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