Pain Pharmacology

1. •PHARMACOLOGY OF PAIN

2. Overview of Pain

3. Overview of Pain
• In order to gain better understanding of the mechanism of action of
analgesics, first we need to quickly review the transmission of pain
again.
• Pain begins at the nociceptors, which are simply the branching ends
of sensory neurons found within the peripheral nervous system.
• These high threshold primary sensory neurons respond to damage to
the body by transmitting the painful stimulus to the second-order
neurons in the dorsal horn of the spinal cord.
• From there the signal is carried through the spinothalamic tract to the
thalamus, and then to the somatosensory cortex where pain is
perceived.

4. Afferent & Efferent neurons
A cross-sectional look at the spinal cord
reveal three types of neurons that are of
importance to us
1. Afferent neurons which carry signals to
the CNS from sensory receptors in
peripheral tissues
2. Efferent neurons that carry signals from
the CNS to the effector organs such as
muscle
and
3. interneurons which are located in
between afferent and efferent neurons and
integrate information that flows between
the two

5. Overview of Pain-2

6. Overview of Pain-2
• On a microscopic level, the pain signal takes the form of a series of action potentials
Neurotransmission of pain signal that fire repeatedly depending on the intensity of pain.
• To enhance movement across the synaptic cleft, transmitter chemicals are released from the
presynaptic neurons, including glutamate, substance P, and calcitonin gene-related peptide,
(CGRP).
• Glutamate is one of the most important neurotransmitters for pain and can activate both NMDA and AMPAreceptors, which permit influx of
positively charged calcium and sodium ions respectively. This flow of positively charged ions into the neuron, makes the neuron more likely to
fire. In this way glutamate excites the second-order neurons in the dorsal horn, which leads to propagation of a sharp, localized pain signal.
• Substance P, on the other hand, binds to the neurokinin-1 (NK-1), which leads to intracellular signaling that involves activation of arachidonic
acid pathways, nitric oxide synthesis and activation of NMDA receptors. NMDA receptors are activated when Substance P attaches to NK-1
receptors and then gets incorporated into the cell, activating Protein Kinase-C. This action removes the magnesium that under normal
conditions is blocking NMDA receptor. This in turn allows glutamate to attach to the NMDA receptor and thus permit the inflow of calcium ions,
ultimately causing the pain signal to increase and fire more frequently.
• Lastly, the released CGRP binds to its receptor on second order neurons leading to changesin receptor expression and function and thereby
altered neuronal activity. This in turn contributes to the so-called central sensitization that is characterized by lowered threshold for evoking
action potentials.

8. Outline
• Introduction
• Review of Pain origin
• Source
• Function
• Current Views

9. • Opioids, sometimes called narcotics, are a group of drugs that act on
the central nervous system to produce morphine-like effects such as
pain relief and euphoria.
• This pharmacology lecture covers topics such as nociceptive pain
pathway, role of glutamate, substance P, and calcitonin gene–related
peptide (CGRP) in pain processing, endogenous opioids
(enkephalins, endorphins, dynorphins), NMDA, AMPA, NK-1, CGRP
receptors, opioid receptors (mu, delta, kappa) mechanism of action
and side effects of narcotic drugs, development of opioid tolerance
and addiction, partial mu-receptor opioid agonist and antagonist.
• Drugs mentioned include; Morphine, Fentanyl, Hydrocodone,
Hydromorphone, Methadone, Meperidine, Oxycodone, Oxymorphone,
Buprenorphine, and Naloxone.

10. • Human bodies can cope with certain amount of pain by releasing so-called
Endogenous opioids & opioid receptors
endogenous opioids.
• There are three major families of endogenous opioids: the enkephalins, dynorphins,
and endorphins.
• Endogenous opioids exert their effects by binding to opioid receptors, which are
abundantly present in the central and peripheral nervous systems.
There are three major types of opioid receptors, that is; µ (mu), δ (delta) and k (kappa).
• In general, all three receptors differ in their cellular distribution, their relative affinity
for various opioid ligands and their contribution to specific opioid effects.
• All opioid receptors are 7-transmembrane spanning proteins that couple to inhibitory
G-proteins and they are all present in high concentrations in the dorsal horn of the
spinal cord.

11. • Activation of these receptors by an agonist, such as the endogenous μ-opioid
peptide endorphin causes closing of the voltage-gated calcium channels on the
presynaptic nerve terminals which in turn decreases the release of
neurotransmitters, such as glutamate, substance P and calcitonin-gene-related-
peptide.
• In addition to that, activation of opioid receptors leads to opening of potassium
channels, allowing efflux of potassium ions which in turn results in
hyperpolarization, rendering neurons less sensitive to excitatory inputs.
• The majority of currently available opioid analgesics act primarily at the μ-opioid
• Synthetic opioids receptors essentially mimicking the effects of endogenous
opioid peptides.
• However, while naturally-derived opioids can only reach a certain potency, the
synthetically-produced opioids are refined and processed to be much more
powerful.

12. Review on Opioid
• Opioid Analgesics
• Endogenous opiate peptides represented by
• Endorphins
• Enkephalins
• Dynorphins
• Has 3 receptor family types:µ; ƙ; Δ
• Found Pre/Post synaptically
• Cause inhibition through Gi coupling
• Decrease cAMP
• CNS Depressant
• µ receptor pharmacology is for pain and it’s the most
important pharmacologically.
• Morphine is the prototype of µ Agonist

13. Pharmacology of Morphine
• They are dissociative drugs in nature.
• Analgesia:
• Has central, spinal and peripheral effects.
• Sedation
• Respiratory depression:
• µ receptor are at the PCO2 centre in the brain stem
• CVS
• Minimal effects on the Heart
• Histamine mediated release vasodilatation/ hypotension
• Eg Meperidine and morphine
• Meperidine in particular produces tachycardia due to its structural similarity to
Atropine.
• Other opioids generally produce a dose-dependent bradycardia by increasing the
centrally mediated vagal stimulation.

14. Pharmacology of Morphine-2
• Smooth Muscle:
• Longitudinal release
• Circular constriction
• GI: Decrease peristalsis, constipation, cramping
• GU: Urinary retention, Urgency to void, also increase sphincter tone
and thus may cause urinary retention
• Biliary: Increase pressure
• Pupils: Miosis
• They are dissociative drugs in nature.
• Cough Suppressions
• Antitussive action
• Independent of analgesia and respiratory depression eg:
Dexomethophan a selective µ2 receptor Agonist

15. Pharmacology of Morphine-3
• Nausea and vomiting through dopamine receptors.
• Increase histamine release: Morphine behaves like
a hapten
• PK:
• Glucoronidation
• Morphine -6-Glucoronide is highly active.
• Caution in renal dysfunction

16. Morphine
ACTION DRUG CHARACTERISTICS
Full Agonist Meperidine
Methadone
t½ 2-3days
Also antimuscarinic –No miosis, Tachycardia, No spasm
GI/GU/Gall Bladder
Metabolized by CytP450 to normeperidine a serotonin reuptake
inhibitor, which can cause seizure.
Used in maintenance of Opiate Addicts
Partial Agonist Codeine
Burprenorphine,
Pentazocine
Cough Suppressant
Analgesia
Used in Combination with NSAIDs
Precipitation of withdrawal
Mixed Agonist Nalbuphine Ƙ Agonist- Spinal anaesthesia and dysphoria
µ Antagonist- Precipitation of withdrawal
Antagonist Naloxone
Naltrexone
IV use for reversal of respiratory depression
Also available orally for decreasing craving for alcohol, also used
in opiate addiction

17. Side note
• its important to note that Methadone is not only a potent μ-receptor
agonist but also a potent antagonist of the NMDA receptor as well
as norepinephrine and serotonin reuptake inhibitor.
• These properties make Methadone useful for treatment of both
nociceptive and neuropathic pain.
• Opioids are known to be associated with suppression of the
immune system, as opioid receptors are involved with regulation of
immunity.
• Heroin has no medical advantage

18. Side Effects
In addition to producing analgesia, activation of the opioid receptors in
other parts of the body can bring about many side effects.
For example, all opioids produce some degree of nausea, which is due
to direct stimulation of the chemoreceptor trigger zone in the medulla.
All opioids can cause itching via central action on pruritoceptive neural
circuits.
• Toxicity:
• Pinpoint pupil; Respiratory depression, Coma.
• Management of Acute Toxicity: Supportive and IV Naloxone

19. continuation
• the biggest problem with opioids is that they have the potential to cause
addiction by causing both physical and psychological dependence.
• The euphoric effect appears to involve GABA-inhibitory interneurons of the ventral
tegmental area of the brain.
• Normally, GABA reduces the amount of dopamine released in the nucleus
accumbens, which is a brain structure that is part of our pleasure and reward
system.
• However, when opioids attach to and activate the µ receptors in that area, the
release of GABA becomes suppressed.
• This in turn increases dopamine activity and thereby increases the amount of
pleasure felt.

20. Contd
• On the other hand, prolonged, regular use of opioids leads to desensitization of receptor signaling
and down-regulation of the receptors and thus a decrease in sensitivity to the effects of opioids.
• As a result, when regular opioid use is reduced or suddenly stopped, the lack of receptor activity is
manifested as withdrawal symptoms.
• These symptoms generally are opposite to the pharmacological effects of the opioid drugs.
Rather than causing constipation and slowing respiration, the brain stem triggers diarrhea and
elevates blood pressure.
• Instead of triggering happiness, the nucleus accumbens and amygdala reinforce feelings of
dysphoria and anxiety.
• All of this negativity feeds into the prefrontal cortex, further pushing a desire for opioids.

21. Abuse Liability of Opioid Analgesics
• Tolerance: Pharmacodynamics: Occurs to
all effects except miosis and
constipation; urinary retention; Euphoria,
sedation goes away.
• Dependence: Physical and Psychological
• Withdrawal:
• Yawning, lacrimation, rhinorrhea, salivation.
• Anxiety, sweating, goosebumps
• Muscle cramps, spasms, CNS originating
pain

22. Abuse Liability of Opioid Analgesics-2
•Management of withdrawal
•Supportive
•Methadone
•Clonidine

23. Opiate-related drugs with specific
indication
•Loperamide
• Opiates that is not absorbed
• Prevents motility
• Used in Diarrhoea disease
•Dextromethorphan
• Used for cough
• Acts at µ2 receptor
• Devoid of Abuse liability

24. Short Answer
• Mention 3 major toxicity of opioid
• What one side effects can opioid not develop tolerance to?
• Mention 3 non analgesic uses of opioid

25. •THE
END

26. Local Anaesthesia(LA)

27. Outline
• Overview
• What is local anesthesia?
• Mechanism of action
• Factors affecting anesthesia
• Criteria for good anesthetic action
• Pharmacological actions
• Adverse effects
• Classification of local anesthetics
• Learning Points

28. Overview
• Local anesthetics are used to block nerve transmission, to reduce or
eliminate sensation of pain in small area of the body without affecting
consciousness.
• Drugs mentioned include; Bupivacaine, Lidocaine, Mepivacaine,
Procaine, Ropivacaine, and Tetracaine.

30. What is local anesthesia?
•LA are drugs that block
sensory transmission
from a local area to the
CNS.
•They do this reversibly

31. Mechanism of action
• They are weak bases with hydrophillic and
lipophyllic groups and unionized to cross
membrane of nerves
• At tissue pH(7.4), they exist as partly ionized or
partly unionized
• Ionized= Water soluble- likely excreted easily by
kidney (increased renal clearance)
• Non-ionized= Fat soluble- Quickly reabsorbed
• Weak base in basic medium is unionized
• Only non-ionized forms undergo active secretion and
active or passive reabsorption

32. Mechanism of action-2
• Partly Non-Ionized
• Enters the nerve axoplasm->Re- Ionization of LA->Finds its receptor in
open state(Na+), blocking the Na+ channel from inside-> binds more tightly
to the Inactivated state -> prolongs this inactivation-> no Na+ entry/ No
AMP-> No impulse to CNS; Hence Local Anaesthesia
• Add Bicarbonate to a local anaesthetic to hasten MOA
• Non-ionized forms crosses axonal membrane
• From within ionized form block the inactivated sodium channels
• Slow recovery and prevent propagation of action potentials
• Nerve fibres most sensitive to blockage are smaller diameter and have high
firing state
• To minimised or limit spread use α1Agonist
• Cocaine is an uptake inhibitor of NEPR which will cause vasoconstriction, hence when
sniffed can cause nasal septa perforation. Cocaine also has an intrinsic self-sufficient
sympathomimetic activity

33. Factors affecting local anesthesia
• pKa
• If pKa is increased, the ionized fraction is increased and the anaesthetic action is
decreased.
• Plasma Protein Binding (PPB)
• Increased PPB-> Longer duration
• Bupivacaine> Procaine
• Rate of diffusion
• If Initial concentration is higher, then Rapid Onset
• Lipid Solubility(LS)
• Increase in LS-> Increased Potency
• Lignocaine> Procaine
• Vasocontriction
• Increases duration
• Decreases bleeding
• Decreases systemic toxicity

34. Criteria for good local anesthetic action
• pH
• The higher the pH in the tissues for which LA(weak base) is injected, it exists in its
un-ionized form thus rapidly absorbed into its axon
• The lower the pH(eg nerve injury), there will be decreased penetration and
decreased effectiveness
• Diameter
• Smaller> Larger
• The greater the diameter of the nerve fibre, the longer it will take to anesthesize
• Myelination
• Myelinated are blocked faster than non myelinated nerve of the same diameter
• Sensory
• Blocked earlier because of their rapid firing and rapid action potential than non
sensory fibres
• Location
• Fibres located in the circumference of the nerve are blocked 1st

35. Pharmacological actions and Adverse effects
• CNS
• Peripheral
• Anaesthesia starts with
• SENSORY FIBRE: Pain->Temperature->Touch->Pressure-
• Anaesthesia Later
• Motor fibres
• Central
• Initial-> CNS stimulation
• Euphoria, Excitement, tremor, twitching and, restlessness
• In High doses-> CNS depression
• Convulsions, Unconsciousness, Respiratory depression, coma, death
• CVS
• Heart
• Depressant action
• Decrease in conductance, contractility, CO, HR; Decrease abnormal or ectopic pace maker
• Increase effective RP
• Bupivacaine is the most cardio toxic with arrhythmias and bradycardia
• Blood vessels
• Vasodilatation; Myocardial depression, decrease venous return then hypotension
• Skin
• Allergic reactions(Via PABA formation)
• often attributed to additives such as metabisulfite or methylparaben
• breakdown product created by the action of serum pseudocholinesterases on the amino ester paraaminobenzoic acid (PABA)
• Mucosal irritation

36. Techniques of local anesthetics
• Infiltration
• Directly into tissue; small area
• Used for abscess drainage, small swelling excision, cut wound lacerations etc
• Conduction block
• Field block
• Area distal to injection site is blocked
• Used for minor procedure of the abdominal wall, extremities, scalp etc
• Nerve block
• Close to nerve; area of the nerve supply is blocked; LA required is less than field block or
infiltration.
• Used in brachial plexus or cervical plexus block
• Spinal
• LA injected into subarachnioid space around L2-3 or L3-4; below the umbilicus
• Used for C-section, Perineum surgeries, Obstetric procedures
• Epidural
• Injected into thoracic or lumber roots, used in obstetric procedures

37. Classification of local anesthetics
• Structure
• Esters
• Procaine, cocaine, benzocaine, metabolised by plasma and tissue esterases (Genotype
polymorphism and hypersensitivity to PABA) ;
• Amides
• Lidocaine, Bupivacaine, mepivacaine metabolised by liver Amides
• Clinical
• Topical(Surface)
• BOBB-TLC: Benzocaine, Oxethazaine, Butylaminobenzoate,
Benoxinate,Tetracaine, Lignocaine, Cocaine
• Injectable
• Slow acting (Low Potency): Please complain
• Intermediates acting(Intermediate potency): about little myco plasma
• Long acting(High potency); To be decent and respectful

38. Characteristics of Structural LA
•
Variable Esters Amides
Duration of action Short Long
Onset of action Slow Rapid
Tissue Penetration Poor Good
Degradation Plasma Cholinesterase Hepatic Microsomal Enzyme
Allergic reaction Common Rare
Examples Cocaine, Procaine, Tetracaine Lidocaine, Bupivacaine,
mepivacaine pivacaine,
Uses Infiltration, nerve block All techniques- Spinal ,
epidural, regional,nerve block,
infiltration, and surface
anesthesia
Others - Binds to α1 acid glycoprotein in
plasma

39. Characteristics of Topical
• Benoxinate
• Corneal anaesthesia; Soluble
• Oxethazaine
• Gastric Anaesthesia; Insoluble ;with antacids
• Butylaminobenzoate (Butamben)
• Lozenges, anal fissures, haemorroids; Insoluble
• Benzocaine
• Lozenges, anal fissures, haemorroids; Insoluble (poorly water soluble)
• Tetracaine(Amethocaine)
• Long acting; The only exception used for spinal anaesthesia as an ester
• Lignocaine(Lidocaine
• Prototype of the Amides ; Soluble
• Cocaine
• Intrinsic sympathomimetic activity; Avoid vasocontrictors; Addictive properties; causes
decrease reuptake of NA ; Soluble

40. Characteristics of Injectable
• Slow acting
• Procaine(Ester with slow onset); Although clinically insignificant-has anticholinergic,
antihistaminic, ganglionic and NM blocking action
• Chloroprocaine (ester but has fast onset)
• Intermediate acting
• Articaine: Not used in pulmonary and cardiac patient as it causes methhaemoglobinaemia
• Lignocaine: Amide used for ventricular arrythmia
• Mepivacaine: Not used for surface anaesthesia
• Prilocaine: Not used in pulmonary and cardiac patient as it causes methhaemoglobinaemia
• Long acting
• Tetracaine
• Bupivacaine: severely cardio toxic
• Dibucaine: used as topical anaesthetics
• Ropivacaine: less cardio toxic

41. Comparison between GA and LA
S/No Features GA LA
1 Site of action CNS Peripheral Nerves
2 Area of body involved Whole body Limited Area
3 Consciousness Lost Unaffected
4 Care of vital functions Crucial Typically not
monitored
5 Physiological trespass High Low
6 Poor health Patients Risky Safer
7 Use in non cooperative patients Likely Unlikely
8 Major Surgery Most Suitable Not used
9 Minor Surgery Unnecessary Highly indicated

42. Learning Points

43. Learning Point-2
• Local Anaesthesia
• They produce a transient loss of sensory perception especially of pain in a
localized area of the body without producing unconsciousness
• How does Local Anaesthesia work
• Due to their distinct chemical properties, LA are able to pass through the
neuronal membrane and bind to a specific receptor at the opening of the
voltage gated sodium channel thus preventing sodium influx. This in turn
prevents the initiation and conduction of action potentials which ultimately
leads to loss of sensation in the are supplied by the nerve ‘
• Examples
• Bupivacaine, Lidocaine, Mepivacaine, Procaine, Ropivacaine, and Tetracaine
• SE
• Serious reactions are rare. However with systemic toxicity, patients may
experience blurry vision, lightheadedness, seizures, cardiac arrythmias,

44. •That’s All

45. Short Answer
• Classify LA

46. •ALTERNATIVE MEDICINE

47. Other agents used in Pain management
• Cooling- Ice, Snow, Ethylchloride spray
• Propranolol
• Chlopromazine
• H1 antihistamines
• Quinine
• All have significant LA activity. Use of these
agents as LA are limited due to local irritation and
systemic sides effects

48. Sodium channel toxin
• Tetradotoxin- Produced in the liver and gall bladder
of the fubu or pafa fish; Sodium channel blocker
• Saxitoxin- Red tides
• They block the activated portion of sodium channel
reversibly , decreasing conductance
• Ciguatoxin and Batrachotoxin(found in frog): They
keep sodium channel open for too long
• Grouper or Baracuda- Ciguatera- parasite in fish causing
irreversible damage by lowering the threshold for
sodium channels

49. Alcohols
• Causes depression via GABA A mimetic activity
• Causes metabolic acidosis
• All have GABA A pharmacology
• Examples
• Ethylene glycol, methanol, ethanol
• Metabolism
• By non microsomal oxidation involving dehydrogenases
• It is a 2step process
• Alcohol dehydrogenase
• Aldehyde dehydrogenase
• End point is an acid

50. Alcohols
•Actions of Alcohol on the body
• CNS
• Dose dependent depression
• Initial stimulation then depression
• Facilitate GABA
• Inhibits NMDA receptor

51. Alcohols-2
• Ethylene glycol->Glycoaldehyde->Acid-> glycolic acid->Oxalic Acid
• Causes CNS Depression, nephrotoxicity (due to oxalic acid); resp failure, met acidosis
• Methanol->Formaldehyde->Formic Acid
• Methanol has an intermediate called formaldehyde which causes ototoxicity and blindness;
formic acid causes resp failure, met acidosis, flickering white storm=methanol toxicity
• Treatment: give ethanol as it has higher affinity for alcohol dehydrogenase OR Formepizole- a
long acting inhibitor of aldehyde dehydrogenase
• Ethanol-> Acetaldehyde-> Acetic Acid(Inhibited by disulfiram)
• Acute toxicity: CNS depression; Met acidosis, acute pancreatitis
• 2 Enzymes- Alcohol dehydrogenase(zero order kinetics) and Acetaldehyde
dehydrogenase

52. Non Pharmacologic options
Positive psychology (PS)and improved social connections(SC):
-PS:The study of strengths & virtues that allow individuals & communities to
thrive. It does not minimize misery but rather focuses on amplifying
happiness through positive affect & individual strengths & virtues.
-SC: the quality, state or capability of being connected. Social connectivity
decreases stress & anxiety by activating the parasympathetic nervous system
unlike stress which activates the sympathetic nervous system.
• Mindful Meditation
• Yoga

53. That’s it! Go through this slide-set a couple
of times (at least) until you feel like you
have a handle on it. When you’re ready, do
study past question, which broadens your
understanding of this material in a Q&A
format (and more detail).

54. •THE
END