Non-Opioid Drugs

A.M.TAKDIR MUSBA

DEPARTMENT OF ANESTHESIOLOGY, INTENSIVE CARE AND PAIN MANAGEMENT

FACULTY OF MEDICINE, HASANUDDIN UNIVERSITY
• Paracetamol
• NsNSAIDS
• Selective COX-2 Inhibitor
• Neuropathic Drug
 Good Drug in the Right Doctor
• PHARMACODYNAMIC
 MECHANISM OF ACTION
• PHARMACOKINETIC
 METABOLISM AND ELIMINATION
 PARACETAMOL HISTORY
• 1878, synthesized by Morse
• 1893, introduced for medical usage
• 1955, reintroduced as an analgesic in US
 Most popular and widely used drug for the first line
treatment of fever and pain
• 1985, intravenous a pro-drug preparation,
propacetamol
• Recent introduction to the market of a ready-to-use
intravenous formulation
 Mechanism of Action :
Still under discussion
• Act peripherally and/or centrally ?
• Which analgesic pathway mainly affected ?

But, Efficacy has no doubt

Paracetamol is an effective analgesic for acute pain;

the incidence of adverse effects comparable to
placebo (S) (Level I [Cochrane Review]).
Acute Pain Management: Scientific Evidence, 3 rd edition, ANZCA, 2010
 Potential mechanisms of action

• Inhibition of COX isoenzymes

• Interaction with endogenous opioid pathway
• Activation of serotoninergic bulbospinal
pathway
• Involvement NO pathway
• Increase in cannabinoid/vanilloid tone
Two activities of COX- enzyme
 Inhibition COX isoenzym
• Reducing agent is required to convert COX
enzym from active to inactive
– Paracetamol, a substituted phenol, act as a
reducing agent
• Weak inhibitor of PG synthesis in broken cells
( hydroperoxides is high )
• Peroxide-dependent COX inhibiton
– PCT is not active at peripheral site of inflammation
(high peroxide concentration ),but
– active in the brain (low peroxide concentration)
 Hypothetical mechanism of paracetamol-
mediated inhibition prostaglandin synthesis
PGG2 PGH2
PGG2 *

Fe3+ Fe4+= OPP *

Tyr * 385
Electron
tranfer Tyr * 385 PGG2 *
Peroxidase active
site
APAP Cyclooxygenase
APAP * active site
APAP Fe4+= O
APAP *
Arachidonic acid AA *
2o2 *
Phospholipid

Chandrasekharan NV, Simmons Dl., Genome Biology 2004, 5:241

 Peripheral vs Central effect
• Selective inhibition of COX in CNS support
hypothesis PCT does not possess anti-
inflammatory efficacy similar to NSAIDs
• Not associated with gastric side effect and
inhibition platelet activity
• COX-3 , unlikely to be the elusive target of PCT
in human tissues
 Interaction with endogenous opioid pathway,
serotoninergic and NOS system

 Self-synergistic interaction between spinal

dan supraspinal
 Activation of descending opioid pathways
 Centrally acting component of paracetamol
involves serotoninergic inhibitory descending
pathway
 Inhibitory nitric oxyde synthase ( NOS ) via
inhibited substance P-mediated hyperalgesia
 Safety and toxicity profile
• Safer than NSAIDs
• Small minority  life threatening liver injury
• Toxic metabolite N-acetyl-pbenzoquinine imine
(NAFQI)
• Paracetamol overdoses significant cause
toxicity
– Suicide attempts
– Unintentional overdoses
 Plasma concentration
• Minimum plasma concentration for analgesia
and anti-pyresis 10-20 mg/L
• Potential hepatotoxicity 150 mg/L
• Median dose that will developed acute liver
failure is 24 grams
Intravenous 15 mg/kg  7 mg/L and detectable in CSS
at 5 minutes
Intravenous 1 gr  14.4 mg/L in 20 minutes
Oral 1 gr  large and unpredictable variability
( subtherapeutic plasma conc. in 80 min )
The Metabolism of Acetaminophen
and NAPQI production

N Engl J Med. 2008 July 17; 359(3): 285–292.

Risk factor PCT-induced hepatotoxicity

• Excessive dosing
• Increased P-450 activation
• Decreased gluthatione availability
• Chronic severe ethanol abuse
 Effect in coagulation function
• Weak inhibitor of platelet COX-1 with a dose
dependent anti-aggregatory effect
• Platelet aggregation is more impaired by diclofenac
than PCT
• Antiaggregatory effect does not seems to be clinical
relevant and no surgical bleeding attributable to PCT
• Significant increased in INR and reduction Vit-K
dependant clotting factors in patients receiving
stable treatment warfarin who received PCT 4 gr/day
for 14 days
 Several studies about safety use of
•
PCT
No evidence in the literature of an increased risk of hepatotoxicity in
chronic liver disease with the recommended doses
• Benson GD, et al, Am J Ther 2005;12:133-41
• Alcoholic patients treatment with 4 gr/day for
three consecutive days did not develop increase in
serum transminase or other measures of liver
injury
• Kuffner EK. Et al, BMC Med 2007;53:13
• Only minor effect in on renal function, does not
affect COX-1 enzym
• Koppert W. et al, Anesth Analg 2006; 103:1170-6
Pain relief after IV and Orally

Moller, S. Sindet P. British Journal of Anaesthesia 2005 ; 94 (5): 642–8

 Intravenous Paracetamol
• Faster onset analgesia
• Predictable plasma concentration achieved
• Route of choice when oral administration no
possible
• IV paracetamol was an effective analgesic after
surgery ( Level II, Acute Pain Management: Scientific Evidence, 3 edition, ANZCA, 2010 )
rd
 NsNSAID
 Exhibit a spectrum of analgesic, anti-inflammatory,antiplatelet
and antipyretic by inhibition COX enzyme
 Most commonly prescribed analgesic medications in the
world. i.e. Metamizole, Ketorolac, Diclofenac, Ketoprofen
 Many used as the sole method of treatment mild to moderate
pain
 “Opioid sparing effect“ (20–40 %)
 NsNSAIDs classification
• Low potency, fast elimination
– Aspirin
– Ibuprofen
– Mefenamic acid
• High potency, fast elimination
– Ketoprofen
– Diclofenac sodium
• Intermediate potency, Intermediate elimination
– Naproxen
• High potency, slow elimination
– Piroxicam
– Meloxicam
Non-Specific NSAID efficacy evidence
• Single doses of nsNSAIDs are effective in the
treatment of pain after surgery
( Derry et al 2009 Level I)
• NsNSAIDs are inadequate as the sole analgesic
agent in the treatment of severe
postoperative pain. (Elia et al, 2005 Level I )
• Adverse effects of NSAIDs are significant and
may limit their use
Adverse effect due to
Non-selective COX-1 and COX-2 inhibitor

ARACHIDONATE

COX-1 COX-2

prostaglandins prostaglandins

• “Constitutive” • “Inducible”
• Expressed: • Expressed:
– GI mucosa – Site of injury
– Kidneys – CNS
– Platelets
– Vascular
endothelium
 NSAIDs and Renal Function
• With proper selection and monitoring, the
incidence of NSAID-induced perioperative renal
impairment is low and NSAIDs need not be
withheld in patients with normal preoperative
renal function (Lee A et al, 2007 Level I).
• No differences between patients given diclofenac,
ketorolac, indomethacin (indometacin) or
ketoprofen (Lee A et al, 2007 Level I).
• NSAIDs and Coxib have similar adverse effect on
renal function ( Level I )
 NSAIDs and Bleeding
• In meta-analyses of tonsillectomy in both adult and
paediatric patients, NsNSAIDs were found to increase
the risk of reoperation for bleeding (NNH 29 to 60)
(2003 Level I) but surgical blood loss was not
significantly increased (Moiniche et al, 2003 Level I)
• Looking at studies in children only, there was no
increase in the risk of reoperation for bleeding after
tonsillectomy (Cardwell et al, 2005 Level I).
• After a variety of different operations, the use of
NsNSAIDs showed a significant increase in risk of
severe bleeding from 0 to 1.7% compared with (Elia et
al, 2005 Level I).
 NSAIDs and GI Ulcer
• A large case-controlled study using a general practice
database identified 10 892 patients over4 years with a
‘first ever’ diagnosis of an upper GI ulcer or bleeding
and compared them with matched controls (Hippisley-
Cox et al, 2005 Level III-3).
Where individual drugs were specified in the results,
the risks were shown to be significantly increased for
patients using naproxen, diclofenac, ibuprofen and
aspirin.
• Concurrent use of a proton-pump inhibitor (PPI)
significantly reduced the incidence of NsNSAID-related
peptic ulcer disease (Targownik et al, 2008 Level III-2).
 Selective COX-2 inhibitor
• Larger molecul with side chain fitted the
hydrophilic side of COX-2 isoform but did not
fit COX-1 isoform
• COX-2 in peripheral and central nerve system
• As a part of multimodal analgesia
• Offer significant advantages over NsNSAIDS
with regard to several adverse effect ( not in
renal function )
 COXIB evidence
• Coxibs are effective in the treatment of acute
postoperative pain (N) (Level I [Cochrane
Review]).
• Coxibs were as effective as NsNSAIDs in the
management of postoperative pain (Romsing &
Moiniche, 2004 Level I).
• Preoperative coxibs reduced postoperative pain
and opioid consumption and increased patient
satisfaction (Straube et al, 2005 Level I)
 Efficacy Analgesic

Number needed to treat (NNT) for at least 50% pain relief over 4 to 6 hours
compared with placebo in third molar extraction trials.
British Dental Journal (Barden J, et al. Br Dent J. 2004;197:407-411).
PCT, NSAIDs, COXIBs

J Can Dent Assoc 2002; 68(8):476-82

 PATHOPHYSIOLOGY
• PERIPHERAL MECHANISMS

Peripheral nerve injury

1. Formations of neuroma
2. Formation of ectopic neuronal
pacemakers along nerve and increased
expression of sodium channels and
voltage gated calcium channels. (α-2
delta subunit )
3. Sprouting new nerve projections
among uninjured neighbouring
neurons
 PATHOPHYSIOLOGY
CENTRAL MECHANISMS
Sustained painful stimuli results in spinal
sensitization (neurons within dorsal
horn)

1. Increased spontaneous activity of dorsal

horn neurons, reduced activation
thresholds and enhanced
responsiveness to synaptic inputs.
2. Central sensitization mediated by NMDA
receptors that further release excitatory
amino acids and neuropeptides.
3. Activation microglia
4. Sympathetically maintained pain
 APPROACH TO NEUROPATHIC PAIN
MANAGEMENT
• Treatment must be individualized (benefits- mood, sleep, costs).

• Education regarding natural history of the condition and realistic

treatment expectations – 30% pain reduction is clinically
important.

• Although supportive evidence is limited, polypharmacy may be

helpful.

• If none effective or tolerated – referral to a pain clinic is

warranted.

• Prescribing considerations (drug interactions, overdose toxicity,

side effects, older people.)
ALGORITHM FOR NEUROPATHIC PAIN MANAGEMENT
PRIMARY CARE

Gilron, I. et al. CMAJ 2006;175:265-275

Prescription consideration