
Celerier et al, J Neurosc 2001
Angst (chart)

13. Celerier et al, J Neurosc 2001

14. Acute hyperalgesia after isolated exposure
Celerier et al, Anes 2000
Angst (charts)

15. 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 ↓

16. Evidence for MW in humans
Test
Threshold
Tolerance
CPP
----
MM 42% ↓ PP
No change EP
MM 53% ↓
MM 56% ↓
CPP/EP
MM 43% ↓
MM 74% ↓
MM 15% ↓
MM 34% ↓
MM 76% ↓
Human studies former opioid addicts
Maintained on methadone vs. no maintenance
Show increased sensitivity to some types of pain

17. 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
Gyn
Opioid use HD vs. LD/None
60%↑ HD
120% ↑ HD
85% ↑ HD ND
Postop Pain HD vs. LD/None
30% ↑ HD
50% ↑ HD
Angst Anesth 2006

18. 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

19. OIH: MW Human volunteers Capsaicin-heat for mechanical pain
Pain ↓ remifentanil
Pain & allodynia ↑ after infusion
Wood, Anesth Analg

20. 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

22. OIH: LD Animal Studies
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

23. OIH: LD in Humans
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

25. 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

26. 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

27. 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

28. 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

29. Culprit Medications *Morphine is most common *Dilaudid Oxycodone
most used opioid
*Dilaudid
Oxycodone
Less often fentanyl or methadone
* I have seen clinically this year

30. Mechanism HD Phenantrene structure linked
NMDA linked, with effects on excitatory signals in CNS
? Metabolites of opioid (Morphine-3-glucuronide), this is less discussed in literature

31. Phenantrene ring

32. 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

33. 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

34. 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

35. Bottom Line (cont’d)
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)

36. 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?

38. Bibliography
Angst MA, Clark JD: Opioid induced hyperalgesia. Anesth 2006; 104:
Mercandante S, Ferrera P, et al: Hyperalgesia: an emerging Iatrogenic Syndrome. J Pain and Sympt Management 2003; 2:
Davis MP, Shaiova LA, Angst MS: When opioids cause pain ; 25:
Chang G, Chen L, Mao J: Opioid tolerance and hyperalgesia ; 91:

39. Bibliography
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:
Celerier E, Laulin JP, et al: Progressive Enhancement of Delayed Hyperalgesia Induced by Repeated Heroin Administration: a Sensitization Process. J Neurosc 2001; 21:
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