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

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 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 Angst (charts)

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 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

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

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 LD→hyperalgesia Normal dose→antinociceptic Both reversed with antagonist Theory: LD opioid trigger excitatory signaling cascade

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

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 *Dilaudid Oxycodone 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-3-glucuronide), 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 (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)

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 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: 4497-4498 Chang G, Chen L, Mao J: Opioid tolerance and hyperalgesia. 2007; 91: 199-211

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: 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