• Protective response as reaction of living tissue
• Mediated by
– Amines – Histamine & 5HT,
– Lipids – Prostaglandins
– Small peptides – Bradykinin
– Large peptides – Interleukin 1
Hyper sensitization of free nerve endings – perceived as pain
Pain is real
• Pain is a feeling, the more you feel – the more
It is all in the brain
Pain Thermometer- Faces Pain Scale
Pain is 100%
There is no painometer – all are visual impression
Definition of Pain
• International Association for the
Study of Pain
Defined as an unpleasant
sensory or emotional
experience associated with
actual or potential tissue
Pain is three dimensional
All must be addressed in pain management
WHO on Pain
• Pain is one of the most underestimated
healthcare problems in the world…
• Adequate pain management is a fundamental
• Pain is part of the body's defence system.
Pain costs USA- $635 billion/year in medical treatment
and lost productivity.
• The word PG - as it was thought to be
secreted by prostrate.
• No preformed stores of Prostaglandins are
available in blood.
• Synthesized locally in presence of stimulus in
almost all tissues of the body.
• Lung & Spleen can synthesize all range of
• Platelets : Thromboxane A2
• Endothelium of Vessels : PG I2
COX in two forms
• COX-1, COX-2,
• COX-1 PGs are "housekeeping“ and
constitutively expressed in almost all tissues.
• Responsible for homeostatic functions:
– Integrity of the gastric mucosa,
– Platelet function, and
– Regulating renal blood flow.
COX in two forms
• COX-2 PGs inducible and tightly regulated.
• Under normal conditions, COX-2 expression is
• COX-2 is dramatically unregulated during
• COX-2 play constitutive role only at
brain, bone & kidney.
• Most extensively used medications in the
• Fifth most utilized medication in all age
• The prevalence in aged above 65 is 70%.
• NSAID-related hospital admissions is from 7%
to 11%. (Preventable)
NSAIDs -- Benefit
Closure of Ductus arteriosus in new born
Anticancer – colonic cancer
NSAIDs annually account for 70 million prescriptions
and 30 billion OTC medications sold in the USA alone.
NSAIDs - Toxicity
Gastric mucosal damage
Salt & water retention
Delayed fracture healing (PGE-2↓)
Bone marrow suppression
Prolongation of labor
Asthma & Anaphylaxis
Institute of Medicine: the annual cost of chronic pain
in the U.S. is $560-635 billion - 2011.
Sitting is a busy OPD
Prescriptions of analgesic is a reflex
rather than a well thought of analytic process.
Clinical situation - 1
A 60 f was on analgesics for sometime,
Developed acute drop in blood pressure,
Had black color stool,
Admitted with diagnosis of Acute GI bleed,
Gastrointestinal Effects of NSAIDs
• ↓ production of prostaglandins in the
epithelial cells of gastric mucosa.
• ↓ epithelial mucus,
• ↓ secretion of bicarbonate,
• ↓ mucosal blood flow,
Gastrointestinal Effects of NSAIDs
• ↓ epithelial proliferation,
• ↓ mucosal resistance to injury.
• ↑ exposure of GI mucosa to as gastric
acid, pepsin, and bile salts.
• These effects are - systemic absorption of
• NSAIDs given by any route can damage gastric
NSAIDs & G.I. Bleed
Bleeding also occur in lower intestinal tract and colon
Clinical situation - 2
60 f was on analgesics for some time.
Developed puffy face,
Decreased urinary output,
Admitted for Acute renal shutdown.
• Renal PGs are vasodilator & have
little influence on renal blood flow
and GFR in normal conditions.
• PGs are necessary to compensate for
angiotensin induced renal vasoconstriction in
• NSAIDs block the production of PGs →
unopposed vasoconstriction → acute renal
• COX-2 NSAIDs →inhibition of juxtraglomerular PGs → Salt and water retention
• Idiopathic direct toxic - Acute interstitial
Clinical situation - 3
• A 60 m was on analgesics for some
• Developed chest pain
• Decreased urinary output
• Developed Hypertension
• Admitted with a diagnosis of Acute
COX-2 & MI
• ↓ PG-I2 synthesis without affecting
Thromboxane A2 synthesis .
• Tx A2 – pro-aggregatory for platelets
• PG-I2 – anti-aggregatory for platelets
• Non selective NSAIDs - ↓platelet aggregation
• Selective NSAIDs -↑ platelets aggregation –
CVA and MI
Selective Cox 2 inhibitors
• Rofecoxib & Valdicoxib were banned in USA in
2004 for 4X ↑ in Acute MI and Stroke.
• ↑ incidence of Thromboembolism.
• Etoricoxib rejected in USA - is still in use in
CV Effects - NSAIDs
• NSAIDs do not cause, but can worsen preexisting Heart Failure.
• ↓ in renal blood flow and ↑ retention of
sodium and water
• ↑ volume can decrease the effects of
diuretics used for CCF.
• ↑ Systemic vasoconstriction can potentially
exacerbate the pre-existing CCF.
Other clinical situations
Any patient on analgesics for the first time,
Developed skin rashes,
Acute hemolytic anaemia (G6PD↓).
Acute precipitation of Bronchial asthma.
Total & Differential WBC
• Neutropenia is another, albeit
rare, complication of NSAID therapy.
• ↑ risk of neutropenia with NSAID use.
• Analgin (Metamizole) banned in India in 2013
• Phenylbutazone banned –
agranulocytosis, and bone marrow
suppression, apastic anaemia, G.I.Bleed
Are these all real?
• All these clinical conditions are “REAL”.
• Events follow Murphy’s third law:
– If any thing is going to go wrong, they are going to
go wrong today with you!
• Remember “consumer forum is watching you”
Who are at risk
Diabetes & Hypertension.
Cardiac on polypharmacy:
Known H/o drug allergy.
Pregnancy and lactation.
Risk factors - G.I.Bleed
Age greater than 60 years,
Prior history of GI event (ulcer, haemorrhage),
Duration of NSAID use,
Multiple NSAID use,
Concurrent use of corticosteroids/anticoagulants.
Helicobacter pylori status.
We are unique
• Continue/discontinue//substitute drugs on
• Few continue drugs for indefinite time.
• Do not seek another consultation regarding
• Same prescription continue for years.
Drug dispensing system is very poorly monitored.
Our females are unique
Females do not disclose:
Other diseases and drugs.
• Identification of
“Who are at risk”
• Investigate before
• CBC: preexisting
Urinary albumin }
A quick history
Preexisting renal disease
How to Start
Stop – look - proceed
WHO - three-step "ladder"
• Administration of drugs in the following order:
– nonopioids (aspirin and paracetamol)
– + as necessary, mild opioids (codeine)
– + strong opioids such as morphine,
– until the patient is free of pain.
• Judicial use of adjuvants
Given “round the clock”, rather than “on demand”
Treat the first episode of pain as best as possible
• Nimesulide has never been approved for use
in USA, & other developed countries.
• In 2011, India put ban on Nimesulide in
• Relative COX – 2 inhibitor.
Safe in asthmatic patients where aspirin and NSAIDs
with cross sensitivity to aspirin can cause asthma.
• Rational prescribing of analgesics in elderly is
complex due to heterogeneity in
– drug disposition,
– co-morbid medical conditions,
– poly-pharmacy and
– variability in analgesic response.
“NSAIDs cause approximately 3500 hospitalisations
for and 400 deaths from ulcer bleeding per annum
in the UK in those aged 60 years and above”
on long term drugs
Calcium and Vit D
Hypoglycemia in diabetics
Blunting the effect of HT/Diuretics
• Mild opioids carry an unacceptable risk of falls
and fracture in older people which highlights
the need to limit their use.
• Patients must be worn for
– possible sedation
– Should be taken at home
– Preferably at bed time
– Minimum effective dose
• Carried a black box warning in the U.S., stating:
Propoxyphene should be used with extreme caution, if
at all, in patients who have a history of
substance/drug/alcohol abuse, depression with
suicidal tendency, or who already take medications
that cause drowsiness (e.g., antidepressants, muscle
relaxants, pain relievers, sedatives, tranquilizers.
• In 2009 - banned in USA,
• In 2013 – banned in India due to ↑ in Cardiac arrhythmias.
Effects on Pregnancy
• The use of NSAIDs around the time
of conception may be associated
with a risk of miscarriage due to
Interfere in implantation, leading
to abnormal implantation.
• Paracetamol is safe in women who
are trying to conceive.
• Anti-acid are safest in 1st trimester
• Use H2 – blocker rather than PPI
Effects on Pregnancy
During the third trimester of
pregnancy NSAIDs can cause:
– prolonged gestation and labour,
– increased bleeding,
– premature closure of the Ductus
Analgesics during Lactation
• All drugs transfer into breast milk.
• Paracetamol, ibuprofen, naproxen and
codeine are considered to be 'safe', due to low
transfer into breast milk.
• Topical preparations - creams, sprays or
inhalers carry less risk.
• Feeding immediately prior to a dose
minimises infant exposure.
Pharmacological of Pain
– Steroids : ↓ formation of Arachidonic acid from
free phospholipids of cell wall.
– NSAIDSs: ↓ formation of Prostaglandins from
– Opioids – Centrally acting.
• No single drug is superior to other for every
• Selection depends on nature of pain:
– Acute or chronic
– Mild, moderate, severe
– Inflammatory – non inflammatory
• Risk factors
• Past experience
• Acceptability & individual preference.
Depends on etiology of pain
NSAIDs + Combination therapy
Anti convulsions – Gabapentin/Pregabalin
Anti-acids – H2 blocker/PPI
Lyrica – approved for Fibromyalgia, Diabetic neuropathy
Seizures, and Herpes zoster pain.
All other uses in pain management is “Off the Label”
• Centrally acting analgesic COX -3 blocker
• Weak peripheral anti-inflammatory
• No effect on GI, renal, CVS, platelets and
• Cause hepatic failure in chronic alcoholics.
• Not safe in premature infants – hepatotoxicity.
Paracetamol + NSAIDs combination is additive & rational
A combination of two NSAIDs is not additive
• Centrally acting - ↓ µ,ĸ, and δ receptors
• Concomitant use with NSAIDs is supraadditive
• Provide additional analgesia beyond “ceiling
• Locally acting drugs and patches
– Local high concentration in tissue
– Systemic toxicity are minimized
Safety / efficacy ?
• Local rubeficiant
• Physical therapy – heat, massage, and TNS
Fear of unknown
Treat the fear psychosis
Contribute 50% of pain perception
Brain is the culprit
Multiplication of pain perception occur in the
brain due to previous experience.
works better than drugs
• Mild to moderate pain
– Paracetamol / Brufen
• Acute short lasting / Post operative
– Diclofenec, Nimesulide, Ketorolac
• Acute injury / musculoskeletal
– Paracetamol , Diclofenec
Route of entry - as per severity & availability
• Acute exacerbation – any chronic conditions
– Naproxen, Piroxicam, Indomethacin
• G.I. Intolerance
– Selective COX-2, Paracetamol
– Nimesulide, COX-2 inhibitors
Piroxicam & Indomethacin SR have better
compliance as once a day dose.
Complications of Long-term Proton Pump
• Alteration of absorption of vitamins and minerals
– Calcium↓, Magnesium↓, Iron↓, Vitamin C↓, B12↓
• Metabolic effects on bone density,
– ↑ Hip fractures ? ↑ BMD (anti osteoclastic)
• Drug interactions: Clopidogrel - common pathway
• ↑ Methotrexate toxicity.
• Infection risk: ↑ Pneumonia, ↑Clostridium
Difficile, ↑Traveler's Diarrhoea, Small Intestinal
Bacterial Overgrowth, Spontaneous Bacterial
• Hypersensitivity response : Interstitial Nephritis.
• Is a synthetic PGE1 analogue approved for
prevention of NSAID induced gastric ulcers.
• It acts upon gastric parietal cells,
– inhibiting secretion of gastric acid via G-protein
coupled receptor mediated inhibition of Adenylate
– which leads to decreased intracellular cyclic
– and decreased proton pump activity at
the apical surface of the parietal cell.
• H2-receptor antagonists and PPIs, are more
effective for the treatment of acute peptic
• Not to be given during pregnancy.
• Used in induction of labor, treat missed
miscarriage, induction of abortion, and to
• It can cause rupture of uterus and fetal distress.
Malpractice award of $70 million was awarded due to off
the label use of Misoprostol to induce labor in USA. 2012
• Nitroxyparacetamol: potent NO-releasing
version of paracetamol that has both analgesic
and also anti-inflammatory properties.
• Cannabinoids: as anti-nociceptive
• Cyclooxygenae inhibitors + NO donor
– Nitric oxide cause local vasodilatation which
negotiates the vasoconstriction by NSAIDs
• Ziconotide: snail venom as neurotrammiter
• This presentation is prepared for dissipation of general
knowledge about Non-steroidal anti-inflammatory drugs
amongst students of orthopaedic surgery.
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heighten the specific points in this presentation.
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