opioid hyperalgesia

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