NSAIDs in clinical orthopaedic practice

Vinod NaneriaGirish Yeotikar

Arjun WadhwaniChoithram Hospital & Research Centre, Indore, India

NSAIDs

Pain

Inflammation Prostaglandin

Drugs

Inflammation

• Protective response as reaction of living tissue to injury.

• 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 you get.

It is all in the brain

Pain Thermometer- Faces Pain Scale

0 1 2 3 4 5

There is no painometer – all are visual impression

Wong-Baker

Pain is 100%

Definition of Pain

• International Association for the Study of Pain

Defined as an unpleasant sensory or emotional experience associated with actual or potential tissue damage.

Pain is three dimensional

All must be addressed in pain management

Cognitive dysfunction

Emotional disturbances

Pain

Physical disability

WHO on Pain

• Pain is one of the most underestimated healthcare problems in the world…

• Adequate pain management is a fundamental human right.

• Pain is part of the body's defence system.

Pain costs USA- $635 billion/year in medical treatment and lost productivity.

Prostaglandins

• 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.

Prostaglandins

• Lung & Spleen can synthesize all range of Prostaglandins

• Platelets : Thromboxane A2

• Endothelium of Vessels : PG I2

Membrane Phospholipid

Arachidonic Acid

Phospholipase A ChemicalMechanical Stimulous

PGG 2

PGH 2

Isomerases Thromboxane Prostacyclin

PGE 2PGD 2PGF 2a

TXA 2

TXB 2

PGI 2

6keto-PGF 1a

Cyclooxygenase Lipooxygenase

HydroperoxyArachidonicacid

LTE4

LTF4

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

highly restricted.• COX-2 is dramatically unregulated during

inflammation.• COX-2 play constitutive role only at brain,

bone & kidney.

NSAIDs

• Most extensively used medications in the world.

• Fifth most utilized medication in all age groups.

• The prevalence in aged above 65 is 70%. • NSAID-related hospital admissions is from 7%

to 11%. (Preventable)

NSAIDs -- Benefit

• Analgesia• Anti-pyraxia• Anti-inflammatory• Anti-thrombotic• 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• Bleeding tendency• Salt & water retention• Delayed fracture healing (PGE-2↓)• Bone marrow suppression• Prolongation of labor• Asthma & Anaphylaxis• Hepatotoxic

Institute of Medicine: the annual cost of chronic pain in the U.S. is $560-635 billion - 2011.

Prescriptions of analgesic is a reflex rather than a well thought of analytic process.

Sitting is a busy OPD

ParacetamolBrufen

Dolonex

Indomethacin Voveran

UltracetNaproxen

कु� छ भी� दे�दे या�र!

Clinical situation - 1

• A 60 f was on analgesics for sometime,• Developed acute drop in blood pressure,• Had black color stool,• Had hematemesis,• Admitted with diagnosis of Acute GI bleed,• Peptic perforation?• Chronic anaemia?

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• NSAIDs given by any route can damage gastric

mucosa.

NSAIDs & G.I. Bleed

G.I. Ulcer 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,• Pedal edema,• Headache,• Decreased urinary output,• Admitted for Acute renal shutdown.

Renal prostaglandins

• Renal PGs are vasodilator & have little influence on renal blood flow and GFR in normal conditions.

Renal prostaglandins

• PGs are necessary to compensate for angiotensin induced renal vasoconstriction in volume-depleted states.

• NSAIDs block the production of PGs → unopposed vasoconstriction → acute renal failure.

Renal prostaglandins

• COX-2 NSAIDs →inhibition of juxtra-glomerular PGs → Salt and water retention

• Idiopathic direct toxic - Acute interstitial necrosis.

Clinical situation - 3

• A 60 m was on analgesics for some time

• Developed chest pain• Decreased urinary output• Developed Hypertension• Admitted with a diagnosis of Acute

myocardial infarction.

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

India.

CV Effects - NSAIDs

• NSAIDs do not cause, but can worsen pre-existing 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,• Purpuric rashes,• Stevens–Johnson syndrome,• Acute hemolytic anaemia (G6PD↓).• Agranulocytosis.• 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”.• Rare.• 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

• Elderly patients.• Diabetes & Hypertension.• CRF.• Cardiac on polypharmacy:– Aspirin/Clopedogrel– Anti-coagulants

• Known asthmatics• Known H/o drug allergy.• Pregnancy and lactation.• Helicobacter pylori

Risk factors - G.I.Bleed

• Age greater than 60 years,• Aspirin,• Prior history of GI event (ulcer, haemorrhage), • High dosage, • Duration of NSAID use,• Multiple NSAID use, • Concurrent use of corticosteroids/anticoagulants.• Helicobacter pylori status.

Renal Toxicity – Risk factors

– Elderly– Diabetes – Hypertension– CRF– CCF – Dehydration– Diuretics– Cirrhosis

We are unique

• Continue/discontinue//substitute drugs on our own.

• Few continue drugs for indefinite time.• Do not seek another consultation regarding

drug continuation.• Same prescription continue for years.

Drug dispensing system is very poorly monitored.

Our females are unique

• Females do not disclose:• Marital status,• Pregnancy,• Lactation,• Menopause,• Other diseases and drugs.

Management

• Identification of “Who are at risk”• Investigate before

committing.

Investigate• CBC: preexisting

• Creatinine }• Urinary albumin }• SGPT• A quick history

Viral feverDrug allergy,AsthmaPoly-pharmacyPregnancy/lactation

Preexisting renal disease

Bone marrow↓, chronic anemia, agranulocytosis, pancytopenia

How to Start

• Start “Low”• Go “slow”• Stop – look - proceed• Monitor

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

Strong OpioidsNSAIDs +/-Adjuvant

Mild OpioidsNSAIDs +/-Adjuvant

NSAIDs +/-Adjuvant

Persistent pain

Persistent pain

Pain

Be careful

• Pediatrics• Geriatrics• Pregnancy• Lactation

Paediatrics

• GI safety profile OK• COX-2 not indicated• Safe drugs – Paracetamol, Naproxen, &

Ibuprofen, • Aspirin – Rheumatic fever, • Reye’s syndrome – Aspirin + viral

Hepatic Encephalopathy

Nimesulide

• Nimesulide has never been approved for use in USA, & other developed countries.

• In 2011, India put ban on Nimesulide in children.

• Hepatotoxity.• Relative COX – 2 inhibitor.

Safe in asthmatic patients where aspirin and NSAIDs with cross sensitivity to aspirin can cause asthma.

Geriatric patients

• 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”

Geriatric Patients on long term drugs

• Aspirin• Statin• Anti hypertensive• Diuretics• Anti diabetic• Anti-acids• Anti depressant• Anti absorptive• Alcohol• Calcium and Vit D

Drug interactionHypoglycemia in diabeticsBlunting the effect of HT/Diuretics

Geriatric patients

• 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

Dextropropoxyphen (Proxyvon)

• Carried a black box warning in the U.S., stating:

• In 2009 - banned in USA, • In 2013 – banned in India due to ↑ in Cardiac arrhythmias.

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.

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

arteriosus.

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

• Drugs– Steroids : ↓ formation of Arachidonic acid from

free phospholipids of cell wall.– NSAIDSs: ↓ formation of Prostaglandins from

Arachidonic acids.– Opioids – Centrally acting.

Drug Selection

• No single drug is superior to other for every patient.• Selection depends on nature of pain:

– Acute or chronic– Mild, moderate, severe– Inflammatory – non inflammatory

• Risk factors• Past experience• Acceptability & individual preference.

Adjuvant therapy

• Depends on etiology of pain• Nociceptive• Neurogenic• Mix

NSAIDs + Combination therapy

• Paracetamol• opioids• Muscle relaxants• Anti depressants/anxiolytic• Anti convulsions – Gabapentin/Pregabalin• Anti-acids – H2 blocker/PPI

Lyrica – approved for Fibromyalgia, Diabetic neuropathySeizures, and Herpes zoster pain. All other uses in pain management is “Off the Label”

Paracetamol

• Centrally acting analgesic COX -3 blocker• Weak peripheral anti-inflammatory• No effect on GI, renal, CVS, platelets and

respiration.• Cause hepatic failure in chronic alcoholics.• Not safe in premature infants – hepatotoxicity.

Paracetamol + NSAIDs combination is additive & rationalA combination of two NSAIDs is not additive

Opioids

• Centrally acting - ↓ µ,ĸ, and δ receptors• Rational• Concomitant use with NSAIDs is supra-additive• Provide additional analgesia beyond “ceiling

effect”.

Associated therapy

• Locally acting drugs and patches– Local high concentration in tissue– Systemic toxicity are minimizedSafety / efficacy ?

• Local rubeficiant • Physical therapy – heat, massage, and TNS

Gate theory

Fear of unknownमु�झे� क्या� बी�मु�र� है� ?

• 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.

Talk Talk Talk works better than drugs

Guidelines

• 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

Guidelines

• Acute exacerbation – any chronic conditions– Naproxen, Piroxicam, Indomethacin

• G.I. Intolerance– Selective COX-2, Paracetamol

• Asthma – Nimesulide, COX-2 inhibitors

Piroxicam & Indomethacin SR have better compliance as once a day dose.

Complications of Long-term Proton Pump Inhibitor Use

• 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 Peritonitis.

• Hypersensitivity response : Interstitial Nephritis.

Misoprostol

• 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 Cyclase,

– which leads to decreased intracellular cyclic AMP levels

– and decreased proton pump activity at the apical surface of the parietal cell.

Misoprostol• H2-receptor antagonists and PPIs, are more

effective for the treatment of acute peptic ulcers.

• Not to be given during pregnancy.• Used in induction of labor, treat missed

miscarriage, induction of abortion, and to prevent/treat PPH.

• 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

Recent advancement

• 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

blocker.

Primum non nocere

“First Do No Harm”

NSAIDs

Thank You

Think Before committing

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