The minimum local analgesic concentration for labor analgesia · • EC50 - ED50 and relative potencies of local anesthetics • Analgesia • Motor block • Sensory – motor separation

The minimum local analgesic concentration for labor analgesia

Giorgio Capogna

Department of Anesthesiology

Città di Roma Hospital

[email protected]

• The up-down sequential allocation model is the first

systematic application of dose-response pharmacodynamics

to regional anesthesia

• Comparison of drugs relative potency

(the ratio of equieffective concentrations) (EC50)

• Potency should not be confused with efficacy

• Efficacy: the maximum effect of a drug (Emax)

% e

ffect

% e

ffect

PotencyEfficacy

• is ideally suited to sensitivity experiments and

has had applications in engineering,

psychology, industrial chemistry and

anesthesia (MAC)

• the response must be binary (yes/no,

dead/alive, effective/ineffective) in an up-down

manner with each subsequent patient's dose

varying according to the previous patient's

response

Up-down sequential allocation method

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0 10 20 30 40

patient number

effective

ineffectivedru

g c

once

ntration %

w/v

EFFECTIVE:• requires a VAPS of 10 mm or less at the height of painful uterine contraction within 30 min• directs a decrement of the concentration of the study drug for the next woman.

INEFFECTIVE:INEFFECTIVE:• requires a VAPS greater than 10 mm that responds to a rescue bolus with a high concentration of local anesthetic • directs an increment of concentration of the study solution for the next woman.

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effective

ineffective

dru

g c

once

ntration %

w/v REJECTREJECT :

• failure of the rescue bolus (failure of the spread of the solution)• progression of laborsame concentration for the next woman

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0,60

0,80

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1,20

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patient number

effective

ineffective

conce

ntration %

w/v

mlac

• testing is eventually concentrated around the median

• allows the reduction (30-80%) in the sample size

• increases the accuracy with which the median is estimated

• EC50 - ED50 and relative potencies of local anesthetics

• Analgesia

• Motor block

• Sensory – motor separation

• ED50 and relative potencies of opioids

• Sparing effect

• Obstetric factors influencing local anesthetic requirements

• Stage of labor (cervical dilatation)

• Dystocia

• Induction of labor


• Analgesia

• Motor block



• Sparing effect



• Dystocia


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0.11

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0.17

0.20

0.23

0 10 20 30 40

patient number

Ropivacaine

Bupivacaine

Conce

ntration %

EC50 for Analgesia of Epidural

Bupivacaine & Ropivacaine

Capogna G et Al. BJA 1998

0.156% (0.136-0.176)

0.093% (0.076-0.110)

Potency ratio: 0.60 (0.47-0.75)

Concentration-response plots for analgesia Bupivacaine vs Levobupivacaine

Lyons G et Al. BJA 1998

Potency ratio: 0.98 (0.67-1.41)

Molar Potency ratio: 0.87 (0.60-1.25)

EC50

0

0,1

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0,8

0,9

1

0 0.02 0.04 0.06 0.08 0.10 0.12 0.14 0.16 0.18 0.20

Concentration (%)

Cum

ula

tive

Resp

onse

Bupivacaine

Levobupivacaine

Bupivacaine 40% > Ropivacaine

Capogna G et Al. BJA 1998; Polley LS et Al. Anesthesiology 1998

Bupivacaine 2-13% > LevobupivacaineLyons G et Al. BJA 1998

Levobupivacaine > Ropivacaine?

Levobupivacaine ≥≥≥≥ Ropivacaine

Polley LS et Al. Anesthesiology 2003; Benhamou D et Al. Anesthesiology 2003

MLAC for Analgesia: Ropivacaine vs Levobupivacaine

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Number

Conce

ntration (%

)

Levobupivacaine

Ropivacaine Polley LS et Al. Anesthesiology 2003

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Number

Conce

ntration (%

)

Levobupivacaine

Ropivacaine

Benhamou D et Al. Anesthesiology 2003

Potency ratio: 0.98 (0.8-1.2)

Potency ratio: 0.84

Methodological confounding variables

– Cervical dilatation up to 7 cm Polley L et Al Anesthesiology 2005

Threefold increase in EC50 from 2 to 5 cm dilatation Capogna G et Al. BJA 1998

– Cervical dilatation assessed 30 min before the study

Possible progression of labor Polley L et Al. Anesthesiology 2005

– High % Rejects (second stage of labor before completion of the study)

Polley L et Al. Anesthesiology 2005

– Low VAPS at inclusion Benhamou D et Al. Anesthesiology 2005

– Mixed sample (Parity & Oxitocin?)

Controversial results with levobupivacaine

Bupi=Levo=Ropi ?Bupi>Levo>Ropi ?

• Traditional comparisons: high/equal concentrationbupi=levo=ropiBurke D et Al. Br J Anaesth 1999; Gaiser RR et Al. J Clin Anesth 1997; Writer et Al. Br J Anaesth 1998

• Comparisons at equipotent concentrations bupi ≥ levo> ropi Fernandez-Guisasola J et Al. Anesth Analg 2001; Camorcia M et Al. Eur J Anaesth 2003; Sah N et Al. J Clin Anesth 2007

• MLAC potency ratio studies: bupi ≥ levo>ropi

Analgesic Concentration - Response Curve

Potency

% E

ffect

Concentration

Comparisonsat highconcentrations

MLAC comparison

Relative Potencies of Epidural Pipecoloxylidines

Relative potencies (95%CI)Analgesia

0.98 (0.67- 1.41)

0.87 (0.60-1.25)

Bupivacaine: Levobupivacaine

0.60 (0.47- 0.75)Bupivacaine: Ropivacaine

Polley L et Al. Anesthesiology 1998; Lyons G et Al. Br J Anaesth 1998; Lacassie HJ Anesth Analg 2002; Lacassie HJ Anesth Analg 2003

Relative potencies (95%CI)Motor Block

0.87 (0.77- 0.98) Bupivacaine: Levobupivacaine


Epidural Sensory - Motor Separation

EC50 for Analgesia EC50 for Motor Block

Polley LS et Al Anesthesiology 1998 and Lacassie HJ et Al. Anesth Analg 2002 & Anesth Analg 2003

0.0625 0.125 0.25 0.5

Log2 concentration (%)

Ropivacaine

Levobupivacaine

Bupivacaine

IT Analgesic potency ratio

0.76 (0.50- 0.96)Levobupivacaine: Ropivacaine


0.81 (0.69-0.94)Bupivacaine: Levobupivacaine

Relative potencies (95%CI)


Camorcia M et Al. Anesthesiology 2005

Sia AT et Al. Anesthesiology 2005

IT motor block potency ratio

0.71 (0.51-0.98)Bupivacaine: Levobupivacaine

Relative potencies (95%CI)


0.59 (0.42-0.82)Bupivacaine: Ropivacaine

Camorcia M et Al. Anesth Analg 2007

Spinal Sensory - Motor Separation

ED50 for Analgesia ED50 for Motor Block

Camorcia M et Al Anesthesiology 2005 and Camorcia M et Al. Anesth Analg 2007

Log2 Dose (mg)

1 2 4 8

Ropivacaine

Levobupivacaine

Bupivacaine

Epidural / Spinal Separation ratios

0 1 2 3

Ropivacaine

Levobupivacaine

Bupivacaine

1 2 4 8

Motor Block: Analgesia Ratio

Capogna G et Al. Br J Anaesth 1998; Lyons G et Al. Br J Anaesth 1998; Polley L et Al Anesthesiology 1999; Camorcia M et Al Anesthesiology 2005; Camorcia M et Al. Anesth Analg 2007; Lacassie HJ et Al. Anesth Analg2002 & Anesth Analg 2003


• Analgesia

• Motor block


•• ED50 and relative ED50 and relative potenciespotencies of of opioids opioids

•• SparingSparing effecteffect



• Dystocia


Sparing effect

• Previous studies: No differences in analgesic efficacy with the

addition of epidural fentanyl to bupivacaine Youngstrom P et Al Anesthesiology 1984; Scriutton M et Al. IJOA 1998; Asik I et Al. EJA 2002

• Fentanyl and Sufentanil: up to 91% reduction in the EC50 for

epidural & intrathecal local anesthetics Polley LS et Al. Anesth Analg 1996; Lyons

G et Al. BJA 1997; Polley LS et Al. Anesthesiology 1998; Palm S et Al. Anaesthesia 2001; Stocks G

et Al. Anesth Analg 2001; Robinson AP et Al. Anesth Analg 2001, Van De Velde M et Al. IJOA 2007

• Epinephrine, Clonidine, Neostigmine: statistical but not clinical

sparing effect Kenneth NE et Al. Anesthesiology 1999; Aveline C et Al. Anesth Analg 2002;

Polley LS et Al. Anesthesiology 2002

Sparing effect of opioids

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control 1 mcg/mL 2 mcg/mL 3 mcg/mL 4 mcg/mL

Bupivaca

ine

%

Lyons et Al. BJA, 1997

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control 0.5 mcg/mL 1 mcg/mL 1.5 mcg/mL

Bupivaca

ine

%

Polley et Al. Anesthesiology 1998

Fentanyl

Sufentanil

EC50

8 16 32 64 128 2560.00

0.25

0.50

0.75

1.00SufentanilFentanyl

Log2 dose (µg)

Cum

ula

tive

resp

onse

Relative analgesic potency ratioEpidural Opioids

Potency ratio: 5.9 (5.6-6.3)Capogna G et Al. Anesth Analg 2003


• Analgesia

• Motor block



• Sparing effect



• Dystocia


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bupiv

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ine c

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MLAC of Epidural Bupivacaine increases with progression of labor

0.048% (0.037 -0.058) early labor

Capogna G et Al. BJA 1998

0.14% (0.132- 0.150) late labor

LA LA requirementsrequirements increaseincrease in in earlyearly laborlabor in in womenwomen withwith dystocicdystocic laborslabors

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0,12

Vaginal delivery CS for dystocia

Panni MK & Segal S. Anesthesiology 2003

Bupivacaine EC50

Capogna G et Al. Anesthesiology 2002

Prostaglandin induction of labor

increases analgesic requirements

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patient number

SpontaneousInduced

27.3 µg (23.8-30.9)

21.2 µg (19.6-22.8)

Epidural sufentanildose (µg)

Future perspectives

Anesthetic potency and

• Intrathecal Dose & Concentration

• Gender & Pregnancy

• Genetic Factors

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patient number

Ropivacaine 0.1%

Ropivacaine 1%

Dose

(m

g)

Less concentrated intrathecal solutions cause less motor block

9.1 mg (5.1-7.1)

6.1 mg (7.8-10.3)

Camorcia M et Al. Anesth Analg 2004 Motor block efficacy ratio: 1.5 (1.2-1.9)

0

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9

10

male female pregnant

ITBupivaca

ine

dose

Pregnancy and Gender may affect local anesthetic potency

Camorcia M et Al. IJOA 2007

Potency Ratio:Male-Female 1.45 (1.13-1.86)

Female-Pregnant 1.52 (1.18-1.95)

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patient number

A118 A118G, G118

ITFenta

nyl

dose

(µg

)

µ-opioid receptor polymorphism and interindividual opioid requirements

26.8 µg (22.7-30.9)

17.7 µg (13.4-21.9)

Landau R et Al. Anesthesiology 2005

• Comparison between local anesthetics at

equipotent concentrations/doses

• Contribution of opioids to analgesic mixtures

• Pharmacological rationale for labor analgesia

• Tool for assessing the effects of interindividual

and labor variables on LA requirements and

potency

Conclusions

Thank You!

Documents

The minimum local analgesic concentration for labor analgesia · • EC50 - ED50 and relative potencies of local anesthetics • Analgesia • Motor block • Sensory – motor separation