analgesic cme final

8/11/2019 Analgesic CME Final

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AZZA BARAKAProfessor of Clinical Pharmacology

Faculty of Medicine

Alexandria University


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Types of Pain The physical causes of pain have been divided into two types

NOCICEPTIVE PAIN - Examples include bone fractures,burns, inflammation , When nociceptors are activated, they transmit pain signals(via the peripheral nerves as well as the spinal cord) to thebrain.The pain is typically

1. well localized, constant, and often with an aching or

throbbing quality.2. usually time limited, meaning when the tissue damageheals, the pain typically resolves.

3. tends to respond well to treatment with analgesics.


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Types of Pain (Cont..) 2-NEUROPATHIC PAIN - Examples include diabetic neuropathy

. Neuropathic pain is the result of an injury in the peripheral orcentral nervous system.The pain frequently has burning or electric shock qualities.

Neuropathic pain is frequently chronic, and tends to have a lessresponse to treatment with analgesics, but may respond well toother drugs such as anti-seizure and antidepressant medications.


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ANALGESICS

Drugs that relieve pain due to multiple causes .

They are classified into 2 major groups: Opioid or narcotic analgesics .

Non-opioid or analgesic/antipyretics.


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Timing of analgesic administration There is a common MisconceptionPatients should wait as long as possible before taking a painmedication. This abstinence will teach them to have a bettertolerance for pain. Pain that is untreated often escalates.

Without treatment, sensory input from injured tissue reachesspinal cord neurons and causes subsequent responses to beenhanced.

Aggressive pain prevention and control that occurs before,during, and after a painful event such as dental surgery canyield both short- and long-term benefits. Patients should beencouraged to use analgesics before pain becomes severe anddifficult to control.


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Describes any drug with a primary indication other than pain, but with analgesic properties in some painful conditions

o Ergot alkaloids (Ergotamine) used for migraine.

o Nitrates (Nitroglycerine) used for angina pectoris.o Tricyclic antidepressants (Amitriptyline) used in

neuropathic pain.

o Anti-epileptics (Gabapentin/ lyrica ) used in neuropathic

pain.

o Skeletal muscle relaxants: for musculoskeletal pain

Adjuvant Analgesics


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Analgesic Ladder Bottom of ladder (mild pain): Non opioid +/-adjunctive

Middle of ladder (moderate pain): Weak opioid +/- nonopioid +/- adjuvant

Highest of ladder (severe pain): Strong opioid +/- non opioid+/- adjuvant


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Choice of Analgesics

In choosing analgesics, the severity of pain determinesthe choice of agent; the WHO pain ladder specifies mildanalgesics as its first step.

As a general rule, any analgesic regimen should include anonopioid drug, even if pain is severe enough to requirethe addition of an opioid.Analgesic choice is also determined by the type of pain:for neuropathic pain, traditional analgesics are lesseffective, and there is often benefit from adjuvantanalgesics.


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IMPORTANT NOTE

It is important to note that analgesics do nothave any therapeutic effect on the

underlying disease and they essentially onlyact by blocking the pain sensation beingexperienced by the patient.

Hence, analgesics should only be adjuncts toother treatment.


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Analgesic Antipyretics

Mild moderate analgesics that works on subcortical

centers, they include:

1. Non-Steroidal Anti-inflammatory Drugs

(NSAIDs)

2. Paracetamol.


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Timing of administration

Non-opioid Analgesics are most effective in treatingpostprocedural pain when given before the procedure (or immediately following a short procedure), thuspreventing the synthesis of prostaglandins that quicklyfollow the surgical insult.The delayed use of these analgesics post-procedurallyinhibits the subsequent prostaglandin synthesis andprovides analgesia, but it does not interfere with theeffects of those prostaglandins already produced.Preoperative administration of NSAIDs delays the onsetof postoperative pain and lessens its severity and

subsequent analgesics requirements.


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Classification of Analgesic Antipyretics

Nonselective COX-inhibitors Salicylates : Aspirin

Propionic acid derivatives : Ibuprofen Acetic acid derivatives : Diclofenac

Pyrrolo-pyrrole derivatives : KetorolacOxicam derivatives : Piroxicam

Indole derivatives : IndomethacinPyrazolone derivatives :Phenybutazone

Analgesic-antipyretic with no anti-inflammatory effectParacetamol /Acetaminophen

(panadol-abimol-tylenol)

Selective COX-2 inhibitors Celecoxib


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I. Non-steroidal anti-inflammatory drugs NSAIDs

NSAIDs are group of drugs that share in

common the capacity to induce: Analgesic effect.

Antipyretic effect.

Anti-inflammatory effect.

Aspirin only has antiplatelet action


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Mechanism of action of NSAIDs: NSAIDs cause competitive reversible inhibition of

COX enzymes. Acetyl salicylic acid is the only NSAID that causes

irreversible inhibition of COX.

Celecoxib is a selective COX-2 inhibitor .

NSAIDs


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NSAIDsNon-selective COX inhibitors

1. Salicylates, e.g. acetyl salicylic acid (Aspirin).

2- Other NSAIDs : e.g.Ibuprofen & naproxen. piroxicam (Feldene)

Diclofenac sodium (Voltaren)Diclofenac potassium (Cataflam). Indomethacin (Indocid).

Ketorolac (Ketolac)


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Absorption: well absorbed after oral administration butdelayed with food.

Onset of analgesia occurs rapidly with all NSAIDs,usually within one hour.

Diclofenac potassium (Cataflam) is very rapidlyabsorbed thus provides rapid analgesic reliefcompared to diclofenac sodium (Voltaren),acharacteristic essential in the management of acutepain.

Pharmacokinetics of NSAIDs


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Variable first-pass metabolism,

consequently have different bioavailability(diclofenac 50% vs ibuprofen 100%)

Distribution:- Extensively protein boundSO DRUG INTERACTIONS FREQUENT .

Elimination: mainly in liver.Inter-patient differences in the metabolic clearancesof individual NSAIDs can be large leading to

considerable variability in plasma levels.

Renal Excretion:- Small component of the elimination ofNSAIDs


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NSAIDs difference in potency &

elimination half life

Low potency & short elimination half life (even in patients with liver or renal disease) used for transient inflammatorypain : ibuprofen (low incidence of GIT AR bec more selective

for COX 2 compared to COX 1)High potency & short elimination half life : diclofenac (lowincidence of GIT AR but low oral bioavailability ) ,ketoprofen, indomethacin, ketorolac (v high potency but

high incidence of GIT AR)High potency & long elimination half life (slow metabolism& slow elimination)used for persistent inflammatory painbut carries a high incidence of GIT & renal AR : piroxicam


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Topical NSAIDs Topical application leads to relatively high NSAIDconcentrations in the dermis.Concentrations achieved in the muscle tissue below theite of application are variable.NSAIDs applied topically reach the synovial fluid, butin a small amount.


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Topical NSAIDs There are five components to the successful use of topical

therapies:Correct diagnosisType of lesion being treated Vehicle (the base in which the active medication is delivered)Method used to apply the medication


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Topical NSAIDs(Cont..)

1-Vehicle used

If the correct medication but the wrong vehicle isused, the response to therapy may be delayed,inadequate, or in some cases, worsened.As examples,

1- Use of gel on skin inflammation (dermatitis) andfissures will cause increased pain and stinging due tothe alcohol base of the gel.

2- Treating a moist lesion with an ointment may causefolliculitis secondary to its occlusive properties.


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ypes o ve c esOintments

Ointments consist of water suspended in oil.This type of vehicle decreases transepidermal water loss,provides enhanced medication absorption, and issemiocclusive. They are generally the most potent vehiclesdue to their occlusive effect.Patient acceptance may be low because they are greasy, andthey are not useful in hairy areas.


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Creams

Creams are semisolid emulsions of oil in water and can be washed off with water. They are the most cosmeticallyappealing vehicle type for delivering topical medications.Creams are less potent than ointments.


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Lotions Lotions (as well as aerosols) are the least potent topicaltherapies, but are useful in hairy areas and in conditions where large areas have to be treated.They consist of powder-in-water; thus, patients mustshake the container before each application to receive thedesired therapeutic concentration (and therefore thedesired effect). As lotions evaporate, they provide a cooling and dryingeffect, making them useful for treating moist dermatosesand/or pruritus.


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Topical NSAIDs(Cont..)2-Type of lesion

"If a lesion is wet, use agents to make it dry, and "If a lesionis dry, make it wet" (eg, use an ointment base to increasehydration to the affected area).

Thus, for acute exudative dermatoses, treatments in liquid vehicles (eg, lotions) are generally recommended. Incontrast, when treating dry lesions, therapeutic agentsincorporated into ointments ( or creams) may help to retain

native moisture and provide relief to dry, pruritic skin.

l ( )


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Topical NSAIDs(Cont..)3-Method of application

Topical drug penetration into the skin is determined by themethod of topical application.For optimal absorption of most topical drugs, apply them to

moist skin either immediately after bathing or after wetsoaks.Occlusive dressings will also enhance drug absorption, oftenby a factor of 10.The site of an application is also important as variations inthe epidermal layer will alter the extent of drug absorption.


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Side effects & Toxicity: GIT: Gastric irritation, bleeding & ulceration.Hypersensitivity:(Inhibition of COX & shift to LTs)bronchoconstriction, urticaria,...

Kidney : N ephropathy.

Aspirin might cause Reye's syndrome: severehepatic injury & encephalopathy in case of viralinfections in both children and adolescents.


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The most common risk of NSAIDsGIT side effects include: N, V, D , gastric ulceration.Risk of ulceration with duration of therapy and with higher doses.

Enteric coated products ,injectable or suppository formulationsdo not eliminate the problem of gastric mucosal damage.

use the lowest effective dose for the shortest period of time.

take with food or directly after a meal.

Misoprostol (PG analogue) or drugs that decrease gastric acidity(H 2 blockers) are used for prophylaxis against ulcers.Recommended in high risk patients if NSAIDS cannot be avoided.


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Ketorolac, Indomethacin, ketoprofenand piroxicam appear to have the highest

prevalence of gastric ADRs, whileibuprofen (lower doses) and diclofenac appear to have lower rates.


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Nephrotoxicity

Nephrotoxicity from NSAIDs is rare in healthy patientsbecause both renal blood flow and glomerular filtrationdo not depend on prostaglandin levels,But the risk of nephrotoxicity increases for patientswho are volume depleted, who have congestive heartfailure, or who have hepatic cirrhosis, because thesepatients rely on renal prostaglandin synthesis toensure sufficient renal blood flow and to maintain anadequate GFR.Signs of nephrotoxicity include development of oliguriawith sodium and water retention.


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AERD Aspirin exacerbated respiratory disease(AERD) is a clinicalentity characterized by aspirin- and NSAID-induced respiratoryreactions in patients with chronic rhinosinusitis and asthma.Administration of NSAID leads to inhibition of COX-1 , thus

arachidonic acid is preferentially metabolized in the 5-lipoxygenase pathway, resulting in increased production ofleukotrienes.All routes of administration can precipitate bronchospasm in

sensitive asthmatics even ophthalmic drops.Selective COX-2 inhibitors do not cause reactions in patientswith AERD and can be taken safely.


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Selective COX-2 InhibitorsCelecoxib (Celebrex)

A selective COX-2 inhibitor that spares COX-1, thus does notinhibit synthesis of protective PGs in the gut. Hence, associatedwith less GI adverse effects .

-But there are concerns regarding cardiovascular side effects(due toalterating the balance of antithrombotic and prothrombotic

pathways in a way that promotes thrombogenesis )

- due to inhibition of COX-2 in endothelium responsible forsynthesis of PGI2( a PG responsible for inhibiting plateletaggregation) . Decreased formation of PGI2 increase chance for

platelet aggregation.

-Thus, it is advised not to prescribe COX-2 inhibitors to patientswho have a history of myocardial infarction or ischemic stroke.


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Important Note

High levels of COX-2 are detected in activated andproliferating vascular tissues, for example angiogenicmicrovessels, atherosclerotic lesions, and inflamedtissues.High levels of COX-2 are expressed in certain disease; Alzheimers disease, cancer where PGs are responsiblefor angiogenesis & invasion of tumor, thus NSAIDs arerecently reported to protect against certain cancers & Alzheimers disease.

na ges c nt pyret cs


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na ges c nt pyret cs

It effectively inhibits PG synthesis in thenervous system resulting in analgesic &antipyretic effects

But does not inhibit COX in peripheraltissue thus has no anti-inflammatoryeffect .

II. Paracetamol

l


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Mechanism of action:

Paracetamol

Analgesic, antipyretic: as it inhibitsCOX enzyme centrally.No anti- inflammatory action (doesntinhibit COX peripherally)No antiplatelet action


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- Peptic ulcers (it causes no GIT disturbances)

- Bleeding tendency (it does not affect platelet function)

- Allergy to salicylates .

- Viral infections in children ( to avoid Reyes syndrome).

- Pregnancy .

Paracetamol

Commonly used instead of NSAIDs incases of:


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- Of particular significance to older people is the use of

paracetamol in the management of osteoarthritis

where it is recommended as first-line treatment

Paracetamol

An Important Therapeutic Use

Paracetamol


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ParacetamolIts protein binding is insignificant

The usual dosage for adults is 500 m g every four to sixhours as needed.

No more than 4 g should be taken in 24 hours, to

avoid toxicity in the form of: Liver damage (with acute

over dosage).

Since paracetamol is metabolized in the liver, patientswith liver disease need to take care. ( given half dose)


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Considerations during therapy with NSAIDs 1. Consider drug interactions between NSAIDs &

anticoagulants, hypoglycemics.2. Anti-inflammatory activity often requires a week or more to

become established. For this reason, an adequate trial of 1-2 weeks should be allowed before increasing the dose or

changing to another NSAID.3. Combining NSAIDs is NOT recommended as it has no

additive effect and increases risk of toxicity. Butcombination of NSAIDs with paracetamol increases painrelief compared with NSAIDs alone.

4. NSAIDs differ in analgesic potency: NSAIDs of considerableanalgesic potency are ketorolac & diclofenac.

5. Remain upright 30 minutes after administration of NSAIDto reduce astric irritation or ulcer formation.

4 Patients who can tolerate NSAIDs should be first given


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4. Patients who can tolerate NSAIDs should be first givenmaximally effective doses before adding or shifting to anopioid.

5. In patients who have CVD, studies have found thatconcomitant intake of NSAIDs decrease thecardioprotective effects of aspirin

6. Combining NSAID with aspirin interferes with theantiplatelet action of aspirin.

7. Because nonselective NSAIDs interfere with normal bleeding time, they should be discontinued several days to

one week before any surgical procedure. Cox-2 NSAIDsdo not decrease platelet aggregation. As a result, Celebrexmay be used perioperatively

8. NSADs blunt the effect of some antihypertensive drugs.


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NSAIDs blunt antihypertensive effect

Monitor blood pressure in hypertensive patients usingNSAIDs chronically. Adjust antihypertensive drugs asnecessary.Recommend a calcium channel blocker if a patientneeds an antihypertensive thats less affected byNSAIDs


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Case Study(I) A 70-year-old woman has been treated for diabetes mellitusfor the past 10 years. She complains of burning pain in bothfeet. The pain is severe enough that she reports substantiallimitations in her physical activities and severe disruption ofher sleep. She has undergone electrodiagnostic testing,which demonstrated abnormalities consistent with diabetic

polyneuropathy. The patients general medical status isnoteworthy in that she had a mild myocardial infarction 3years ago, with subsequent angioplasty. The patient has ahistory of hypertension adequately controlled withLisinopril. What are the analgesic(s) that this patient can be

advised to take??


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Case Study(II) Mr A is a 52-year-old patient suffering from osteoarthritis(OA). He iscurrently experiencing lumbosacral back pain. He takes 600mg ofIbuprofen twice daily for his OA.An analgesic that is better to be given to this patient is:

1. Paracetamol

2. NSAID3. COX-2 inhibitor4. Opioid5. None of the above

An adjuvant analgesic that can be given to this patient is:1. Anticonvulsant2. TCA3. Skeletal muscle relaxant4. None of the above


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analgesic cme final

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