MULTIMODAL ANALGESIA

Presenter- Dr. Suresh PradhanModerator- Prof. UC Sharma

Pain

• Latin – Poena – Pain

• International Association for the Study of Pain IASP – ‘An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage’

• more than 80% of patients who undergo surgical procedures experience acute postoperative pain

• and approximately 75% of those with postoperative pain report the severity as moderate, severe, or extreme

Classification of Pain

PAIN

SOMATIC

SUPERFICIAL( skin &

subcutaneous tissues )

e.g. : cuts, burns

DEEP(muscle, bone, periosteum,

fascia )e.g. : fractures, arthritis,

muscle belly rupture

VISCERALe.g. : angina

pectoris, renal colic, intestinal

colic

Physiological Effects of Pain

• cardiovascular system– increases heart rate, blood pressure and peripheral

vascular resistance– MI, dysrhythmias

• gastrointestinal system– impaired gastrointestinal function-delayed gastric

emptying & reduced bowel motility, anastomotic failure• respiratory system

– respiratory dysfunction– atelectasis and pneumonia

• genitourinary system– increase the release of hormones and enzymes

• musculoskeletal system– reflex muscle spasm– venous stasis increased blood coagulability

• immune system– depression of the immune system

• hypercoagulable state: DVT, PE

• psychological and cognitive effects– anxiety and depression, fatigue

• nausea and vomiting

• chronic pain

Methods to Treat Pain• Pharmacologic

– Medications (po, iv, im, sc, pr, transdermal)• Acetaminophen• NSAIDs• Opioids• Gabapentinoids• NMDA antagonists• Alpha-2 agonists

– Procedures• Regional Anesthesia• LA infiltration at incision site

• Surgical Intervention• Non-Pharmacologic / Non-Surgical

WHO analgesic ladder for treating pain

New Adaptation of the analgesic ladder

• the cornerstone of the WHO document rests on 5 simple recommendations for the correct use of analgesics to make the prescribed treatments effective

• this advice is applicable today, not only for cancer patients with pain, but also for all patients with either acute or chronic pain who require analgesics

• The 5 points for the correct use of analgesics are as follows:

1. Oral administration of analgesics–oral form of medication should be privileged whenever possible

2. Analgesics should be given at regular intervals– to relieve pain adequately, it is necessary to respect the

duration of the medication’s efficacy and to prescribe the dosage to be taken at definite intervals in accordance with the patient’s level of pain

– the dosage of medication should be adjusted until the patient is comfortable

3. Analgesics should be prescribed according to pain intensity as evaluated by a scale of intensity of pain– pain-relief medications should be prescribed after

clinical examination and adequate assessment– prescription must be given according to the level of

the patient’s pain and not according to the medical staff’s perception of the pain

– if the patient says that s/he has pain, it is important to believe her/him

4.Dosing of pain medication should be adapted to the individual

– there is no standardized dosage in the treatment of pain–every patient will respond differently– the correct dosage is one that will allow adequate relief

of pain– the posology should be adapted to achieve the best

balance between the analgesic effect and the side effects

5. Analgesics should be prescribed with a constant concern for detail

–the regularity of analgesic administration is crucial for the adequate treatment of pain

–once the distribution of medication over a day is established, it is ideal to provide a written personal program to the patient

–in this way the patient, his family, and medical staff will all have the necessary information about when and how to administer the medications

Combining drugs may have 3 types of effects

1. Synergetic ............. 2+2>4

2. Additive ................ 2+2=4

3. Subadditive ........... 2+2=3

Multimodal Analgesia

• is a pharmacologic method of pain management which combines various groups of medications for pain relief

• is achieved by combining different analgesics that act by different mechanisms and at different sites in the nervous system, resulting in additive or synergistic analgesia with lowered adverse effects of sole administration of individual analgesics

• the most commonly combined medication groups include NSAIDs acetaminophen opioids gabapentinoids alpha-2 agonists NMDA antagonist local anesthetics

• these regimens must be tailored to individual patients, keeping in mind – the procedure being performed– side effects of individual medications– patients’ pre-existing medical conditions

• multimodal analgesia is beneficial as:– different drugs with different mechanisms/sites

of action along pain pathway are used– each can be used in a lower dose than if used

alone– provides additive or synergistic effects– provides better analgesia with less side effects

(mainly opiate related)

Why we need multimodal analgesia for post-operative pain?

no single analgesic is perfect and nosingle analgesic can treat all types of pain

Multimodal Analgesia-potentiating in efficacy, reduced doses, minimal adverse

effect. Overall- improve the outcome

most of the pain is a multifaceted and multiple-sources

Local anesthetics

NSAIDsCOXIBs

Local Anesthetic

CNS

DRG

OpioidsGabapentinoids

Clonidine

KetaminParacetamol

COXIBs

Transduction

TransductionModulation

Perception

TransmissionModulation

Target Points of Analgesic Drugs

REGIMENSThere are many regiments for multimodal analgesia, but

the most popular are:

Opioid Local AnestheticParacetamol

NSAIDs and Coxibs

NMDA Antagonist (Ketamin)

-2 antagonist (Clonidine)

2 (subunit of Ca Channel)

agonist (Gabapentinoid)

Paracetamol Acetaminophen

Para-aminophenol

Analgesic Effects Antipyretic Effect

Route of Administration- Orally- Intravenously- Rectally

No Anti-Histamine Effects

Central Antinociceptive EffectMechanism Of Action

Central COX (Cyclooxygenase) Inhibition1

Activation of the endocannabinoid system and serotonergic pathways2

prevent prostaglandin production at the cellular level

3

Paracetamol is very safe drug as long as it is given within recommended doses

(Adult < 4 gm/day, Infant and children 20-40 mg/kgBW)

1. All Age – from Infant to Elderly

2. From pregnant to Lactating Woman

3. Can be used for patients with renal and

hepatic impairment

Paracetamol

PARACETAMOL , NSAIDS & COXIBS Guidelines line for postoperative pain management state that:

“Unless contraindicated, all patients should receive an around-the clock(ATC) regimen

on NSAIDs, COXIBs, or Paracetamol”

American Society of Anesthesiologists Task Force on Acute Pain Management 2004;100:1573-1581

Hyllested M, Jones S, Pedersen JL et al (2002) Comparative effect of paracetamol, NSAIDs or their combination in postoperative pain management: a qualitative review. Br J Anaesth 88(2): 199–214.

Paracetamol can be the best alternative to NSAIDs especially for high risk patients

It is appropriate to administer acetaminophen with NSAID, or COXIBs additive or synergistic effects

Intravenous form of paracetamol has more predictable onset and duration of actions

Qualitative Review of Paracetamol and NSAIDs

1. Sindet-Pedersen S.1997. Data on file.

* I.V. paracetamol was administered as a bio-equivalent dose of propacetamol.

Fast onset of action *1

Sindet-Pedersen S, 1997

Rapid onset: 5minPeak at ideal time: 30min

IV paracetamol for dental

Good residual effect at >6hrs

Paracetamol has Opioid Sparing Effects

I.V. paracetamol in these studies was administered as a bio-

equivalent dose of propacetamol.

Quantitative Systemic Review 2010Paracetamol and NSAIDs (cox1 and cox2)

Combination of paracetamol and an NSAIDs may offer superior analgesia compared with either drug alone

(Anesth Analg 2010)

Combination of paracetamol and parecoxib may useful in

patients who are susceptible to haemorrhagic

complications of NSAIDs

Parecoxib and Acetominophen

A combination of 1000 mg paracetamol and 30mg codeine was

significantly more effective in controlling pain for 12 hours following

third molar removal, with no significant difference of side effects

during the 12 hour period studied

Paracetamol vs Paracetamol + CodeineIn post-operative dental pain

Tramadol/paracetamol combination tablets provided analgesic efficacy with

a better safety profile to tramadol capsules in patients postoperative pain

following ambulatory hand surgery.

Paracetamol + Tramadol

META-ANALYSIS

META-ANALYSISAdvantages of Multimodal Analgesia

Elia N, Lysakowski C & Tramer MR (2005) Does multimodal analgesia with acetaminophen, nonsteroidal antiinflammatory drugs, or selective cyclooxygenase-2 inhibitors and patient-controlled analgesia morphine offer advantages over morphine alone? Meta-analyses of randomized trials. Anesthesiology 103(6): 1296–304.

Acetaminophen, NSAIDs, or

COXIBs

Added ToPCA Morphine

All of analgesic agent provided an opioid-sparing effect

However, the decrease in morphine use did not consistently result in a decrease in opioid-releted adverse effects

NSAIDs + Morphine was associated with a decrease in the incidence of PONV and sedation

SYSTEMIC REVIEWNSAIDs vs COXIBs For Postoperative Pain

Romsing J & Moiniche S (2004) A systematic review of COX-2 inhibitors compared with traditional NSAIDs, or different COX-2 inhibitors for post-operative pain. Acta Anaesthesiol Scand 48(5): 525–46.

Demonstrate Equipotent Analgesic Efficacy After Minor and Major Surgical Procedure

NSAIDs COXIBs

COXIBs Better Alternative TO NSAIDs in the perioperative

setting

COXIBs associated with:

Reduce gastrointestinal side effects

Absence of anti-platelet activity

Limitation of Traditional NSAIDS:(Aspirin/NSAID) sensitive asthma

The COX-2 selective inhibitors celecoxib1,2 and rofecoxib3,4 given orally do not cause bronchospasm in patients with

aspirin/conventional NSAID-sensitive asthma

1. Gyllfors et al. Allergy Clin Immunol 2003;111:1116;2. Martin-Garcia et al. J Investig Allergol Clin Immunol 2003;13:20;

3. Stevenson et al. J Allergy Clin Immunol 2001;108:47; 4. Martin-Garcia et al. Chest 2002;121:1812

KETAMINEAnesthesia Dose more than 2 mg/kg (iv) anesthesia + produce side effects such us Psychomimetic effect

• Excessive sedation• Cognitive Dysfunction• Hallucination• Nightmares

Subanesthesic Dose (Low Dose) < 1 mg/kg demonstrated significant analgesic efficacy without these

side effectsVery Low dose (0.15 mg/kg) single intraoperative

injection of ketamine 0.15 mg/kg improve analgesia and passive knee mobilization 24 hour after arthroscopy

KetamineMore Frequently Use in Postorthopedic Surgical Pain Management

Arthroscopic Anterior Cruciate Ligament

Surgery

Outpatient Knee Arthroplasty

Total Knee Arthroplasty

A Single intraoperative injection of ketamin (0,15 mg/kg) improved analgesia and passive

knee mobilization 24 hour after surgery

Improved Postoperative Outcome

When combine with epidural or femoral nerve block, increase postoperative pain relief

for total knee arthroplasty.

• Menigaux C, Guignard B, Fletcher D, Dupont X, Guirimand F, Chauvin M. Anesth Analg. 2000;90:129–135.• Menigaux C, Guignard B, Fletcher D, Sessler DI, Dupont X, Chauvin M. Anesth Analg. 2001;93:606–612.

• Himmelseher S, Ziegler-Pithamitsis D, Agiriadou H, Martin Jjelen-Esselborn S, Koch E. Anesth Analg. 2001;92: 1290–1295.• Adam F, Chauvin M, Du Manoir B, Langlois M, Sessler DI, Fletcher D. Anesth Analg. 2005;100:475–480.

KETAMINE

• Low-dose ketamine is not really an ‘analgesic’, but better described as:

‘anti-hyperalgesic’

‘anti-allodynic’

‘tolerance-protective’ of opioid

Opioid-induced Hyperalgesia

GABAPENTINOIDS

GABAPENTINOIDSGabapentin and Pregabalin

Eckhardt K, Ammon S, Hofmann U, Riebe A, Gugeler N, Mikus G. Anesth Analg. 2000;91:185–191.Hurley RW, Chatterjea D, Rose Feng M, Taylor CP, Hammond DL.. Anesthesiology. 2002; 97:1263–1273.

Gilron I, Orr E, Tu D, O’Neill JP, Zamora JE, Bell AC. Pain. 2005;113:191–200.Reuben SS,Buvanendran A,Kroin JS, Raghunathan. Anesth Analg. 2006;103:1271–1277.

Enhanced Analgesic effects of:Gabapentin Morphine NSAIDs

COXIBs

Gabapentin and Pregabalin

Provide anti-hyperalgesia

can synergically with NSAID

PregabalinSuperior to either single drugs for postoperative

pain following spinal fusion surgery

and Celecoxib

Sedation can be interpreted as a negative outcome of gabapentin, however its can be benefical in the perioperative setting as an

anxiolysis

Paracetamol and Gabapentin

Paracetamol +

Gabapentin

Analgesic+

Antihyperalgesic

postoperative pain scores &

Rescue Analgesics

BUTmore episodes of nausea and vomiting and higher levels of sedation

MULTIMODAL ANALGESIA….contd

World Federation of Societies of Anesthesiologists (WFSA)

Analgesic Ladder• has been developed to treat acute pain• initially, the pain can be expected to be severe

and may need controlling with strong analgesics in combination with local anesthetic blocks and peripherally acting drugs

• the oral route for the administration of drugsmay be denied because of the nature of the surgery and drugs may have to be given by injection

• normally, postoperative pain should decrease with time and the need for drugs to be given by injection should cease

• the second rung on the postoperative pain ladder is the restoration of the use of the oral route to deliver analgesia

• strong opioids may no longer be required and adequate analgesia can be obtained by using combinations of peripherally acting agents and weak opioids

• the final step is when the pain can be controlled by peripherally acting agents alone

WFSA Analgesic Ladder

ClonidineAlpha-2 Agonist

De Kock MF, Pichon G & Scholtes JL (1992) Intraoperative clonidine enhances postoperative morphine patient-controlled analgesia. Can J Anaesth 39(6): 537–44.Jeffs SA, Hall JE & Morris S (2002) Comparison of morphine alone with morphine plus clonidine for postoperative patient-controlled analgesia. Br J Anaesth 89(3): 424–

7.Marinangeli F, Ciccozzi A, Donatelli F et al (2002) Clonidine for treatment of postoperative pain: a dose-finding study. Eur J Pain 6(1): 35–42

Potentiation

Clonidine (intravenous)

Opioid (iv or PCA)

REDUCED DOSES• Opioid postoperative requirements

IMPROVED EFFECACY• Improved Postoperative Analgesia

REDUCE SIDE EFFECTS• Nausea and Vomiting

Cautions !!!• Sedation and Hypotension dose-

dependent

Clonidine

Intrathecal (SAB)

De Kock MF, Pichon G & Scholtes JL (1992) Intraoperative clonidine enhances postoperative morphine patient-controlled analgesia. Can J Anaesth 39(6): 537–44.Jeffs SA, Hall JE & Morris S (2002) Comparison of morphine alone with morphine plus clonidine for postoperative patient-controlled analgesia. Br J Anaesth 89(3): 424–

7.Marinangeli F, Ciccozzi A, Donatelli F et al (2002) Clonidine for treatment of postoperative pain: a dose-finding study. Eur J Pain 6(1): 35–42

AdvantagesClonidine 15-150 mcg + Local anesthetic

Prolonged time of regression Prolonged time to analgesic request Increased speed of onset and duration Improved early analgesia Prolonged analgesia

• systemic perioperatve administraton (oral, IM, IV) of the alpha-2 agonists clonidine and dexmedetomidine decreases– postoperatve pain intensity– opioid consumption– nausea

• without prolonging recovery times (Blaudszun 2012 , 30 RCTs, n=1,792)

• common adverse effects include arterial hypotension and bradycardia

• effects on development of chronic pain or hyperalgesia remain unclear due to lack of data

Peripheral Nerve Block (PNB)

Continuous PNB

Chelly JE, Ben-David B,Williams BA,KentorML.. Orthopedics. 2003;26:S865–S871.Capdevilla X, Barthelet Y, Biboulet P, Ryckwaert Y, Rubenovitch J, d’Athis F.. Anesthesiology. 1999;91:8–15.

Richman JM, Liu SS, Courpas G, et al.. Anesth Analg. 2006;102:248–257.

Advantages• superior pain relief with movement• reduce surgical stress• improved rehabilitation• reduced opioid consumption• reduced opioid-related side effects

Disadvantages • require technical skill• infrastructure to manage catheter,

especially outpatient

Peripheral Nerve Block (PNB)

Adams HA, Saatweber P, Schmitz CS, Hecker H. Postoperative pain management in orthopedic patients: no differences in pain score, but improved stress control by epidural anaesthesia. Eur J Anaesthesiol. 2002;19:658–665.

De Leon-Casasola OA. When it comes to outcome, we need to define what a perioperative epidural technique is. Anesth Analg. 2003;96:315–318.

Advantages: Significant pain relief Reduced Neuroendocrine Response Superior to either PNB or PCA in blunting surgical

response ↓ Incidence of pulmonary complications, myocardial

infarction, DVT and Pulmonary Embolism

Epidural Blockade

Reuben SS, Buvanendran A, Kroin JS, et al. Postoperative modulation of central nervous system prostaglandins E2 by cyclooxygenase inhibitors after vascular surgery. Anesthesiology. 2006;104:411–416.

Samad TA, Sapirstein A,Woolf CJ. Prostanoids and pain: unraveling mechanisms and revealing therapeutic targets. Trends Mol Med. 2002;8:390–396.

Limitation

Has no effects on humoral cytokine

proinflammatory response (it may be

blocked only by COXIBs).

Epidural BlockadeEpidural can only block pain tranmissions but not humoral response

EPIDURAL BLOCK

Epidural BlockLocal Anesthetic

NeuroendocrineStress Response

ACTHADHGHTSH

Central COX-2

inhibition

CytokinesIL-1βIL-2IL-6TNF

NorepinephrineEpinephrineCortisolAldosteroneRenin

Sympathetic efferent

Humoral stress response

From this theory

• we can conclude that epidural with LA alone, may not able to prevent/block release cytokines due to tissue injury

• so combine Epidural with Coxibs may produce excellent analgesia

• it can be the future analgesia

Multimodal AnalgesiaUsing 5 Type of Analgesic Drugs

(a preliminary study)

1. Gabapentin 1200 mg

2. Dexamethasone 8 mg 3. Ketamine 0.15 mg/kgBW

4. Paracetamol 1000 mg

5. Ketorolac 15 mg

1. Paracetamol 1000 mg

2. Ketorolac 15 mg

3. Placebo

superior in pain control than

Group I Group II

OPI

OID

NSA

ID

COXI

B

Tram

adol

Keta

min

e

Gaba

pent

anoi

d(G

abap

entin

, Pre

gaba

lin)

PARACETAMOL

Local Anesthetic (Epidural Block, Nerve Block)

Clon

idin

e

Multimodal

Analgesia Improved Analgesia

Lowered Dose Reduced Side Effects

• Early Mobilization• Early Enteral Feeding• Rapid Recovery • low cost

Aggressive pain management with multimodal analgesia, including epidural or nerve block not only produce optimal analgesia but also may prevent the occurrence of chronic pain after surgery

Conclusion

Crile 1913

“Patients Given Inhalation anesthesia still need to be protected by regional anesthesia, otherwise they might suffer persistent central nervous systems changes and enhanced postoperative pain ”

Stated That: This is not new

THANK YOU!!!