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Opioid Induced Opioid Induced HyperalgesiaHyperalgesia
Jill Mosby, MDJill Mosby, MD
June 18June 18thth 2008 2008
History OIHHistory OIH
1880: Rossbach “When 1880: Rossbach “When dependence on opioids dependence on opioids finally becomes an finally becomes an illness of itself, opposite illness of itself, opposite effects like effects like restlessnessrestlessness, , sleep disturbance, sleep disturbance, hyperesthesia, hyperesthesia, neuralgia, and irritability neuralgia, and irritability become manifest” become manifest” 22
History OIHHistory OIH
Six decades later Six decades later Himmelsbach Himmelsbach described opioid described opioid abstinence syndrome: abstinence syndrome: “aching in bones, “aching in bones, joints, muscles is joints, muscles is probably the most probably the most common withdrawal common withdrawal symptom” symptom” 22
DefinitionsDefinitions
AnalgesiaAnalgesia absence of sense of painabsence of sense of painNociceptiveNociceptive Causing pain Causing pain AgonistAgonist a chemical substance capable of activating a chemical substance capable of activating
a receptor to induce a full or partial a receptor to induce a full or partial pharmacological response pharmacological response
AntagonistAntagonist a drug that counteracts the effects of a drug that counteracts the effects of
another drug another drug
More definitionsMore definitionsTOLERANCETOLERANCE Exposure to a drug induces changes that Exposure to a drug induces changes that
cause decreased response to drug’s effects cause decreased response to drug’s effects over timeover time
Can develop quickly or slowlyCan develop quickly or slowly Cross tolerance can occur (ie: with opioids)Cross tolerance can occur (ie: with opioids)
SENSITIZATIONSENSITIZATION A form of nonassociative learning A form of nonassociative learning
characterized by an increase in characterized by an increase in responsiveness upon repeated exposure to a responsiveness upon repeated exposure to a stimulusstimulus
Standard Risks of OpioidStandard Risks of Opioid
Physical dependencePhysical dependence ToleranceTolerance AddictionAddiction OverdoseOverdose Typical side effects Typical side effects
? Opioid Induced Hyperalgesia? Opioid Induced Hyperalgesia
Opioid Induced HyperalgesiaOpioid Induced Hyperalgesia
Enhanced pain response to a noxious Enhanced pain response to a noxious stimulusstimulus
Evidence for changes/ source in spinal Evidence for changes/ source in spinal cord and braincord and brain
AKA: Opioid NeurotoxicityAKA: Opioid Neurotoxicity
Types of OIHTypes of OIH
Maintenance therapy and withdrawal Maintenance therapy and withdrawal (MW)(MW)
Very high dose, or escalating dose Very high dose, or escalating dose (HD)(HD)
Ultra-low dose (LD)Ultra-low dose (LD)
Early evidence OIH: MW Early evidence OIH: MW Rodent Studies SummeryRodent Studies Summery
Rodents: Rodents: mice, rats, guinea pigsmice, rats, guinea pigs
> 75 studies since 1970’s> 75 studies since 1970’s Multiple opioids Multiple opioids (Morphine, Fentanyl, (Morphine, Fentanyl,
Heroin, experimental)Heroin, experimental)
Multiple routes Multiple routes (IT/SQ/IV/PO/IP)(IT/SQ/IV/PO/IP)
Time frame of OIH: Time frame of OIH: hours, days, or hours, days, or longerlonger
Pain threshold measured: Pain threshold measured: Mechanical, Electrical or Thermal stimuliMechanical, Electrical or Thermal stimuli
This must not be one of the experimental rats…it’s too happy!
Vanderah et al, J Neurosc 2001
Angst (chart)
Rat studies: Rat studies: during opioid during opioid
exposureexposure
Rats: Persistent hyperalgesiaRats: Persistent hyperalgesia
Celerier et al, J Neurosc 2001
Angst (chart)
Rats: Persistent hyperalgesiaRats: Persistent hyperalgesia
Celerier et al, J Neurosc 2001
Angst (chart)
Celerier et al, J Neurosc 2001
Acute hyperalgesia after isolated Acute hyperalgesia after isolated exposureexposure
Celerier et al, Anes 2000
Angst (charts)
Mechanisms studied OIH-MWMechanisms studied OIH-MW Opioid receptors: Mu receptor Opioid receptors: Mu receptor ↑↑ NMDA antagonist (ketamine, MK-801)NMDA antagonist (ketamine, MK-801) ↓↓ NMDA activation NMDA activation ↑↑ PKC inhibitionPKC inhibition ↓↓ IT glutamate/ substance P IT glutamate/ substance P ↑↑ Spinal EAA (increase in chronic opioid use) Spinal EAA (increase in chronic opioid use) ↑↑ IT Cyclooxygenase inhibitors (NSAID)IT Cyclooxygenase inhibitors (NSAID) ↓↓ Spinal dynophinSpinal dynophin ↑↑ Spinal cytokinesSpinal cytokines ↑↑ IT GM1 gangliosideIT GM1 ganglioside ?? Dorsal horn Fos-CDorsal horn Fos-C ?? Hemoxygenase & nitric oxide synthase inhibitorsHemoxygenase & nitric oxide synthase inhibitors ↓↓
Evidence for MW in humansEvidence for MW in humans
Human studies Human studies former opioid former opioid addicts addicts
Maintained on Maintained on methadone vs. methadone vs. no maintenanceno maintenance
Show increased Show increased sensitivity to sensitivity to some types of some types of painpain
TestTest ThresholdThreshold ToleranceTolerance
CPPCPP -------- MM 42% MM 42% ↓↓
PPPP No changeNo change --------
EPEP No changeNo change --------
CPPCPP -------- MM 53% MM 53% ↓↓
CPPCPP -------- MM 56% MM 56% ↓↓
CPP/CPP/EPEP
MM 43% ↓ MM 43% ↓
No changeNo change
MM 74% ↓MM 74% ↓
MM 15% MM 15% ↓↓
CPP/CPP/EPEP
MM 34% ↓MM 34% ↓
No changeNo change MM 76% ↓MM 76% ↓
No changeNo change
OIH: MWOIH: MW
Surgery pts, volunteerSurgery pts, volunteer High vs. low/no opioid dose intraopHigh vs. low/no opioid dose intraop Increased postop pain, opioid use in pts Increased postop pain, opioid use in pts
received high dose received high dose
Angst Anesth 2006
C/S*C/S* TAHTAH ColCol GynGyn
Opioid use HD Opioid use HD vs. LD/Nonevs. LD/None
60%↑ HD60%↑ HD 120% ↑ 120% ↑ HDHD
85% ↑ HD85% ↑ HD NDND
Postop Pain Postop Pain HD vs. HD vs. LD/NoneLD/None
NDND 30% ↑ HD30% ↑ HD 50% ↑ HD50% ↑ HD NDND
Chronic Pain PatientsChronic Pain Patients 6 Pts chronic back 6 Pts chronic back
pain >6 monthspain >6 months Started on LA Started on LA
morphinemorphine ↓ ↓ Tolerance & Tolerance &
Threshold of CPPThreshold of CPP Pain scores ↓ 30%Pain scores ↓ 30% Secondary Secondary
outcomes not outcomes not changedchanged
Angst J Pain 2006
OIH: MWOIH: MW
Human volunteersHuman volunteers Capsaicin-heat for Capsaicin-heat for
mechanical painmechanical pain Pain Pain ↓↓ remifentanil remifentanil Pain & allodynia Pain & allodynia ↑ ↑
after infusionafter infusion
Wood, Anesth Analg
Clinical significance of MWClinical significance of MW
Argues acute & chronic opioid use Argues acute & chronic opioid use may have new risk: OIH (MW)may have new risk: OIH (MW)
Opioids may worsen initial pain & Opioids may worsen initial pain & ↑ ↑ sensitivity to other sources of painsensitivity to other sources of pain
Query NMDA antagonists future role Query NMDA antagonists future role help prevent OIHhelp prevent OIH
OIH: LD OIH: LD Animal StudiesAnimal Studies
Animal studies opioid 1000x lower Animal studies opioid 1000x lower normal dose: OIH to mechanical & normal dose: OIH to mechanical & thermalthermal
Locally injected LDLocally injected LD→→hyperalgesia hyperalgesia Normal doseNormal dose→→antinocicepticantinociceptic
Both reversed with antagonistBoth reversed with antagonist
Theory: LD opioid trigger excitatory Theory: LD opioid trigger excitatory signaling cascadesignaling cascade
OIH: LD in HumansOIH: LD in Humans
1940’s study biphasic response to 1940’s study biphasic response to morphine in 7/57 former addicts. Mild morphine in 7/57 former addicts. Mild hyperalgesia to heat at low dose, hyperalgesia to heat at low dose, analgesia at high dose.analgesia at high dose.
1979 study showed LD opioid & antagonist 1979 study showed LD opioid & antagonist had improved post op pain, but was not had improved post op pain, but was not confirmed repeat studiesconfirmed repeat studies
No controlled studies in humansNo controlled studies in humans
OIH: HD in Animal studiesOIH: HD in Animal studies IT morphine 10x normal: scratching/ biting/ IT morphine 10x normal: scratching/ biting/
aversion to touch, not resolved with naloxoneaversion to touch, not resolved with naloxone
IT strychnine: allodynic/ hyperalgesicIT strychnine: allodynic/ hyperalgesic
Spinal cord EP studies: HD opioids act similar Spinal cord EP studies: HD opioids act similar to IT Strychnineto IT Strychnine
IT injected Glycine: attenuates allodyniaIT injected Glycine: attenuates allodynia
OIH: HD in Animal StudiesOIH: HD in Animal Studies
33 opioid related structures studied, 33 opioid related structures studied, characteristic of chemicals produce characteristic of chemicals produce allodynia/ hyperalgesia:allodynia/ hyperalgesia:• Phenantrene structurePhenantrene structure• Hydrogen at position 14Hydrogen at position 14• Ether bondEther bond• One or no methyl group on nitrogenOne or no methyl group on nitrogen• Free 3-OH position ro glucuronide/sulfate conjugateFree 3-OH position ro glucuronide/sulfate conjugate
OIH: HD in humansOIH: HD in humans Nine case reports pts with allodyniaNine case reports pts with allodynia 22 pts, 8 had myoclonus22 pts, 8 had myoclonus Most patients morphineMost patients morphine Routes: PO, IV, ITRoutes: PO, IV, IT Reducing dose opioid or rotation resolved/ Reducing dose opioid or rotation resolved/
reduced sx in 21/22 ptsreduced sx in 21/22 pts
This is the OIH that is seen clinically This is the OIH that is seen clinically in palliative care, ? Rad-Oncin palliative care, ? Rad-Onc
OIH: HD Clinical PictureOIH: HD Clinical Picture
Severe Severe allodyniaallodynia Intractable, escalating pain on HD/ED Intractable, escalating pain on HD/ED
opioidopioid < 50% < 50% myoclonus myoclonus (?), more at rest(?), more at rest Delirium, mental status changesDelirium, mental status changes Increased doses caused Increased doses caused ↑↑ pain pain Can lead to sz, coma, deathCan lead to sz, coma, death Reducing doseReducing dose or or rotating opioidrotating opioid
reversed sx in almost all patientsreversed sx in almost all patients
Culprit MedicationsCulprit Medications
*Morphine is most common*Morphine is most common• most used opioidmost used opioid
*Dilaudid*Dilaudid OxycodoneOxycodone
Less often fentanyl or methadoneLess often fentanyl or methadone * I have seen clinically this year* I have seen clinically this year
Mechanism HDMechanism HD
Phenantrene structure linkedPhenantrene structure linked
NMDA NMDA linkedlinked, , with effects on with effects on excitatory signals in CNSexcitatory signals in CNS
? Metabolites of opioid (Morphine-3-? Metabolites of opioid (Morphine-3-glucuronide), this is less discussed in glucuronide), this is less discussed in literatureliterature
Phenantrene ringPhenantrene ring
Barriers to TreatmentBarriers to Treatment
Clinicians often do not know about, Clinicians often do not know about, recognize, or understand OIHrecognize, or understand OIH
Family/ patients understanding: How Family/ patients understanding: How can my Morphine do harm?can my Morphine do harm?
Both groups need educationBoth groups need education
Management of HDManagement of HD
Pain controlled/ mild: Pain controlled/ mild: ↓↓ opioid dose opioid dose
Uncontrolled pain: Uncontrolled pain: ↓↓ dose + adjuvant dose + adjuvant OROR rotate to non-phenantrene opioid rotate to non-phenantrene opioid
BenzodiazapinesBenzodiazapines Fluids Fluids EducateEducate
Davis M, Walsh D
Bottom LineBottom Line
Future of pain control will be greatly Future of pain control will be greatly influenced by this area of researchinfluenced by this area of research
Peripheral nerves, spinal cord & CNS all Peripheral nerves, spinal cord & CNS all involved in OIH involved in OIH
Chronic pain could be worsened by Chronic pain could be worsened by acute and ongoing opioid therapyacute and ongoing opioid therapy
Bottom Line (cont’d)Bottom Line (cont’d)
For Patients with resistant/ escalating pain, For Patients with resistant/ escalating pain, hyperalgesia should be considered hyperalgesia should be considered
OIH (HD) treat with decreased opioid dose OIH (HD) treat with decreased opioid dose or rotation to another opioidor rotation to another opioid
I hope this has given some insight into I hope this has given some insight into some of the challenges in treating painsome of the challenges in treating pain
I hope this helps you recognize OIH (HD)I hope this helps you recognize OIH (HD)
Questions to ponderQuestions to ponder
Opioid tolerance & hyperalgesia linked?Opioid tolerance & hyperalgesia linked?
Worsening chronic non-malignant pain?Worsening chronic non-malignant pain?
Are there genetic differences that cause OIH Are there genetic differences that cause OIH MW & HD?MW & HD?
What is on horizon to help HD OIH? What is on horizon to help HD OIH? Ketamine like medication?Ketamine like medication?
BibliographyBibliography
1)1) Angst MA, Clark JD: Opioid induced Angst MA, Clark JD: Opioid induced hyperalgesia. Anesth 2006; 104: 570-87hyperalgesia. Anesth 2006; 104: 570-87
2)2) Mercandante S, Ferrera P, et al: Mercandante S, Ferrera P, et al: Hyperalgesia: an emerging Iatrogenic Hyperalgesia: an emerging Iatrogenic Syndrome. J Pain and Sympt Syndrome. J Pain and Sympt Management 2003; 2: 769-775Management 2003; 2: 769-775
3)3) Davis MP, Shaiova LA, Angst MS: When Davis MP, Shaiova LA, Angst MS: When opioids cause pain. 2007; 25: 4497-4498opioids cause pain. 2007; 25: 4497-4498
4)4) Chang G, Chen L, Mao J: Opioid tolerance Chang G, Chen L, Mao J: Opioid tolerance and hyperalgesia. 2007; 91: 199-211and hyperalgesia. 2007; 91: 199-211
BibliographyBibliography5)5) Ballantyne JC, et all: Opioid Induced Hyperalgesia. Pain: Ballantyne JC, et all: Opioid Induced Hyperalgesia. Pain:
Clinical Updates 2008; 16: 1-4Clinical Updates 2008; 16: 1-46)6) Celerier E, Rivat C, et al: Long-lasting Hyperalgesia Celerier E, Rivat C, et al: Long-lasting Hyperalgesia
Induced by Fentanyl in Rats. Anesth 2001; 92: 465-72Induced by Fentanyl in Rats. Anesth 2001; 92: 465-727)7) Celerier E, Laulin JP, et al: Progressive Enhancement of Celerier E, Laulin JP, et al: Progressive Enhancement of
Delayed Hyperalgesia Induced by Repeated Heroin Delayed Hyperalgesia Induced by Repeated Heroin Administration: a Sensitization Process. J Neurosc 2001; Administration: a Sensitization Process. J Neurosc 2001; 21: 4074-8021: 4074-80
8)8) Chu LF, Clark DJ, et al: Opioid Tolerance and Hyperalgesia Chu LF, Clark DJ, et al: Opioid Tolerance and Hyperalgesia in Chronic Pain Patients after one month of oral morphine in Chronic Pain Patients after one month of oral morphine therapy: a preliminary prospective study. J Pain 2006; therapy: a preliminary prospective study. J Pain 2006; 7:43-487:43-48
9)9) Hood DD, Curry R, Eisenach JC: Intravenous remifentanyl Hood DD, Curry R, Eisenach JC: Intravenous remifentanyl produces withdrawal hyperalgesia in volunteers with produces withdrawal hyperalgesia in volunteers with capsaicin-induced hyperalgesia. Anesth Analg 2003; 97: capsaicin-induced hyperalgesia. Anesth Analg 2003; 97: 810-5810-5