opioid hyperalgesia
TRANSCRIPT
Iperalgesia da oppioidi: impatto
clinico
UOC Anestesia e Rianimazione Ospedale Santa Maria dei Battuti, Ca’ Foncello, Treviso
Antonio Farnia
Opioid hyperalgesia: clinical
impact
outline
• historical considerations
• definition
• background
• neurobiology of OIH
• experimental models (in vitro and animals)
• humans data (clinical scenario)
• conclusion
historical considerations
“Does morphia tend to encourage the very pain it pretends to relieve?”
not a new observation
“On the abuse of hypodermic injections of morphia,” Clifford Albutt, Practitioner 1870; 3:327-330.
……. but I speak only about
postoperative opioid hyperalgesia
patients with cronic pain are beyond the scope of this
presentation
definition
Opioid-induced hyperalgesia
Opioid-induced hyperalgesia (OIH) is defined the
increased sensitivity to painful stimuli
as a result of opioid use
Opiod-induced hyperalgesia
an increased resonse to a stimulus that normally provekes pain
Opiod-induced hyperalgesia
OIH is
a paradoxical response
to an opioid agonist
Opiod-induced hyperalgesia
there is an increase in pain perception
VAS NRS
background
Opioid induced hyperalgesia (OIH)
OIH has been shown
to occur in the perioperative period
Anesthesia
• Hypnosis
• Pain
propofol
remifentanil
Fentanil ?
the anesthesiologist will be confronted not infrequently with the following clinical scenario:
‘‘He needed 500 µg fentanyl in the operating room for a toe amputation and has received 20 mg morphine, and he’s still complaining of severe pain . . . . Do you think he may need more morphine?’’
differential diagnosis?
clinical scenario
…. but are we sure that everything we do Intraoperatively (strategy, drug choice)
can have no implications?
neurobiology
activation of pronociceptive mechanism
The neurobiology of OIH is complex
• NMDA receptor activity (activation of central glutaminergic pathway)
• G-proteins• descending pinal facilitation from the the rostro-ventral
medulla via changes in activity of on- and off- cells• substance P acting via NK-1 receptors• transient receptor potential (TRP)-V1• Cholecystokinin CCK (descending facilitation)• spinal dynorphins• spinal cycloxygenase-2 protein• 5-Hydroxytryptamine (5HT3)• Immune system (astrocytes activation and cytokines
release)
The neurobiology of OIH is complex
• Genetics factors
Homozygous for the COMT met 158 allele met–met polymorphism Abcb 1b glycoprotein drug transporter gene variants of the b2-adrenergic receptor gene
dynamic balance
changeopposite change
homeostasis
Pain tolerance
Opioid-induced analgesia
Opioid-induced hyperalgesia
Adapted from: Solomon R, American Psychologist 1980; 35(8):691-712; Koob GF, et al, Neuroscience & Biobehavioral Reviews 1989;13:135-140.
Opponent Process theory
Opioid administration
Activation of N-methyl-D – aspartate (NMDA) receptor
Mg2+
µ-opioid
PKC
µ-opioid
Targeting Opioid-Induced Hyperalgesia in Clinical Treatment: Neurobiological Considerations. CNS Drugs (2015) 29:465–486
in vitro experimental models
Bolus 30µg/kg
Bolus 30 µg/kg + an infusion 450 µg.kg-
1.h-1
19 volunteers
Heat pain test (HPT)
animal experimental models
Paw-pressure vocalization test
modification of the Randall-Selitto method (Kayser et al., 1990),
the paw-pressure vocalization test,
in which a constantly increasing pressure is applied to the hindpaw until the rat squeaks
a 600 gm cutoff value was set to prevent tissue damage
Paw-pressure vocalization test
opioid
Analgesia
hyperalgesia
Pai
n t
hre
sho
ld
basal
Celerier E, Rivat C, et al. Anesthesiology 2000 Feb; 92: 465-472
Celerier E, Rivat C, et al. Anesthesiology 2000 Feb; 92: 465-472
Celerier E, Rivat C, et al. Anesthesiology 2000 Feb; 92: 465-472
Celerier E, Rivat C, et al. Anesthesiology 2000 Feb; 92: 465-472
Celerier E, Rivat C, et al. Anesthesiology 2000 Feb; 92: 465-472
Ketamine doses
• Ketamine group patients received 0.2 mg/kg of IV ketamine
• 0.3 mg/kg of ketamine was injected following a continuous dosage of 3ug/kg/min in the ketamine group
• 0.5 mg/kg ketamine IV• 0.5 mg/kg ketamine IV before surgery, followed
by ketamine infusion 600 µg/kg/h, until wound closure
• 0.5 mg/kg ketamina, 2 µg/kg/min sino alla fine dell’intervento
clinical scenario
Opioid-induced hyperalgesia
in surgical patients, OIH, acute tolerance or both ave been identified
mainly
after remifentanil-based anesthesia
• 50 adult patients• Undergoing major abdominal surgery• Randomized for two due anesthetic
regimens:• desflurane constant at 0.5 MAC and remifentanil titrate
on autonomic responses (remifentanil group)
• remifentanil 0.1 µg/kg/min and titrate desflurane on autonomic responses (desflurane group)
• morphine bolus 0.15 mg/kg 30 min before the end of surgery
• Morphine given to the need by the PACU nurse unaware of group assignment
• Following patient-controlled analgesia (PCA) also not aware of the group assignment
• Pain score record
• Morphine consumption for 24 hour post-surgery
• Intraoperative haemodynamic control similar in both groups
• Post-operative Pain Score significantly higher in remifentanil group
• Remi group required morphine significantly before
• Morphine consumption in the first 24 hours approximately double in remi group
Results:
meta-analysis
Propofol vs. Isoflurane
Anesthesia Matters: Patients Anesthetized with Propofol Have Less Postoperative Pain than Those Anesthetized with Isoflurane. Anesth Analg 2008;106:264 –9
persistent or chronic post-surgical pain
• High-dose remifentanil (average effect-site concentration 5.6 ng/mL) with epidural analgesia started and at the end of surgery
• low-dose remifentanil (average effect site concentration 2.0 ng/mL) with epidural analgesia with 0.5% ropivacaine started at the beginning of anesthesia
9-13 MONTHS
The ultimate aim would be to predict, based on the type of intervention, patient history and genetic and epigenetic factors, which patients are at risk of experiencing acute and chronic pain, and to tailor the anaesthetic and surgical plan accordingly, allocating analgesic resources to patients who need it most.
conclusion
hyperalgesia by high doses of opioid to rapid kinetics
• Possible explanation for some episodes of higher than expected pain
• Highest pain score
• Higher postoperative opioids consumption
Approaches that might antagonize or limit the phenomenon of hyperalgesia
• Do not use opioids in preemptive analgesia
• Postoperative multimodal analgesia with analgesic transition in the appropriate time frame
• Regional analgesia
Approaches that might antagonize or limit the phenomenon of hyperalgesia
• Avoid the intraoperative use of high doses of opioids?
• Low doses and concentrations of intraoperative remifentanil (<0.2 μg.kg-1.min-1 or TCI <7 ng.ml-1)
• Discontinuation of remifentanil in a progressive manner
Approaches that might antagonize or limit the phenomenon of hyperalgesia
• Propofol versus vapors• Ketamine• N2O• Magnesium sulfate• Clonidine/dexmetetomidine• Cox-2-inhibitors • Pregabalin, gabapentin• Paracetamol• propranolol• Ondansetron
unexplored issues
is useful combine fentanyl and remifentanil?
thank you