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