ANALGESICSANALGESICS

Pain ManagementWhat is pain?

– A protective mechanism to warn of damage or the presence of disease

– Part of the normal healing process

ANALGESICSANALGESICSI. Opioid (narcotic) analgesics

1. Agonists of opioid receptors – morphine hydrochloride, promedol, omnopon, fentanyl, codeine;

2. Agonists – antagonists and partial agonists of opioid receptors – pentazocin, buprenorphine.

II. Non-opioid analgesics and non steroidal anti-inflammatory drugs -

NSAIDs acetylsalicylic acid, paracetamol, analgin, indometacin,

butadion, ibuprofen, pyroxicam, diclofenac-sodium, ketorolac, ketoprofen.

III. Substances with mixed mechanism of action (opioid and non-oioid components)

tramadole

The structures that take part in perception of pain: thalamus, hypothalamus, reticular formation, limbic system, occipital and frontal areas of cortex

System which conducts and perceives pain - nociceptivenociceptive

System which protects organism from pain –

antinociceptiveantinociceptive

Classification of Pain By Onset and Duration

Acute painSudden in onsetUsually subsides once treated

Chronic painPersistent or recurringOften difficult to treat

Major Sources of PainSource Area Involved Characteristics Treatment

Somatic body framework

throbbing, stabbing

narcotics, NSAIDS

Visceral kidneys, intestines, liver

aching, throbbing, sharp, crampy

narcotics, NSAIDS

Neuropathic Nerves burning, numbing, tingling

narcotics, NSAIDS,antidepressants, anticonvulsants

OPIOIDOPIOIDAANALGESICSNALGESICS

History of Opioids• Opium is extracted from poppy seeds

(Papaver somniforum)• Used for thousands of years to

produce:– Euphoria– Analgesia– Sedation– Relief from diarrhea– Cough suppression

History cont’d

• Used medicinally and recreationally from early Greek and Roman times

• Opium and laudanum (opium combined with alcohol) were used to treat almost all known diseases

Friedrich Wilhelm Adam Sertürner, a German pharmacist, isolated Morphine from opium, in 1805.

Morpheusis the Greek god of dreams and sleep.

History and Background• Invention of the hypodermic needle

in 1856 produced drug abusers who self administered opioids by injection

• Controlling the widespread use of opioids has been unsuccessful because of the euphoria, tolerance and physiological dependence that opioids produce

Opioid Opioid receptors• group of G-protein coupled receptors with

opioids as ligands. • The endogenous opioids are dynorphins,

enkephalins, endorphins, endomorphins and nociceptin.

Subtypes of opiod receptors: mu, delta, kappa, epsilon, sigma

Opiod Receptor Activation

Response Mu-1 Mu-2 Kappa Delta Sigma

Analgesia

Respiratory depressionEuphoria

Dysphoria

Decrease GI motilityPhysical

DependenceMania,

hallucination

Morphine CNS

Depressant effects• Analgesia• Indifference to

surroundings• Mood and subjective effects• Depression of respiration • Cough centre • Temperature regulating

centre • Vasomotor centre

Stimulate effects • CTZ (nausea, vimiting)• Edinger Wesphal nucleus(III nerve –producing miosis)• Vagal centre (bradycardia)• Certain cortical areas and

hippocampal

Morphine can be used as an analgesic to relieve:

pain in myocardial infarctionpain associated with surgical conditions, pre- and

postoperatively (pre-anesthetic medication, balanced anesthesia, surgical analgesia)

pain associated with trauma, burns severe chronic pain, e.g., cancerpain from kidney stones, renal colic, ureterolithiasis, etc

(pain may be valuable for diagnosis: should not be relived by analgesic unless proper assessment of the patient has been done)

traumas of thorax accompanied by cough (morphine depresses central links of coughing reflexes)

Acute left-ventricular cardiac failure(cardiac asthma)

Reduce preload on heard due to vasodilatation Tending to shift blood from pulmonary to

systemic circuit; relieves pulmonary congestion and edema

Allays air hunger by depressing respiratory centre

Cuts down sympathetic stimulation by calming the patient

• ,

Applications in Dentistry

• Narcotic (opioid) analgesics are extremely effective in reducing acute dental and postoperative pain.

• The narcotic analgesics have established a niche for the treatment of pain in those situations where the NSAIDs are less effective.

• Hydrocodone, oxycodone, codeine, and occasionally meperidine are the narcotics used to treat dental pain.

MORPHINE HYDROCHLORIDEMORPHINE HYDROCHLORIDE

routes of administrationroutes of administration subcutaneously and intramuscularly (analgesic action after 10-15 min) oral administration – presystemic elimination ( 20-60 % enters general blood circulation) sublingually – quick absorption i.v. is indicated even in emergency Epidural or intrathecal ( into the spinal canal )

injection produces segmental analgesia lasting 12 hours without affecting other sensory, motor or autonomic modalities

Duration of analgesic action – 4-6 hoursMaximum single dose of morphine is 0,02 g,

maximum daily dose – 0,05 g

Side effects of Side effects of morphinemorphine

Respiratory depression Vomiting (excitation of starting zone of

vomiting center) bradycardia (increasing of tone of n.

vagus nuclei) spasm of sphincters of gastro-intestinal

tract accompanied by constipations increasing of tone of smooth

musculature of urinary and bile-excreting tracts (retentions of urination, bile stasis)

Decreasing of BP

CONTRAINDICATIONS FOR ADMINISTRATION CONTRAINDICATIONS FOR ADMINISTRATION OF MORPHINEOF MORPHINE

acute respiratory depression renal failure (due to accumulation of the metabolites morphine-3-

glucuronide and morphine-6-glucuronide) chemical toxicity (potentially lethal in low tolerance subjects) raised intracranial pressure, including head injury (risk of worsening

respiratory depression) Biliary colic

Precauntation pain that accompanies chronicchronic inflammatory pain children before the age of 22 years years

Tolerance • Tolerance is a diminished responsiveness to the

drug’s action that is seen with many compounds• Tolerance can be demonstrated by a decreased

effect from a constant dose of drug or by an increase in the minimum drug dose required to produce a given level of effect

• Physiological tolerance involves changes in the binding of a drug to receptors or changes in receptor transductional processes related to the drug of action

• This type of tolerance occurs in opioids

Addiction• Physical dependence • Physiological dependence• Withdrawal reactions

Tolerance and Dependence

Withdrawl ReactionsAcute Action

• Analgesia• Respiratory Depression• Euphoria• Relaxation and sleep• Tranquilization• Decreased blood pressure• Constipation• Pupillary constriction• Hypothermia• Drying of secretions• Reduced sex drive• Flushed and warm skin

Withdrawl Sign• Pain and irritability• Hyperventilation• Dysphoria and depression• Restlessness and insomnia• Fearfulness and hostility• Increased blood pressure• Diarrhea• Pupillary dilation• Hyperthermia• Lacrimation, runny nose• Spontaneous ejaculation• Chilliness and “gooseflesh”

OMNOPONOMNOPON• contains mixture if opium alkaloids

(48-50% morphine)• does not cause spasms of smooth

musculature, as it contains alkaloids of isoquinoline raw

• is used for analgesia according to all the indications of morphine hydrochloride, for example, colics

Promedol (trimeperidine) Promedol (trimeperidine) • produces similar effects to other opioids, such as

analgesia and sedation, along with side effects such as nausea, itching, vomiting and respiratory depression which may be harmful or fatal.

• duration of analgesic action - 3-4 hours• moderate spasmolytic influence on smooth

musculature of internal organs• stimulation of rhythmic contractions of uterus • can be used for analgesia• in case of pain syndrome connected with spasms

of smooth musculature

Fentanyl Fentanyl • synthetic opioid analgesic of

short action• analgesic activity is 300 times

higher than of morphine• analgesic effect after intravenous

introduction – after 1-3 min, lasts for 15-30 min

• used with neuroleptic droperidol (complex drug – “talamonal”) for neuroleptanalgesia

fentanyl transdermal system

• should be used for long-term (chronic) pain requiring continuous narcotic pain

• Is designed to release the drug into the skin at a constant rate ranging from 25 to 100 micrograms/h,

Codeine Codeine opium alkaloid analgesic action is not strong,

but anticough effect is considerable

administered as an anticough drug of central action

combination with non opiod analgesics (eg. Paracetamol) is supra-additive

Pentazocin Pentazocin agonist-antagonist of opioid receptors comparatively with morphine, it is a bit less

dangerous in the aspect of addiction development indicated in case of pain of medium intensity in

such conditions like other opioid analgesics. In case of strong pain its administration is limited as in case of increasing of dose of the drug excitation appears

it can cause increasing of blood pressure and tachycardia that’s why it’s not advised to use in case of acute myocardium infarction

if it is administered for people with narcotic addiction manifestations of abstinence develop

Buprenorphine Buprenorphine • Partly agonist of mu-opioid receptors • Acts longer than morphine (approximately 6 hours) • Analgesic activity is higher than of morphine,

that’s why it’s used in doses of 0,3-0,6 mg• In case of breathing depression, which it causes,

naloxon is less effective since buprenorphine is slowly released from the connection with mu-receptors

• Indicated for pain decreasing in the same situations as other narcotic analgesics

• May be used for detoxication and supporting treatment of individuals who is addicted to heroine

Acute poisoning with opioid analgesics

• Respiratory Depression• Euphoria• Relaxation and sleep• Tranquilization• Decreased blood pressure• Constipation• Pupillary constriction• Hypothermia• Drying of secretions• Flushed and warm skin

Triad in case poisoning with

morphine

Acute miosis (Pinpoint pupils)

Cheyne Stokes

respiration

deep tendon reflexes

increased

Treatment of acute poisoning

NaloxonNaloxon (antagonist of opioid receptors) intravenously - 0,4-1,2 mg

general dose of naloxon should not overcome 10 mg stomach lavage (for morphine enterohepatic

circulation is typical) with 0,05-0,1% solution of potassium permanganate and 0,5 % tannin solution

suspension of 20-30 g of activated charcoal salt laxative agents (sodium sulfate) forced diuresis atropine sulfate inhalation of carbogen (5-7 % СО2 and 93-95 % O2)

NON-OPIOID NON-OPIOID ANALGESICSANALGESICS

Pharmacodynamic Effects Pharmacodynamic Effects

• Analgesic• Antipyretic

• Anti-inflammatory (except

paracetamol)

Mechanism of action of non-opioid analgesics

• depression of cyclooxygenases activity• decreasing of prostaglandins synthesis in

peripheral tissues and in central nervous system

• decreasing of sensitivity of nervous endings and depression of transmission of nociceptive impulses on the level of CNS structures

• pain-relieving action of non-opioid analgesics is partly connected with their anti-inflammatory activity

Effects of COX Inhibition by Most NSAIDS

COX-1

Gastric ulcers

Bleeding

Acute renal failure

COX-2

Reduce inflammation

Reduce pain

Reduce fever

NSAIDs : anti-platelet—decreases ability of blood to clot

COX Enzyme:Prostaglandin Effects

COX-1: beneficial COX-2: harmful

Peripheral injury site

Inflammation

Brain Modulate pain perceptionPromote fever (hypothalamus)

Stomach protect mucosa

Platelets aggregation

Kidney vasodilation

Indications for administration of non-narcotic analgesics

headache toothache backache neuralgias pulled muscles joint pain dysmenorrhea for potentiating of their action – combinations

paracetamol with codeine, metamizol with dimedrol, metamizol with

codeine

Applications in Dentistry• Toothache• Post extraction pain• Periodontitis• Neuritis• Stomatitis• Arthritis • Local usage as keratoplatic agents for hyperkeratosis,

hyperesthesia

Paracetamol (Acetaminophen)

• analgesic and antipyretic drug• maximal effect if the drug is

introduced orally – after 2 hours, lasts approximately for 4 hours

• in case of durable administration of big doses – damaging of liver and kidneys, production of met-hemoglobin

Paracetamol (Acetaminophen)N-Acetyl-P-Aminophenol

Classification: analgesic, antipyretic, misc. not an NSAID

Mechanism: inhibits prostaglandin synthesis via CNS inhibition of COX

(not peripheral)- doesn’t promote ulcers, bleeding or renal failure; peripherally blocks generation of pain impulses,

inhibits hypothalamic heat-regulation center

Paracetamol

• Tablets • Suppositories • Syrups • Soluble tablets• Capsules

PARACETAMOLPARACETAMOL

Pharmacokinetics: paracetamolparacetamol

Metabolism: major and minor pathwaysHalf-life: 1-3 hoursTime to peak concentration: 10-60 min

Treatment for overdose: Acetylcysteine

ParacetamolParacetamol Liver Metabolism 1. Major pathway —Majority of drug is metabolized to

produce a non-toxic metabolite2. Minor pathway —Produces a highly reactive

intermediate (acetylimidoquinone) that conjugates with glutathione and is inactivated.

• At toxic paracetamolparacetamol levels, minor pathway metabolism cannot keep up (liver’s supply of glutathione is limited), causing an increase in the reactive intermediate which leads to hepatic toxicity and necrosis

Acetylsalicylic acid Blocks irreversibly COX As antipyretic and analgesic

drug – 0,25 and 0,5 g per time As an anti-inflammatory – 3-4

g per day (for arthritis, myocarditis, pleuritis, bronchitis etc.

As platelets inhibitor - for prophylaxis of thrombus-formation (in case of ischemic heart disease, thrombophlebitis etc.) – daily dose – 80-100 mg

Pharmacokinetics: ASAAbsorption: from stomach and intestineDistribution: readily, into most fluids/tissuesMetabolism : primarily hepatic • ASA contraindicated for use in children with

viral fever –can lead to Reye’s Syndrome• Fatal overdose is possible

Similar pharmacokinetics for ibuprofen and related NSAIDs

Analgin (metamizol-sodium)

Baralgin Baralgin ((maxiganmaxigan, , spazganspazgan, , spazmalgonspazmalgon, , trigantrigan))

metamizol-sodium +pitophenon hydrochloride+pheniverinium bromide

Ampoules tablets suppositories

Analgesic and spasmolytic activity

Traditional and selective COX-2 inhibitors

Ketorolak (ketanov)• according to analgesic activity it

prevails over effect of acetylsalicylic acid, indometacin and equals to opioid analgesics

• moderate anti-inflammatory, antipyretic and anti-aggregate effects

• high effectiveness in case of pain in postoperative period, in oncology, during child delivery, traumas, colic

• i/m, i/v, orally NOT indicated

for chronic pain syndrome

Ketoprophen Ketoprophen ((ketonalketonal))• strong analgesic, anti-inflammatory

and antipyretic agent• administered in case of arthroses

and arthritis, ancilizing spondilitis, pain of different genesis (after surgeries, in case of traumas, painful menstruations etc.)

• administered orally, intramuscularly, in forms of suppositories and ointments

TRAMADOLTRAMADOLAnalgesic activity is similar to the activity

of morphine

Abuse potential is low

Less respiratory depressionHemodynamic effects are minimal

In case of intravenous administration effect develops after 5-10 min, if administered

orally – after 30-40 min, action lasts for 3-5 hours.

Tramadol possesses agonist actions at the μ-opioid receptor and affects reuptake at the noradrenergic and serotonergic systems

ADMINISTRATION OF TRAMADOLADMINISTRATION OF TRAMADOL

surgery, traumatology, gynecology, neurology, urology, oncology

For all kinds of acute and chronic pain of

moderate and considerable intensity, including

neuralgias, postoperative, traumatic pain

diagnostic and therapeutic interventions

oncologic pathology

Thank you!

QUESTIONS?!QUESTIONS?!