Non-Opioid Analgesics

Dr Clare Guilding
I am available to answer questions and clarify points via:
• Email: clare.guilding@ncl.edu.my
• Approach before/after lectures
• One on one in SO (email for appointment)

Case 23
 Learning outcomes

• Describe the mechanism of action and clinical use of non-opioid

analgesic drugs

• Describe the major pharmacokinetic characteristics which affect the

clinical use of non-opioid analgesic drugs

• Describe the major side effects of non-opioid analgesic drugs

Case 23
 Links of this lecture to Case 23

• Poor Tom’s had his problems as well... He tried all sorts to manage it
but couldn’t get away with any of the painkillers he was tried on
and soldiered on with paracetamol and a walking stick.
• Sean talking about conversation with Roger: ‘I didn’t think we
should use a NSAID given his age and history of hypertension so we
agreed on codeine.’

• I did his bloods for him and we agreed on a non-steroidal anti-

inflammatory, naproxen, and I checked his bloods.

Case 23
Non-opioid analgesic and compound analgesic drugs

Non-opioid analgesic drugs

• Non-steroidal anti-inflammatory drugs
– Ibuprofen, aspirin, naproxen, diclofenac, celecoxib
• Paracetamol

Compound analgesic drugs

• Are made from a combinations of two different drugs, most
commonly:
– Paracetamol
– Aspirin
– Codeine - see Opioids analgesics
Uses of analgesics

Increasing pain

Mild Moderate Severe

Simple non-opioid Compound Opioid analgesics
analgesics: analgesics:

paracetamol Co-codamol codeine

aspirin Co-dydramol tramadol
ibuprofen Tramacet morphine
Local hormones

• Also called autocoids • Are formed by the tissues on which

they act (act near site of synthesis)
• Include: • Are produced in many tissues
– Histamine rather than in specific endocrine
– Eicosanoids glands
 Prostaglandins • Effects are mostly localised but
 Prostacyclin large amounts can be produced
 Thromboxanes and moved into circulation (thus
 Leukotrienes may have systemic effect)
– Seretonin (5-HT) • Are metabolised locally and have
– Nitric oxide brief duration of action
– Kinins
Eicosanoids
Eicosanoids
 Prostaglandins (inc. PGE2 and PGF2)
 Prostacyclin (or PGI2) Prostanoids
 Thromboxanes (inc. TXA2)
 Leukotrines (inc. LTB4, LTC4, LTD4)

• Not pre-formed, generated in response to stimuli

• Synthesised in virtually all tissues
• Have diverse physiological roles

• Eicosanoids are synthesised from arachidonic acid by 2 main pathways

1. Cyclooxygenase pathway
2. Lipoxygenase pathway
Eicosanoid synthesis
Phospholipids in plasma membrane

Phospholipase A2

Arachidonic acid

Cyclooxygenase 1 or 2
Lipoxygenase
PGH2

Synthase/reductase/isomerase enzymes
Leukotrienes
PGI2 TXA2

PGE2 PGD2 PGF2

Cytosolic PLA2 is activated (and hence arachidonic acid
liberated) by phosphorylation. This occurs in response to signal
transduction events triggered by many stimuli, such as
thrombin action on platelets, C5a on neutrophils, bradykinin on
fibroblasts and antigen-antibody reactions on mast cells.
General cell damage also triggers the activation process.

Arachidonic acid is acted on by the enzyme COX which

produces various unstable intermediates which are
immediately acted on by various synthase enzymes (cyclic
endoperoxidases)
Specific synthases, presence and abundance of which varies
between cells convert endoperoxidae PGH2 to various
prostaniods
 Prostanoid functions
In endothelial cells Prostacyclin synthase Thromboxane synthase In platelets

PGI2 TXA2
• Vasodilator
• Vasoconstrictor
• Inhibits platelet
aggregation • Promotes platelet
aggregation
• Hyperalgesic

PGI2 produced by vascular endothelial cells. The local balance

between TXA2 and PGI2 is critical in the regulation of systemic
blood pressure and thrombogenesis
Imbalances lead to hypertension, ischemia, thrombosis. Mi or
stroke.
Hyperalgesic – increases sensitivity to pain
 Prostanoid functions
In endothelial cells Prostacyclin synthase Thromboxane synthase In platelets

PGI2 TXA2
• Vasodilator
• Vasoconstrictor
• Inhibits platelet
aggregation • Promotes platelet
aggregation
• Hyperalgesic

PGE2 PGD2 PGF2

Prostanoid synthesis and functions
Synthetic Tissue expressing Functions
enzyme synthetic enzyme
PGE2 PGE2 Many tissues, –Potentiation of responses
isomerase including to painful stimuli
macrophages and –Vasodilation
mast cells –Cytoprotective
–Inflammatory cell
activation
–Induce fever
PGD2 PGD2 Mast cells –Bronchoconstriction
synthase Neurons –Sleep control
–Vasodilation
–Inhibits platelet aggregation
PGF2 PGF2 Vascular and uterine –Vascular tone
reductase smooth muscle –Bronchoconstriction
–Uterine contraction
Prostanoids and pain
• Stimulation of nociceptive endings is mostly chemical in origin

• Substances which stimulate pain endings in the skin include:

– Serotonin
– Kinins e.g. bradykinin

 Prostanoids enhance the pain producing effects of other agents

 Prostanoids do not themselves cause pain
 Prostanoids released in inflammation sensitise C-fibres
Prostanoid functions summary

Vasodilation Powerful Synergy with Redness and

vasodilators other vasodilators increased
e.g. histamine, blood flow in
bradykinin areas of acute
inflammation
Vascular No effect Potentiate Swelling
permeability alone permeability (oedema) in
effects of areas of
histamine and inflammation
bradykinin
Pain No effect Potentiate effects Pain
alone of bradykinin by
sensitising
afferent C-fibres
NSAID mode of action (Non-steroidal anti-inflammatory drugs)
Phospholipids in plasma membrane

Phospholipase A2

Arachidonic acid

Cyclooxygenase 1 or 2 - NSAIDs
Lipoxygenase
PGH2

Synthase/reductase/isomerase enzymes
Leukotrienes
PGI2 TXA2

PGE2 PGD2 PGF2

Comparison of COX-1 and COX-2

Property COX-1 COX-2

Expression Constitutive Inducible, not

normally present in
most tissues
Tissue expression Ubiquitous Inflamed and
expression activated tissues
Role Protection and Proinflammatory
maintenance functions,
functions transmission of pain
Induction Generally no Induced by LPS,
induction TNF, IL-1, IL-2, IFN
Pharmacological NSAIDS NSAIDS and COX-2
inhibition selective inhibitors
COX inhibitors
• These drugs have three major therapeutic actions, presumed to stem from the
suppression of prostanoid synthesis in inflammatory cells through inhibition of
COX-2

1. An anti-inflammatory action

2. An analgesic effect

3. An antipyretic effect
IL-1 releases prostaglandins in the central nervous system, where they elevate
the hypothalamic set point for temperature control, thus causing fever.
NSAIDs prevent this.
Effects of NSAIDs

1. Anti-inflammatory
The decrease in PGE2 and prostacyclin reduces:
– Vasodilation
– Oedema (indirectly - the vasodilatation facilitates the action of
mediators such as histamine that increase endothelial permeability)

 No effect on processes that contribute to

tissue damage in chronic inflammatory
conditions e.g. rheumatoid arthritis
Effects of NSAIDs

2. Analgesic
– Less sensitisation of nociceptive nerve endings
– Mainly effective in acute inflammation or tissue damage e.g.
- toothache
- arthritis
conditions associated
- pain of postpartum states with increased
- dysmenorrhoea prostanoid synthesis
- pain of muscular or vascular origin
- pain of cancer metastases in bone
– Can be used in conjunction with opioids to reduce opioid requirements in post
operative pain
– In headache effectiveness probably due to decreased PG mediated vasodilatation
Clinical use of NSAIDs for pain and inflammation
• Very widely used prescribed therapeutic agent

• Also used commonly without prescription (OTC) for minor aches and
pains

• None are ideal in controlling or modifying pain and inflammation

• Unwanted side effects - especially in elderly

Side effects of NSAIDs https://www.uptodate.com/contents/nonselective-nsaids-
overview-of-adverse-effects

Responsible for over 25% of all adverse drug reactions in UK

• GI disturbances
– Most common unwanted effect
– Largely due to inhibition of COX1
(PGE2 normally inhibits acid secretion and protects mucosa)

Case 23
Tom: ‘The doctor… explained that I’d been taking double the maximum dose and that I should have been
taking something to protect my stomach as well… I had to have an endoscopy the next morning which
showed that I had an ulcer in my stomach that had been bleeding.’

Sean: ‘The discharge stated that he’d had acute gastric ulceration thought to be secondary to inadvertent
non-steroidal overuse without PPI cover. I didn’t know what to think at first. I knew I’d made a mistake and
that I should have prescribed a PPI when I started the naproxen.’
Side effects of NSAIDs

• Skin reactions
– Reported in 1–2% of patients using NSAIDs orally
– Including morbilliform rash, urticaria and angioedema

• Cardiovascular effects
– Are associated with an increased risk of cardiovascular disease events in patients
with and without cardiovascular disease.
– The most important adverse cardiovascular events include cardiovascular death,
myocardial infarction (MI), and stroke
Side effects of NSAIDs

• Renal effects
– Can cause acute renal failure (PGs involved in maintenance of normal kidney
function)
– All NSAIDs in doses adequate to reduce inflammation and pain can increase
blood pressure in both normotensive and hypertensive individuals.
– In addition, NSAID use may reduce the effect of all antihypertensive drugs
except calcium channel blockers
– The prohypertensive effect is dose dependent and probably involves inhibition
of COX-2 in the kidneys, which reduces sodium excretion and increases
intravascular volume

Case 23
Sean: ‘I didn’t think we should use a NSAID given his age and history of hypertension so we agreed on
codeine.’
Selectivity of NSAIDs
Increasing selectivity for COX-1
Celecoxib Naproxen Ibuprofen Aspirin
Weakly selective Weakly selective Weakly selective Weakly selective
for COX-2 for COX-1 for COX-1 for COX-1
Pharmacology of aspirin
• Irreversibly acetylates COX-1 (weak COX-2 activity)
• Inhibits expression of the transcription factor NFκB
• Antiplatelet activity

• Weak acid – mostly neutral in the acidic gut thus facilitating its passage
across the mucosa
• Most absorption occurs in the ileum, because of the extensive surface area
of the microvilli

• Aspirin is rapidly hydrolysed by esterases in plasma and tissues, particularly

the liver, yielding salicylate
• Approximately 25% of the salicylate is oxidised; some is conjugated to give
the glucuronide or sulfate before excretion, and about 25% is excreted
unchanged
Pharmacology of ibuprofen/naproxen (Propionic acid derivatives)
• Competitive inhibitors of COX-1 (and COX-2)
• Naproxen directly inhibits leukocyte function

• Well absorbed on oral administration

• Extensively plasma protein bound (>99%)
• Plasma protein binding is saturable at high concentrations
 Conditions that alter plasma protein concentration can result in increased free
drug with potential toxic effect

• Widely distributed  readily penetrate arthritic joints

• Undergo hepatic metabolism and excreted via the kidneys

• t1/2 ibuprofen ~2h t1/2 naproxen ~11h

Pharmacology of celecoxib
• Only blocks COX-2 at therapeutic dose – competitive inhibitor

• Given orally, readily absorbed with peak plasma after 1-3h

• Half life = 11h. Drug usually taken once a day
• Highly bound to plasma proteins (>90%)

• Particularly lipophilic so accumulates in fat and is readily transported to CNS

(central analgesic effect)

• Extensively (>99%) metabolised in the liver by CYP450s

• Excreted in feces and urine

• Less GI side effects than traditional NSAIDs