Farmakologi Obat Nyeri Dr.Datten Bangun MSc,SpFKDept.Farmakologi & TherapeutikFak.Kedokteran UHNM E D A N

Definition of PainPain is an unpleasant sensory and emotional experience. Pain is whatever the experiencing person says it is, existing whenever he says it does. (McCaffery & Pasero, 1989).

It is not the responsibility of clients to prove that they are in pain; it is the nurses responsibility to believe them. (Crisp & Taylor, 2005).

Chronic pain is difficult to define but understood as persistent pain that is not amenable to routine pain control methods0

Categorize Type of PainBone/Soft Tissue (Somatic) Paintender, deep, achingarthritis, myofascial pain, bony metsNeuropathic Painshooting, burning, stabbing, scaldingtrigeminal neuralgia, diabetic neuropathy, post stroke, reflex sympathetic dystrophy Visceral Painspasms, crampingbowel obstruction, adhesions0

Types of PainSuperficial: - Stimulation of skin & mucous membranes - Fast response Deep: - Arises from muscles, joints, tendons, heart ..etc. - Slow response

Sources of PainNociceptivefree nerve endings that receive painful stimuliNeuropathic damaged nerves

Physiology of PainNociceptorsStimulus TransmissionTerminationModulation

NoxiousstimulusTransductionConductionTransmissionprimary sensory neuron central neuronModulationNociceptionOuch Pain

Mechanisms of Pain and NociceptionPolymodal nociceptors (PMN) are the main type of peripheral sensory neuron that responds to noxious stimuli. The majority are non-myelinated C-fibres whose endings respond to thermal, mechanical and chemical stimuli.

Mechanisms of Pain and NociceptionChemical stimuli acting on PMN to cause pain include bradykinin, 5-HT, and capsaicin. PMN are sensitised by prostaglandins, which explains the analgesic effect of aspirin-like drugs, particularly in the presence of inflammation.Nociceptive fibres terminate in the superficial layers of the dorsal horn, forming synaptic connections with transmission neurons running to the thalamus.

Mechanisms of Pain and NociceptionChemical stimuli acting on PMN to cause pain include bradykinin, 5-HT, and capsaicin. PMN are sensitised by prostaglandins, which explains the analgesic effect of aspirin-like drugs, particularly in the presence of inflammation.Nociceptive fibres terminate in the superficial layers of the dorsal horn, forming synaptic connections with transmission neurons running to the thalamus.

Mechanisms of Pain and NociceptionPMN neurons release glutamate (fast transmitter) and various peptides (especially substance P) which act as slow transmitters. Peptides are also released peripherally and contribute to neurogenic inflammation.Neuropathic pain, associated with damage to neurons of the nociceptive pathway rather than an excessive peripheral stimulus, is frequently a component of chronic pain states, and may respond poorly to opioid analgesics.

Modulation of Pain TransmissionTransmission in the dorsal horn is subject to various modulatory influences, constituting the gate control mechanism.Descending pathways from the midbrain and brainstem exert a strong inhibitory effect on dorsal horn transmission. Electrical stimulation of the midbrain periaqueductal grey (PAG) causes analgesia through this mechanism.

Modulation of Pain TransmissionThe descending inhibition is mediated mainly by enkephalins, 5-HT, noradrenaline and adenosine. Opioids cause analgesia partly by activating these descending pathways, partly by inhibiting transmission in the dorsal horn, and partly by inhibiting excitation of sensory nerve terminals in the periphery.

Can use 0-10 scale individually or as part of your OPQRSTCan use visual aids to measure pain.

How is pain measured?

O Onset P Palliative/Provocation Q QualityR Region/RadiationS Severity T TimeVerbal Assessment of Pain

Analgesics DefinitionDrugs that selectively inhibit the perception (sensation) of the pain Classification 1- Peripheral (miscellaneous): - Causal - Non-causal2- Central: - Narcotic - Non-narcotic

Peripheral Analgesics Causal -Treat the causeExample: Atropine (antispasmodic) Non-causal- Not treat the causeExamples:1- Local anaesthetics (for superficial tumor)2- Counter-irritant (apply pain that counteract or mask the original one e.g. acupuncture)

Central Analgesics Narcotics The class - Opioids (morphine & morphine like drugs) Examples 1- Natural (as codeine) 2- Semi synthetic e.g. di-hydromorphine& diacetylmorphine (heroin) 3- Synthetic e.g. pethidine 4- Endogenous opiates as endorphins & encephalins

Central Analgesics Non-narcotic- NSAID (Non selective COX inhibitors)

1- Salicylates : Aspirin ,diflunisal2- Para-aminophenol: Acetaminophen,parasetamol3- Aryl-acetic acid :Diclofenac4- Oxicam derivat :Piroxicam,tenoxicam5- Propionic acid derivat :Ibuprofen6-Indole derivat : Indomethacin etc.

Where do NSAIDs Work?Arachidonic AcidProstaglandinsLeukotrienesLipoxygenaseCyclooxygenasePhospholipase A2Cell MembraneSteroids works here:NSAIDs

Two main forms of Cyclooxygenases (COX)Cyclooxygenase-1 (COX-1)

Constitutively expressedPlays an important role in Gastric mucosaKidney PlateletsProduces prostaglandins that mediate homeostatic functionsVascular endotheliumCyclooxygenase-2 (COX-2)

Produces prostaglandins that mediate inflammation, pain, and fever.Induced mainly in sites of inflammation by cytokines

Preferential COX2 Inhibitor- Nimesulide-Meloxicam- Nabumatone

Selective COX2 Inhibitors: - celecoxib - etoricoxib - parecoxib

Analgesic-antipyretic with poor antiinflammatory actionPara-aminophenol derivat.: Acetaminophen (parasetamol)

Pyrazolon dervat. : Metamizol

NSAIDs We Know And Love:Salicylates AspirinPropionic Acid DerivativesIbuprofen, naproxenIndolacetic AcidsIndomethacin

Lllmann, Color Atlas of Pharmacology 2nd Ed. (2000)

WHO Ladder1. Mild AspirinAPAPNSAIDs+/- Adjuvants2. ModerateCodeineHydrocodoneOxycodoneDihydroxycodoneTramadol+/- Adjuvants3. SevereMorphineHydromorphoneMethadoneLevorphanolFentanylOxycodone+/- Adjuvants

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Onset: Pain has been present since she awoke this morningPalliative: Nothing is making the pain betterProvocative: It hurts slightly worse when palpated, but much worse when pressure on it is released

OPQRST

Quality: Sharp, stabbing painRegion: Pain in the lower right quadrant of her abdomenRadiation: NoneSeverity: 10/10Time: Constant since it began and it keeps getting worse

OPQRST

Mechanism of action of NSAIDsAntiinflammatory effectdue to the inhibition of the enzymes that produce prostaglandin H synthase (cyclooxygenase, or COX), which converts arachidonic acid to prostaglandins, and to TXA2 and prostacyclin.

Mechanism of action of NSAIDsAspirin irreversibly inactivates COX-1 and COX-2 by acetylation of a specific serine residue. This distinguishes it from other NSAIDs, which reversibly inhibit COX-1 and COX-2.

Mechanism of action of NSAIDsAnalgesic effectThe analgesic effect of NSAIDs is thought to be related to: the peripheral inhibition of prostaglandin production may also be due to the inhibition of pain stimuli at a subcortical site.NSAIDs prevent the potentiating action of prostaglandins on endogenous mediators of peripheral nerve stimulation (e.g., bradykinin).

Mechanism of action of NSAIDsAntipyretic effect The antipyretic effect of NSAIDs is believed to be related to: inhibition of production of prostaglandins induced by interleukin-1 (IL-1) and interleukin-6 (IL-6) in the hypothalamus the resetting of the thermoregulatory system, leading to vasodilatation and increased heat loss.

Clinical Pearls on NSAIDS

pathogens or toxins (+) PMNs pyrogen release (+) hypothalamus PG E2 synthesis and release (+) body temperature-regulating center in hypothalamus set point for body temperature heat productionand heat dissipation body temperature(fever)

AspirinBrand Names : A.S.A., Alka-Seltzer, Entrophen, NovasenUses:Low to moderate pain, RA and osteoarthritis, reduce risk of TIA and MIWatch: Not for use in children with chickenpox or influenza due to Reyes syndromeRisk of GI bleedTake with lots of water

Aspirin(Acetylsalicylic acid,(ASA) pharmacokineticsmetabolized in liver by the hydrolyzation to salicylate and acetic acid by esterases . in oral small dosemetabolized in first-order kinetics and half life is 3.5 h, in large dose (1g/time,>4g/day), metabolized in zero-order kinetics because hepatic metablic pathway becomes saturated, which prolong t1/2 of aspirin to 15 h or more to lead to toxication.

pharmacologic effectsAspirin is rapidly deacetylated by esterases in body, producing salicylate which has anti-inflammatory, analgesic,and antipyretic effects. Aspirin irreversibly acetylates cyclooxygenase to inhibit the enzyme activity.1. antipyretic action: rapid and moderate in potency.2. analgesic effects: effective for mild, moderate dull pain.3. antiinflammatory effects: to treat rheumatoid and rheumatic arthritis, symptomatic relief.4.antiplatelet effects: to inhibit platelet aggregation and secondary release of ADP from activated platelets by inhibition of TXA2 production.*

Therapeutic uses 1. hyperpyrexia: middle dose. 2.dull pain: e.g. headache, arthritis, dysmenorrhea etc. middle dose.3.rheumatic fever and rheumatoid arthritis (first-line drugs) in relatively large dose.4. prevention of thromboembolism, stroke, myocardial infarction in small dose. decreasing incidence of transient ischemic attack and unstable angina as well as that of coronary artery thrombosis.5.chronic use of aspirin reduces incidence of colorectal cancer.*

Adverse effects1.gastrointestinal reaction: epigastric distress, nausea, vomiting, gastric ulceration and bleeding. taking aspirin with meal or with sodium bicarbonate, taking enteric- coated aspirin.2. hepatic damage: mild, reversible.3. prolonging bleeding time due to inhibition of platelet functions in small dose and reduction of plasma prothrombin level in large dose.4.large dose of aspirin uncouples oxidative phosphorylation. Energy normally used for production of ATP is dissipated as heat, which explains hyperthermia caused by salicylates when taken in toxic quantities.5.hypersensitivity or allergy.

6.Reyes syndrome: seen during viral infectionsfatal, especially in childrenmanifestations: fulminating hepatitis with cerebral edemachildren should use acetaminophen instead.7.Salicylate toxication (salicylism): mild toxication: headache, mental confusion, drowsiness, difficulty in hearing, vomitingsevere toxication: hyperventilation, severe CNS disturbulance, respiration depression and marked alteration in acid-base balance Medication: discontinuation of salicylates, gastric lavage, relieving symptoms, intravenous infusion of NaHCO3 and dialysis.

Aminophenol Derivatives Acetaminophen=parasetamol Acetaminophen inhibits prostaglandin synthesis in CNS,but less effect on peripheral cyclooxygenase.antipyretic and analgesic effects are similar to aspirin in potencyno anti-inflammatory activity. Use: dull pain and hyperpyrexia., choice for children with viral infections or chicken pox. Adverse effects: skin rash and drug fever, hypoglycemic coma, renal tubular necrosis and renal failure in long-term administration, acute hepatic necrosis in large dose.

ADVERSE EFFECTS of parasetamol Mainly on liver due to its active metabolite ( N-acetyl-p-benzoquinone).At therapeutic doses increases hepatic enzymes.At high doses causes hepatic necrosis & renal necrosis.Treatment of paracetamol toxicity with N-acetylcystine (SH donor ) as life saving

IbuprofenBrand Names : Advil, Motrin, Ibuprin, MediprenUses:Chronic RA, goutWatch: Caution with bleeding abnormalities, renal failureCan cause hyponatremiaA larger loading dose is often used (400-600 mg in adults), followed by 200 mg

Ibuprofenanti-inflammatory, analgesic and antipyretic activity.chronic treatment of rheumatoid and osteoarthritis.less intense of gastrointestinal effects than that of aspirin.

IndomethacinBrand Names : Indameth, Indocid, IndocinUses:Also used with rheumatoid, gouty arthritsCloses PDAs in premature infantsClinical Pearls:Dizziness, hallucinations not uncommon

NaproxenBrand Names : Apo-Naproxen, Naprosyn, Naxen, WalproxUses:Also used with rheumatoid, gouty arthritisClinical Pearls:An OTC drug in Canada, can be purchased without a script in the USMore sustained duration of action than ibuprofen

Other Organic AcidsIndomethacinPharmacologic effectsanti-inflammatory, analgesic and antipyretic effectsmore potent than aspirin as an anti-inflammatory agentinferior to the salisylates at dose tolerated by patients with rheumatoid arthritis. therapeutic uses rheumatoid and rheumatic arthritis, not routinely for analgesia and antipyresis because of its toxicity and side effects.

Adverse effects 35%-50% of patients report some adverse effects and most adverse effects are dose-related.1. gastrointestinal complains.2. CNS effects: frontal headache, dizziness, vertigo, mental confusion etc.3. hematologic effects: neutropenia, thrombocytopenia, inpaired platelet functions, rare aplastic anemia.4. contraindication: in pregnancy or nursing women, patients with psychiatric disorders, epilepsy, parkinsonism, renal diseases, peptic ulcers and machine operators.

Other drugsSulindacfenamates (mefenamic acid, meclofenamate)tolmetinpropionicacid derivatives (naproxen, fenoprofen, ketoprofen, flurbiprofen)piroxicamnabumetoneetodolac, diclofenac, ketorolacin single agent or in the compound preparations.

Summary for this chapter

effects and uses of NSAIDmechanism of action of NSAIDpharmacological basis of small dose of aspirin for prevention of thromboembolismcharacterastics of aspirin, acetaminophen, indomethacin and ibuprofen

COX-2inhibitors Selective (coxibs) PreferentialCOX-3inhibitorsAntipyretic analgesicsNonselectiveCOX-1/COX-2inhibitorsNSAIDsCOX inhibitors

Beneficial actions of NSAIDs dueto prostanoid synthesis inhibition

1. Analgesia prevention of pain nerve ending sensitization2. Antipyresisconnected with influence of thermoregulatorycentre in the hypothalamus3. Antiinflammatory actionmainly antiexudative effect4. Antithrombotic actionin very low daily doses5. Closure of ductus arteriosus

Shared toxicities of NSAIDs dueto prostanoid synthesis inhibition

1. Gastric mucosal damageconnected with PGE inhibition 2. Bleeding: inhibition of platelet function (TxA2 synthesis)3. Limitation of renal blood flow Na+ and water retention4. Delay / prolongation of labourconnected with PGF2 inhibition5. Asthma and anaphylactoid reactionsconnected with PGF2 inhibition

Mechanisms by which NSAIDs may induce mucosal injury Lllmann, Color Atlas of Pharmacology 2nd Ed. (2000)

Opioid AnalgesicsThere are three main families of endogenous opioid peptides; these have analgesic activity and have many physiological functions, but they are not used as drugs.Opioid drugs include:Phenanthrene derivatives, structurally related to morphineSynthetic compounds with dissimilar structures but similar pharmacological effects

Opioid Receptors-receptors are thought to be responsible for most of the analgesic effects of opioids, and for some major unwanted effects (e.g. respiratory depression, euphoria, sedation and dependence). Most of the analgesic opioids are -receptor agonists.

-receptors are probably more important in the periphery, but may also contribute to analgesia.

-receptors contribute to analgesia at the spinal level, and may elicit sedation and dysphoria, but produce relatively few unwanted effects, and do not contribute to dependence. Some analgesics are relatively -selective.

Opioid Receptors-receptors are not true opioid receptors, but are the site of action of certain psychotomimetic drugs, with which some opioids interact.All opioid receptors are linked through G-proteins to inhibition of adenylate cyclase. They also facilitate opening of K+ channels (causing hyperpolarisation), and inhibit opening of Ca2+ channels (inhibiting transmitter release). These membrane effects are linked to the decrease in cAMP formation.

Morphine Pharmacological effects and MechanismsCNS effectsAnalgesia: increasing tolerance of pain are the most prominent effects. Therefore, help patients to eliminate dysphoria, anxiety. Consciousness is not lost, and the patient can usually still locate the source of pain.

MorphineCNS effectsRespiratory depression and suppression of cough: reducing the responsiveness of the respiratory centers in the brain stem to blood levels of carbon dioxide and inhibiting directly the respiratory center.

MorphineCNS effectsNausea and vomiting: stimulating the chemoreceptor trigger zone. In most cases, after therapeutic dose, subsequent doses of morphine do not produce vomiting.

Miosis: pinpoint pupils are indicative of toxic dosage prior to asphyxia. It can be block with atropine.

Morphine Cardiovascular effects:Orthostatic hypotention can occur due to vasomotor medullary depression and histamine release.Gastrointestinal effect:Reduces gastrointestinal motility, causing constipationDecreases biliary and pancreatic secretions.Constriction at the spincter of Oddi causes an increase in biliary pressure.

Morphine Other systemic effects:Increases detrusor muscle tone in the urinary bladder, producing a feeling of urinary. Vesical sphincter tone is also increased, making voiding

Inhibits the cellular immunity and humoral immunity, which is significant in withdrawal syndrome and tolerant in chronic administration.

Pharmacokinetics of MorphineIs well absorbed from the gastrointestinal tract. However, the analgesic effect is greater when drug is administered intramuscularly or intrvenously. It has a significant first-pass effect. Morphine is metabolised to morphine-6-glucuronide, which is more potent as an analgesic.Ninety percent of a given dose is excreted in the urine; the remaining 10% is excreted in the feces.

Contraindications and cautions

Use in patients with head injuresUse during pregnancyUse in patients with impaired pulmonary functionUse in patients with impaired hepatic or renal function

Therapeutic usesAnalgesia, such as the relief of pain from myocardial infaction, terminal illness, surgery, biliary colic and renal colic (combined with atropine).Dyspnea due to pulmonary edema because of sedative, vascular dilataltion and inhibition of the respiratory centers responsiveness to CO2 .Treating severe diarrhea because of constipating effects.Treating cough (usually insteaded by codeine).

Adverse effectsRespiratory depression is the most important effect.Nausea and sometimes dysphoria can occur.Increase biliary tract pressure. Allergic reactions.Bronchoconstrictive action.Tolerance and Dependence

Tolerance and DependenceTolerance develops rapidly, accompanied by physical withdrawal syndrome.The mechanism of tolerance may involve adaptive up-regulation of adenylate cyclase. It is not pharmacokinetic in origin and receptor down-regulation is not a major factor.

Tolerance and DependenceDependence comprises two components: (a) physical dependence (somewhat resembling severe influenza, with yawning, pupillary dilatation, fever, sweating, piloerection, nausea, diarrhoea and insomnia), associated with the withdrawal syndrome, lasting for a few days; (b) psychological dependence, associated with craving, lasting for months or years.

Tolerance and DependenceWeak, long-acting -receptor agonists, such as methadone, may be used to relieve withdrawal symptoms.Certain opioid analgesics, such as codeine and pentazocine, are much less likely to cause physical or psychological dependence.

Contraindications and cautions

Use in patients with head injuresUse during pregnancyUse in patients with impaired pulmonary functionUse in patients with impaired hepatic or renal function

CodeineAlthough the pharmacologic effects of codeine are similar to those of morphine, it has about one-twelfth the analgesic potency of morphine.Be used mainly for cough suppressant and milder pain. It produces less sedation, respiratory depression, fewer gastrointestinal effects, and less addiction and withdrawal.

Synthetic analgesic: PethidineIt is very similar to morphine (one-seventh to one-tenth potent) in pharmacologic effects by -receptor agonists.Therapeutic uses: analgesic, cardiac asthma, sedation (decrease the dosage of anesthetic )and artificial hibernation. It has no gastrointestinal or antitussive action because of shorter-acting.Adverse effect: also causes respiratory depression and possesses addiction liability, although withdrawal effects are less severe than with morphine.

MethadoneIt is widely used as a means of treating morphine and diamorphine addiction because of its chronic and insignificant addiction.

Opioid receptor mixed agonists/antagonistsOther drugs, such as nalorphine and pentazocine, produce a mixture of agonist and antagonist effects.

Opioid AntagonistsPure antagonists include naloxone (short-acting) and naltrexone (long-acting). They block -, - and - receptors more-or-less equally.Naloxone does not affect pain threshold normally, but blocks stress-induced analgesia, and can exacerbate clinical pain.

Opioid AntagonistsNaloxone rapidly reverses opioid-induced analgesia and respiratory depression, and is used mainly to treat opioid overdose or to improve breathing in newborn babies affected by opioids given to the mother.Naloxone precipitates withdrawal symptoms in morphine-dependent patients or animals.

Clinical Use of Analgesic DrugsThe choice and route of administration of analgesic drugs depends on the nature and duration of the pain.A progressive approach is often used, starting with nonsteroidal anti-inflammatory drugs, supplemented first by weak opioid analgesics, and then by strong opioids.

Clinical Use of Analgesic DrugsIn general, severe acute pain (e.g. trauma, burns, post-operative pain) is treated with strong opioid drugs (e.g. morphine, fentanyl) given by injection. Mild inflammatory pain (e.g. arthritis) is treated with non-steroidal anti-inflammatory drugs (e.g. aspirin) supplemented by weak opioid drugs (codeine, pentazocine) given orally if required. Severe pain (e.g. cancer pain, severe arthritis or back pain) is treated with strong opioids given orally, intrathecally, epidurally or by subcutaneous injection.

Clinical Use of Analgesic DrugsChronic neuropathic pain is often unresponsive to opioids, and treated with tricyclic antidepressants (e.g. amitriptyline), or other drugs, such as carbamazepine.

Terima kasih untuk perhatian

*The pain experience begins with the nociceptors. These are afferent nerves that respond to noxious stimulation. Different nociceptors may preferentially react to a specific kind noxious stimuli, such as mechanical or temperature sensation. Different types of nociceptors may be found in different sites: for example, the most common cutaneous receptor is the polymodal C fiber, which responds to pressure, temperature and chemical stimuli, whereas skeletal muscle contains mostly chemoreceptors. All nociceptors have an initial high threshold to noxious stimuli, which decreases with repeated stimuli.It is tempting to stop at this point and treat pain as a simple reflex, in which the nociceptor receives a noxious response and transmits it to the brain. Much pain treatment is based on this naive assumption. It is, in reality, a long and complicated journey between the nociceptor and the brain. Signals from the nociceptor are transmitted to the spinal cord. This is done mainly by two fibers: Ad fibers and C fibers. Ad fibers are myelinated and provide the initial pain response. C fibers are unmyelinated and probably cause the slower response felt several seconds after an injury.Most of these fibers enter the spinal cord through the dorsal root ganglion and terminate in the dorsal horn of the spinal cord. Generally they terminate ipsilaterally, but a small number will cross to the contralateral side. The clinical significance of this is not clear, but it may explain the incomplete pain relief seen after unilateral surgical ablation of this area. The dorsal horn is organized into areas, called laminae, and certain pain fibers will predictably go to specific laminae. In the laminae the fibers synapse with second order neurons, which take various pathways to the brain. The best understood pathways are the spinothalamic and spinoreticular pathways. These pathways are named after their points of origin and termination. Modulation of the Stimulus.Local chemicals. No "pain transmitter" has been identified. However, many substances can modulate a nociceptor's response to noxious stimuli. The best understood is substance P, which may work indirectly through vasodilatory effects. Other chemicals that have a role in pain modulation include prostaglandin, serotonin, histamine, acetylcholine, bradykinin, slow-reacting substance of anaphylaxis (SRS-A), calcitonin-gene-related peptide (CGRP), and potassium.Higher down-modulation. Virtually every part of the pain system can reciprocally affect other parts, and the system should be envisioned as bidirectional. The cortex, in particular, can influence all previous stages of pain transmission through a variety of means. The most obvious is through attentional processes. Most of us are familiar with stories of combat victims who performed heroic acts after injury, apparently unaware of their pain until hours later. More common are reports from chronic pain patients that their pain seems to get worse at night, presumably when there is less distraction. The meaning of pain can also influence its perception--for example, pain perceived as jeopardizing health (e.g.. cancer pain) can seem worse than pain that is not life threatening. Finally, a variety of learned phenomena, such as cultural factors, can affect one's perception and expression of pain.

Use aids at your disposal to gather the most accurate information as possible. ***