Analgesic

Hendra Wana Nuramin, dr., M.Sc

Department of Pharmacology
Faculty of Medicine
Lambung Mangkurat University

1 10/6/2016
 Pain Management
What is pain?
A protective mechanism to warn of damage or
the presence of disease
Part of the normal healing process
 Classification of Pain
By Onset and Duration
Acute pain
Sudden in onset
Usually subsides once
treated

Chronic pain
Persistent or recurring
Often difficult to treat
 Major Sources of Pain
Source Area Involved Characteristics Treatment

Somatic body throbbing, narcotics,

framework stabbing NSAIDS

Visceral kidneys, aching, narcotics,

intestines, throbbing, NSAIDS
liver sharp, crampy

Neuropathic Nerves burning, narcotics,

numbing, NSAIDS,
tingling antidepressants,
anticonvulsants
 Pain unpleasant
sensory and emotional
experience.
Analgetic any
member of the group
of drugs used to
achieve analgesia -
relief from pain
 Therapeutic Strategies for Pain
and Disability
Pharmacotherapy Surgical approaches
Rehabilitative Neurostimulatory
approaches approaches
Psychologic approaches Complementary and
Anesthesiologic alternative approaches
approaches Lifestyle changes
 Pharmacotherapy for Pain
Categories of analgesic drugs
Opioid analgesics
Nonopioid analgesics
 Indications for NSAIDs administration
headache
toothache
backache
neuralgias
pulled muscles
joint pain
Dysmenorrhea
 COX Enzyme:Prostaglandin Effects
COX-1: beneficial COX-2: harmful
Peripheral injury Inflammation
site
Brain Modulate pain
perception
Promote fever
(hypothalamus)
Stomach protect mucosa
Platelets aggregation

Kidney vasodilation
 NSAIDs
Mechanism
Inhibit both peripheral and central cyclo-
oxygenase, reducing prostaglandin formation
2 isoforms of COX
COX-1: Constitutive, physiologic
COX-2: Inducible, inflammatory
 Mechanism of action of NSAIDs
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
 Common Pharmacological Effects
Analgesic (CNS and peripheral effect) may involve
non-PG related effects
Antipyretic (CNS effect)
Anti-inflammatory (except acetaminophen) due
mainly to PG inhibition
 COX-1

COX-2
Steroids work
here
COX-3

Steroids work
here NSAIDs work
here

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 NSAIDs
Properties
Nonspecific analgesics, but greater effectiveness
likely in inflammatory pains
Dose-dependent effects
Marked individual variation in response to
different drugs
Drug-to-drug variation in toxicities partly
determined by COX-1/COX-2 selectivity
 NSAIDs
Properties
Adverse effects: GI toxicity, renal toxicity, bleeding
diathesis
GI toxicity reduced by proton pump inhibitors,
misoprostol, and possibly high-dose histamine-2
blockers
COX-2 selective inhibitors have better GI safety profile
Use with caution in patients with renal
insufficiency, congestive heart failure, or volume
overload
 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
 Nonopioid Analgesics
Acetaminophen (paracetamol)
Minimal anti-inflammatory effects
Fewer adverse effects than other nonopioid
analgesics
Adverse effects
Renal toxicity
Risk for hepatotoxicity at high doses
Increased risk with liver disease or chronic alcoholism
No effect on platelet function
 Paracetamol (Acetaminophen)
N-Acetyl-P-Aminophenol

Classification: analgesic, antipyretic, misc. not

an NSAID
Mechanism: inhibits prostaglandin synthesis
via CNS inhibition of COX (not peripheral)-
doesnt promote ulcers, bleeding or renal
failure; peripherally blocks generation of pain
impulses,
inhibits hypothalamic heat-regulation center
 Paracetamol
Tablets Pharmacokinetics
Suppositories Metabolism: major and
Syrups minor pathways
Soluble tablets Half-life: 1-3 hours
Capsules Time to peak
concentration: 10-60
min
Treatment for overdose:
Acetylcysteine
 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
Absorption: from stomach and
intestine
Distribution: readily, into most
fluids/tissues
Metabolism : primarily hepatic
ASA contraindicated for use in
children with viral fever can
lead to Reyes Syndrome
Fatal overdose is possible
Similar pharmacokinetics for
ibuprofen and related NSAIDs
 Ketorolac
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
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
Pharmacokinetic
Ong CKS, et al. An Evidence-Based Update on Nonsteroidal Anti-Inflammatory Drugs. Clin Med Res. 2007;5(1): 1934.
Traditional and selective COX-2
inhibitors
(Park, Vascular Health and Risk Management 2014:10 2532)
 OPIOID ANALGESICS
History
Opium is extracted from poppy
seeds (Papaver somniforum)
Used for thousands of years to
produce:
Euphoria
Analgesia
Sedation
Relief from diarrhea
Cough suppression
 History
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
Morpheus
is the Greek god of
dreams and sleep.

Friedrich Wilhelm Adam

Sertrner, a German
pharmacist, isolated
Morphine from opium,
in 1805.
 Opioid Therapy in Pain Related to
Medical Illness

Opioid therapy is the mainstay approach for

Acute pain
Cancer pain
AIDS pain
Pain in advanced illnesses

But undertreatment is a major problem

 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 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
depression +
Euphoria + +
Dysphoria +
Decrease GI
motility +
Physical
Dependence +
Mania,
hallucination +
 Morphine CNS
Depressant effects Stimulate effects
Analgesia CTZ (nausea, vimiting)
Indifference to surroundings Edinger Wesphal nucleus (III
Mood and subjective effects nerve producing miosis)
Depression of respiration Vagal centre (bradycardia)
Cough centre
Temperature regulating
centre
Vasomotor centre
Morphine can be used as an analgesic
pain in myocardial infarction
pain associated with surgical conditions, pre- and
postoperatively (pre-anesthetic medication, balanced
anesthesia, surgical analgesia)
pain associated with trauma, burns
severe chronic pain, e.g., cancer
pain 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)
Opioid Therapy: Routes of Administration

Oral and transdermalpreferred

Oral transmucosalavailable for fentanyl
and used for breakthrough pain
Rectal routelimited use
ParenteralSC and IV preferred and feasible
for long-term therapy
Intraspinalintrathecal generally preferred
for long-term use
 Morphine Hydrochloride
routes 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 hours, Maximum single
dose of morphine is 0,02 g, maximum daily dose 0,05 g
 Side effects of morphine
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 blood pressure
 CONTRAINDICATIONS FOR
ADMINISTRATION OF 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
Precaution
pain that accompanies chronic inflammatory pain
children before the age of 2 years
 Fentanyl
synthetic opioid analgesic of short action
analgesic activity is up to 100 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
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
 TRAMADOL
Administration Analgesic activity is similar
surgery, traumatology, to the activity of morphine
gynecology, neurology, Abuse potential is low
urology, oncology Less respiratory depression
For all kinds of acute and Hemodynamic effects are
chronic pain of moderate minimal
and considerable intensity, In case of intravenous
including neuralgias, administration effect
postoperative, traumatic develops after 5-10 min, if
pain diagnostic and administered orally after
therapeutic interventions 30-40 min, action lasts for
oncologic pathology 3-5 hours.
Tramadol possesses agonist actions at the -opioid receptor and affects
reuptake at the noradrenergic and serotonergic systems
 Opioid Responsiveness
Opioid dose titration over time is critical to
successful opioid therapy
Goal: Increase dose until pain relief is adequate or
intolerable and unmanageable side effects occur
Responsiveness of an individual patient to a specific
drug cannot be determined unless dose was
increased to treatment-limiting toxicity
 Tolerance
Tolerance is a diminished responsiveness to the
drugs 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 Reactions
Acute Action Withdrawl Sign
Analgesia Pain and irritability
Respiratory Depression Hyperventilation
Euphoria Dysphoria and depression
Relaxation and sleep Restlessness and insomnia
Tranquilization Fearfulness and hostility
Decreased blood pressure Increased blood pressure
Constipation Diarrhea
Pupillary constriction Pupillary dilation
Hypothermia Hyperthermia
Drying of secretions Lacrimation, runny nose
Reduced sex drive Spontaneous ejaculation
Flushed and warm skin Chilliness and gooseflesh
Triad in case poisoning with morphine
Acute miosis (Pinpoint
pupils)
Cheyne Stokes
respiration
deep tendon reflexes
increased
 Treatment of acute poisoning
Naloxon (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 % 2 and 93-95 % O2)
Contact: hendranuramin@gmail.com

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