Pharmacology

of Non-Opioid
Analgesics
Moderator
Dr. Karthik
Dr. Mahesh
-By Dr. Chris Nishanth
PAIN
•“An unpleasant sensory and emotional experience
associated with actual or potential tissue damage,
or described in terms of such damage.”
•The pain is a complex neurobiological experience
with a physiologic and emotional component that
is influenced by multiple factors occurring at
multiple areas of the peripheral and central
nervous system.

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PAIN PATHWAY

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PAIN - Classification

(3-6 months)

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Need for Non-opioid Analgesics
• Common side effects of Opioids
• Sedation, dizziness, nausea, vomiting, constipation, physical
dependence, tolerance, and respiratory depression.
• Physical dependence and addiction.
• Less common side effects of Opioids
• Delayed gastric emptying, hyperalgesia, immunologic and
hormonal dysfunction, muscle rigidity, and myoclonus.
• The most common side effects of opioid usage are constipation
(which has a very high incidence) and nausea.
• Difficult to manage and frequently tolerance to them does not
develop. They may be severe enough to require opioid
discontinuation, and contribute to under-dosing and inadequate
analgesia.

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Need for Non-opioid Analgesics

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Non-opioid Analgesics
•Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
•Anticonvulsants
•Antidepressants
•α2-Adrenergic Agonists
•Local Anaesthetics
•Neuroleptics
•Corticosteroids
•Miscellaneous

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Centrally acting analgesics

Peripherally acting analgesics

Nonsteroidal Anti-inflammatory Drugs
(NSAIDs)

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Aspirin

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Aspirin
•INTRODUCTION
• Analgesic, anti-inflammatory and antipyretic effects of
salicylates, derived from the bark of the willow tree,
were described as early as 1763.
• Acetylsalicylic acid (aspirin) was first produced in 1853
• PHYSICAL PROPERTIES
• As 75/100/300/600 mg tablets of aspirin and in a
variety of fixed-dose combinations.
•CHEMICAL PROPERTIES
• An aromatic ester of acetic acid(acetylsalicylic acid).

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Aspirin
• MECH. OF ACTION
• Acetylates, and thereby inhibits, the enzyme Cyclo-oxygenase
(CoX) which converts arachidonic acid to cyclic endoperoxides,
thus preventing the formation of PG and TX.
• PGs are involved in the sensitization of peripheral pain
receptors to noxious stimuli.
• - lipo-oxygenase pathway by an action on hydroperoxyl fatty
acid peroxidase. The drug inhibits cyclooxygenase irreversibly
in platelets, but not in the endothelium.
• PK
• A- Rapidly and completely absorbed from the UGIT,
bioavailability - 70% (extensive first-pass metabolism).
• D- rapidly hydrolysed to salicylic acid. 80–90% protein-bound,
limited ability to cross the blood–brain barrier.
• M & E- in Liver, 50% to salicylurate, 20% to salicylphenolic
glucuronide. Half-life varies with the dose administered.
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Aspirin
•INDICATIONS
• mild to moderate pain and severe bone pain
• anti-inflammatory agent, e.g. in rheumatoid arthritis
and osteoarthritis
• antipyretic
• prevention of recurrence after myocardial infarction
• prevention of graft occlusion after coronary artery
surgery in the treatment of pre-eclampsia
• prevention of transient ischaemic attacks, and deep
vein thrombosis (DVT) prophylaxis post-fractured neck
of femur
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Aspirin
•CONTRAINDICATIONS
• The use of aspirin is associated with the development
of Reye’s syndrome in children.
• Aspirin-induced asthma may affect up to 20% of
persons with asthma. Patients with coexisting chronic
rhinitis and nasal polyps appear to be at most risk. A
history of aspirin-induced asthma is a contraindication
to NSAID use after surgery.
•DOSAGE & DOA
• The adult oral dose is 300–900 mg, 6 to 8th hourly;
aspirin is not recommended for use in children under
12 years of age.

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Paracetamol

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Paracetamol
•INTRODUCTION
• PCT (acetaminophen) - first used in 1893 & the only
remaining p-aminophenol available in clinical practice.
• Active metabolite of the earlier, more toxic drugs
acetanilide and phenacetin.
• Effective analgesic and antipyretic but has negligible
anti-inflammatory activity. In recommended doses, it is
safe and has remarkably few adverse effects.

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Paracetamol
•PHYSICAL PROPERTIES
• tablets and suppositories containing 60/125/250/500
mg
• syrup containing 24/50 mg/ml
• fixed-dose combinations
• intravenous preparation for infusion containing 10
mg/ml of paracetamol in 50 ml and 100 ml vials – s/b
infused over 15 minute period.

•CHEMICAL PROPERTIES
• Acetanilide derivative

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Paracetamol
• MECH. OF ACTION
Acts on prostaglandin synthesis inhibition, and
serotonergic and cannabinoid pathways
• - COX isoenzymes particularly in areas of low
inflammation
• - PG synthesis in CNS(anterior hypothalamus) →
Antipyretic effect
• Nociception
• CENTRAL Action :↑ inhibitory serotonergic pain pathways & ↓
uptake of anandamide, an endocannabinoid, involved in
nociception
• PERI. Action : blocking impulse generation within the bradykinin-
sensitive chemoreceptors responsible for the generation of
afferent nociceptive impulses.

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Paracetamol
•PK
• A- UGIT: rapid absorption, BA - 63–89% due to first-
pass metabolism
Rectal: variable absorption, BA - 24–98%
• D- 0-5% protein-bound, non-ionized, lipid-soluble:
penetrates tissues and the blood–brain barrier well.
Crosses placenta.
• M- Liver: 80-90% to glucuronide and sulfate
10% by cytP450 (CYP2E1) to a highly reactive
intermediate metabolite
(N-acetyl-p-benzo-quinoneimine (NAPQI)
which, in turn, is inactivated by conjugation
with glutathione.
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Paracetamol
•CONTRAINDICATIONS
• Used with caution in Renal or Hepatic impairment
• May ↑INR in patients on Warfarin therapy
•Special Points
• Acute paracetamol poisoning
Occurs especially in small children who have low
hepatic glucuronide conjugating ability. If a large
dose (> 150 mg/kg or > 10 g in an adult) is taken,
serious toxicity can occur. Fatality is common with
>250 mg/kg.

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Paracetamol
• Acute paracetamol poisoning

Highly reactive
intermediate
Hepatic damage Supply of
metabolite
occurs readily with glutathione Centrilobular
(NAPQI)
doses exceeding becomes necrosis
combines with
15g of the drug depleted
hepatic cell
membranes

N-acetylcysteine (NAC) and methionine act as

alternative supplies of glutathione and can protect
against paracetamol-induced liver damage if
administered within 10–12 hours of ingestion.

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Paracetamol
• ADVANTAGES
• The maximum analgesic effect of paracetamol appears to be
greater than that of any other non-opioid analgesic.
• DOSAGE & DOA
• The dose for adolescents and adults weighing >50 kg is
500mg to 1gm 4 to 6 hourly (maximum daily dose 4g) for
the oral, rectal, and intravenous routes.
• Analgesic doses in children range from 60 to 90mg/kg/day
in divided doses, depending on the age and route of
administration.
• Analgesic doses in neonates range from 30 to 60mg/kg/day
in divided doses, depending on the post-conceptual age and
route of administration. A loading dose may be given.

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NSAIDs

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NSAIDs
•INTRODUCTION
• NSAIDs are the popular choice of non-opioid analgesia.
Perioperative analgesia using NSAIDs is free from many
of the adverse effects of opioids, such as respiratory
depression, sedation, nausea and vomiting and GI
stasis.
•MECH. OF ACTION
• All NSAIDs have the same basic mechanism of action –
inhibition of cyclo-oxygenase (COX) enzymes.

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NSAIDs
•PK
• A- rapidly absorbed, weak acids & unionised in the
stomach.
• D- Insoluble, although the sodium salt (diclofenac
sodium, naproxen sodium) is more soluble.
Ketorolac trometamol is the most soluble and can
be given IV as a bolus and IM with less irritation.
Highly protein bound (90%–99%)
• M & E- mostly oxidised or hydroxylated and then
conjugated and excreted in the urine.

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NSAIDs
•PK
•M & E
• Diclofenac – t1/2: 1–2h, E 65% in Urine & 35% in Bile
• Ketorolac trometamol - t1/2: 5h, E 90% in Urine
• Naproxen - t1/2: 12–15h, E in Urine
• Tenoxicam – E 70% in Urine as inactive hydroxypyridyl
metabolite & 30% in Bile as glucuronide.
•PD
• Analgesia:
• Well-demonstrated efficacy both as postoperative analgesics
and in chronic conditions.
• Have significant opioid-sparing effect.
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NSAIDs
•PD
• Analgesia:
• NSAIDs are insufficient alone for severe pain after major
surgery but are valuable as part of a multimodal analgesic
regimen.
• Gastrointestinal system
• Acute and particularly chronic NSAID administration can
result in gastroduodenal ulceration and bleeding; bleeding is
exacerbated by the antiplatelet effect.
• Cardiovascular
• The potential adverse effects of inhibition of the COX
pathways on cardiovascular risks (including acute myocardial
infarction and stroke) were first highlighted in studies of
COX-2 selective agents. Subsequent large-scalestudies
indicate that this increased risk is probably related to all
NSAIDs. 31
NSAIDs
•PD
• Platelet function
• Platelet COX-1 is essential for the production of the cyclic
endoperoxides and thromboxane A 2 that mediate the
primary haemostatic response to vessel injury by producing
vasoconstriction and platelet aggregation.
• Aspirin acetylates COX-1 irreversibly, whereas other NSAIDs
do so in a reversible fashion. This can result in prolonged
bleeding times, and increased perioperative blood loss.
• Renal function
• Renal prostaglandins have many physiological roles,
including the maintenance of renal blood flow and
glomerular filtration rate in the presence of circulating
vasoconstrictors, regulation of tubular electrolyte handling
and modulation of the actions of renal hormones. NSAIDs
can adversely affect renal function.
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NSAIDs
•CONTRAINDICATIONS
• History of a bleeding diathesis
• Peptic ulceration
• Significant renal impairment
• Aspirin- induced asthma
• High-risk groups
• Elderly patients
• Cardiovascular disease
• Dehydrated

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NSAIDs

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NSAIDs

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NSAIDs

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NSAIDs

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α2-Adrenergic Agonists
•Clonidine and dexmedetomidine are examples of
commonly used α2 -agonists.
•When given perioperatively
• Clonidine 1–2µg/kg/hr,
• Dexmedetomidine loading dose 0.5µgkg–1 followed by
an infusion of 0.1–0.4 µg/kg/hr
• there is an associated decrease in pain score
intensity, opioid consumption and postoperative
nausea and vomiting.
•Dose-related adverse effects include hypotension
and bradycardia. 38
α2-receptors

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α2-receptors
α2-receptors
•Regulate release of NE.
•NE in Brain secreted majorly from Locus
COERULEUS (Important modulator of wakefulness).
• α2-R +
• Central - anaesthetic relevance → sedation, anxiolysis &
hypnosis
• Peripheral - descending fibres from LC ↓ pain
transmission & - primary sensory Neurons in Dorsal Horn
of Spinal chord

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Clonidine
•INTRODUCTION
• Imidazoline compound & selective α2 + with α1:α2
ratio of 200:1. Effective in severe hypertension but if
abruptly stopped → Hypotension.
•PHYSICAL PROPERTIES
• Transdermally or solution for IV, IM, Epidural &
Intrathecal use
•PHARMACOKINETICS
• A- Lipid soluble, absorbed rapidly & completely orally
• D- Peak plasma concentration in 60-90min
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Clonidine
•PK
• M- 50% metabolized in Liver
• E- 50% unchanged by Kidneys, T1/2 9-13hrs
•PD
• CNS Effects
• Produces Sedation & Anxiolysis, also POTENT Analgesic
• ↓ requirement of IV & volatile anaesthetic agents, but has a
celing effect to ↓ in MAC.
• Exhibits synergism with Opioids
• Potentiates effects of Local anaesthetics 43
Clonidine
•PD
•CVS Effects ↓HR, ↓Arterial pressure
↓
• Via α2-R + & Imidazole I1 + → ↓Myocardial contractility, ↓BP,↓SVR
↓
↓ Myocardial O2 Demands

•RS Effects
• Minor ↓ in minute ventilation

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Clonidine
•Dosage & DOA
• Premedication: 150-300mcg orally 1-2hr Pre – op
• Analgesia: Adjunct to LA in Central & Peripheral Block
• Critical care: Up to 2mcg/kg/hr as Sedative

• INDICATIONS
• Clonidine in low doses has proved to be a useful adjunct
analgesic when given neuraxially and in combination with
peripheral nerve blocks.
• Data from the systemic administration of clonidine also support
the usefulness of low-dose IV administration as an adjunct for
postoperative pain management.
• Chronic Pain Syndromes 45
Dexmeditomidine
•INTRODUCTION
• Selective α2 + with α1:α2 ratio of 1600:1.(Clonidine
200:1)
•PHYSICAL PROPERTIES
• IV solution for Infusion
•PHARMACOKINETICS
• A- Lipid soluble, absorbed rapidly & completely orally
• D- Peak plasma concentration in 60-90min

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Dexmeditomidine
•PK
• M- metabolized in Liver
• E- 90% unchanged by Kidneys, T1/2 2hrs
•PD
• CNS Effects
• Produces Sedation & Anxiolysis, also POTENT Analgesic
• ↓ requirement of IV & volatile anaesthetic agents - MAC
Sparing effect upto 90%
• Exhibits synergism with Opioids
• Potentiates effects of Local anaesthetics 47
Dexmeditomidine
•PD
•CVS Effects ↓HR, ↓Arterial pressure
↓
• Via α2-R + & Imidazole I1 + → ↓Myocardial contractility, ↓BP,↓SVR
↓
↓ Myocardial O2 Demands

•RS Effects
• Minor ↓ in minute ventilation

•Disadvantage
•Hypotension & Bradycardia
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Dexmeditomidine
•Dosage & DOA
• ICU Sedation: 0.7mcg/kg/hr
• Procedural Sedation: 1mcg/kg over to 10 Mins →
0.6mcg/kg/hr
• INDICATIONS
• Analgesia in Perioperative period

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Antidepressants
• INTRODUCTION
• Most useful for patients with neuropathic pain.
• Older tricyclic agents appear to be more effective analgesics than selective
serotonin reuptake inhibitors (SSRIs).
• Serotonin(SSRIs) and norepinephrine reuptake inhibitors (SNRIs) may
provide the most favorable balance between analgesic efficacy and side
effects.

• MECH. OF ACTION
• Actions are due to blockade of presynaptic reuptake of serotonin,
norepinephrine, or both.

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Antidepressants
MECH. OF ACTION

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Antidepressants
MECH. OF ACTION

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Antidepressants
MECH. OF ACTION

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Antidepressants
• PK

• A- Extensive first-pass hepatic metabolism

• D- Highly lipophilic & large volumes of distribution

• E- Elimination half-lives of most of these medications vary between 1 and 4

days

• Side effects
• Antimuscarinic effects (dry mouth, impaired visual accommodation, urinary
retention, and constipation),

• Antihistaminic effects (sedation and increased gastric pH),

• Adrenergic blockade (orthostatic hypotension),

• Quinidine- like effect (atrioventricular block, QT prolongation, torsades de

pointes).
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Antidepressants

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Antidepressants

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Neuroleptics
•occasionally useful for patients with
• refractory neuropathic pain
• patients with marked agitation or psychotic symptoms.
•The most commonly used agents are
• Fluphenazine,
• Haloperidol,
• Chlorpromazine,
• Perphenazine.
•MOA:
• Due to blockade of dopaminergic receptors in
mesolimbic sites.
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Neuroleptics
• SIDE EFFECTS
• same action in nigrostriatal pathways can produce
undesirable extrapyramidal side effects, such as masklike
facies, a festinating gait, cogwheel rigidity, and
bradykinesia.
• Some patients also develop acute dystonic reactions such
as oculogyric crisis and torticollis.
• Long-term side effects include akathisia (extreme
restlessness) and tardive dyskinesia (involuntary
choreoathetoid movements of the tongue, lip smacking,
and truncal instability).
• Like antidepressants, many of these drugs also have
antihistaminic, antimuscarinic, and adrenergic–blocking
effects.
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Anticonvulsants
•Anticonvulsant medications are useful for patients
with neuropathic pain, especially trigeminal
neuralgia and diabetic neuropathy.
•They suppress the spontaneous neural discharges
that play a major role in these disorders.
• Commonly used Anticonvulsants for Neuropathic pain are
• Gabapentin • Valproic acid
• Pregabalin • Clonazepam
• Phenytoin
• Carbamazepine

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Steroids
• Glucocorticoids - most powerful anti-inflammatory
characteristics of all steroids.
• The primary corticosteroid is hydrocortisone.
• Many synthetic agents that are more potent, have longer
durations of action, have greater anti-inflammatory activity,
and generate fewer unwanted mineralocorticoid side effects
than hydrocortisone have been developed.
• Mineralocorticoids are adrenal cortical steroid
hormones that have a greater effect on water and
electrolyte balance.
• The main endogenous hormone is aldosterone.

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Steroids
• Use of corticosteroids in multimodal analgesia
protocols
• minimizes opioid doses and, therefore, side effects.
• Dexamethasone prolongs local anesthetic block
duration.
• Epidural injection of corticosteroids is used to treat
back pain (mainly due to nerve root irritation).
• The only proven efficacy of epidural steroid
injections is their ability to speed resolution of leg
pain (“sciatica”) in patients with acute intervertebral
disc herniation and associated radicular pain.
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Steroids

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Steroids

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Local Anaesthetics

•Lidocaine produces analgesia by suppressing

the activity of sodium channels in neurons
that respond to noxious stimuli, thereby
preventing nerve conduction and pain
transmission.
•Topical application of 5% lidocaine has been
used in postherpetic neuralgia.

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Miscellaneous
•Magnesium Sulphate
• Magnesium has analgesic properties, primarily
related to the regulation of calcium influx into cells
and antagonism of NMDA receptors in the CNS.
• A meta-analysis of all available trials of systemically
administered magnesium reported a reduction in
postoperative opioid requirements approximately
equal to that of ketorolac.

• Animal Models
• +↑ opioid effect & suppresses neuropathic pain
• - Histologic neurotoxicity

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Miscellaneous
•Magnesium Sulphate
• Clinical Trials
• + Increase in the median duration of analgesia and
decrease in opioid consumption by 25%
• - two case reports of patients suffering from disorientation
and continuous periumbilical burning pain following the
injection of neuraxial magnesium

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Pain Ladder

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Clinical Scenario

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References
• Stoelting’s Pharmacology & Physiology in Anaesthetic Practice,
5E
• Morgan & Mikhail's Clinical Anesthesiology by David C. Mackey
and John F. Butterworth
• Miller's Anesthesia 9E, by Ronald D. Miller
• Essentials of Medical Pharmacology 7E, by KD TRIPATHI
• Smith and Aitkenhead's Textbook of Anaesthesia, 8E
• Drugs in Anaesthesia and Intensive Care 5E, by Edward Scarth
and Susan Smith

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Thank You

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