This set of 17 slides introduces students to the some of the basic physiological processes that are the targets of many analgesic drug classes. It is suitable for beginner/intermediate level learners.

1. Physiological Analgesia and Analgesic
Drugs
Prof. John A. Peters
Email: j.a.peters@dundee.ac.uk

2. Learning Objectives
Following this lecture and further reading students should be able to:
 Describe common pharmacological strategies employed to manage pain and
how these relate to the WHO pain ladder
 Explain physiological analgesia at the segmental and supraspinal levels
 Understand the mechanism of action of opioid analgesics and be able to
state specific examples of such drugs, their usage and the important adverse
effects of opioids as a class
 Describe the mechanism of action of nonsteroidal anti-inflammatory drugs
(NSAIDs) and be able state those commonly employed in the treatment of
mild/moderate inflammatory pain
 Note the chemical diversity drugs used in the treatment of neuropathic pain
specifying examples and their mechanism of action, as far as is known
 Recommended reading:
• Bear MF, Connors BW, Paradiso MA (2016). ‘Neuroscience: Exploring the Brain’ (4th.
ed.). Chapter 12. pp. 439-448 (introductory treatment providing a very good foundation)
• Neal MJ (2016). ‘Medical Pharmacology at a Glance’ (8th.ed.). Chapter 29. (succinct
account of analgesic drugs)
• Rang HP, Ritter JM, Flower RJ, Henderson G (2016). ‘Rang and Dale’s Pharmacology’
(8th.ed.). Chapter 42. (detailed account of analgesic drugs, particularly opioids)

3. Strategies in the Pharmacological Management of Pain
 Analgesics may reduce nociception by:
• acting at the site of injury – decrease nociceptor sensitization in inflammation
[e.g. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)]
• blocking nerve conduction – (e.g. local anaesthetics) – not considered here
• modifying transmission of nociceptive signals in the dorsal horn of the signal
cord (e.g. opioids and some anti-depressant drugs)
• activating (or potentiating) descending inhibitory controls (e.g. opioids)
• targeting ion channels upregulated in nerve damage
A note on nomenclature:
• Opiates – substances extracted from opium, or of similar structure to those in opium
• Opioids – any agent (including endogenous peptides) that act upon opioid receptors
 The WHO (1986) Analgesic Ladder
 Increasing efficacy
• Strong opioid (e.g. morphine, oxycodone,
hydromorphone, heroin, fentanyl)
• Weak opioid (e.g. codeine, tramadol, dextropropoxyphene)
• NSAID (e.g. aspirin, diclofenac, ibuprofen, indometacin, naproxen)
• Paracetamol (which is not an NSAID) alone, or in combination with a weak opioid
NSAID
Weak opioid
Strong opioid
Rung
3
2
1
Combinations of 1+2, or 1+3,
are often used in moderate/
severe pain

4. Physiology of Pain Modulation
 Segmental anti-nociception – gate control theory (see following slides)
 Supraspinal anti-nociception – descending pathways from brainstem
o Brain regions involved in pain perception and emotion (cortex, amygdala, thalamus,
hypothalamus) project back to the brainstem and spinal cord to modify afferent input
o Important brainstem regions include:
PAGElectrical stimulation + opioids+
NRM LC
++
Inhibition of nociceptive transmission in dorsal horn of spinal cord
__ 5-HT
enkephalins
NA
opioids
+
• the periaqueductal grey (PAG). Excitation by electrical
stimulation produces profound analgesia. Endogenous
opioids (enkephalins), or morphine and related
compounds, also cause excitation (by inhibiting inhibitory
GABAergic interneurones, i.e. disinhibition)
• nucleus raphe magnus (NRM; serotonergic and
enkephalinergic neurones). Morphine causes excitation
• locus coeruleus (LC; noradrenergic neurones)
Axons project via the
dorsolateral funiculus (DLF)

5. Regulation of Pain – Afferent (Segmental Antinociception)
 Perception of pain is variable. For the same degree of nociceptor
activity, depending on the level of concurrent non-painful sensory input
and behavioural context more, or less, pain may be perceived
 Pain evoked by activity in nociceptors (C- and Aδ- fibres) can be
reduced by simultaneous activity in low threshold mechanoreceptors
(Aβ-fibres)
 Pain and nociception are not identical
 Pain is awareness of suffering: nociception may occur in the absence
of pain and vice versa – this is essential to understand
 The term ‘nociceptive afferent’ is preferred to ‘pain afferent’
 The Gate Control Theory of Melzack (right) and Wall (left) helps to explain
these complex phenomena stating:
‘....that nerve impulses, evoked by injury,
are influenced in the spinal cord by other
nerve cells that act like gates, either
preventing the impulses from getting
through, or facilitating their passage.’
(Quotation from Melzack)

6. Gate Control Theory
 Certain neurones (P) within the
substantia gelatinosa project to
the spinothalamic tract and are
postulated to be excited by both
large diameter (Aβ) sensory
axons and unmyelinated (C/Aδ)
nociceptive axons
 The projection neurone (P)
inputs are inhibited by an
interneurone (I) and the
interneurone is excited by the
large sensory axon and inhibited
by the nociceptive axon
 Thus, activity in the nociceptive
axon alone maximally excites the
projection neurone, allowing
nociceptive signals to arise to the
brain
Pain
_
_
_
+ +
+
I P
Central control
Aβ
C/Aδ
The original concept
(Melzack and Wall, 1965)
This scheme has been refined (since all
sensory afferents are excitatory), but its
influence has been immense
The original
concept lacks an
element here
Substantia gelatinosa
 Note: central control (regulating
the ‘gate’) is explicitly posited in
this theory

7. Gate Control Theory – Contemporary View
Aβ
C/Aδ
+
+
+
+
+_
_
P
I
E
To higher centres
(e.g. via spinothalamic
tract)
Dorsal horn
(substantia
gelaninosa)
E: Excitatory interneurone
I: Inhibitory interneurone
P: Projection neurone
Redrawn and modified from Michael-Titus, Revest and
Shortland (2010). The Nervous System (2nd. ed.)
 Note in this scheme the introduction of an
inhibitory neurone (I) that suppresses activation
of (i) the projection neurone (P) directly and (ii)
via inhibition of an excitatory interneurone (E)
that drives the projection neurone. Here, all
primary afferent input is excitatory

8. Simplified Overview of the Mechanism of Action of Opioid Analgesics
Modified from Neal (2016). ‘Medical Pharmacology at a Glance’ (8th. ed.)
Rung 3
Rung 2
Aβ mechanoreceptors
pathophysiologically
Nb. Details of dorsal horn
circuitry are not shown
Excitation of PAG and NRM
neurones is by disinhibition

9. Cellular Action of Opioids and Analgesia
 Opioid action is mediated by G protein coupled opioid receptors, all of
which couple, preferentially, to Gi/o to produce:
• Inhibition of opening of voltage-activated Ca2+ channels (presynaptic effect
– suppresses excitatory neurotransmitter release from nociceptor terminals)
• Opening of K+ channels (postsynaptic effect- suppresses excitation of
projection neurones)
 Opioid receptors are widely distributed throughout the nervous
system and are traditionally classed as:
• μ (mu, aka MOP*) responsible for most of the analgesic action of opioids
– but, unfortunately, also some major adverse effects (e.g. respiratory
depression, constipation, euphoria, sedation, dependence)
• δ (delta, aka DOP*) contributes to analgesia but activation can be
proconvulsant
• κ (kappa, aka KOP*) contributes to analgesia at the spinal and peripheral
level and activation is associated with sedation, dysphoria and
hallucinations
• ORL1 activation produces an anti-opioid effect
*these alternative nomenclatures, although officially approved by NC-IUPHAR, have met with hostile resistance!

10. Actions and Applications of Selected Opioids (1)
 AGONISTS: as analgesics, act mainly
through prolonged activation of μ-opioid
receptors
 Morphine
o very widely used in acute severe pain
and chronic pain (rung 3 on the WHO
ladder)
o in acute severe pain may be given IV
(in high-dependency areas, as
incremental doses), IM, or SC
o in chronic pain oral administration is
most appropriate [as immediate (e.g.
Oramorph ®, or modified release (e.g. MST
Continus ®, formulations)
 Diamorphine (3,6-diacetylmorphine,
heroin)
o more lipophilic than morphine
o rapid onset of action when
administered IV (enters CNS rapidly)
o can be used for post-operative pain (in
some countries, including UK, banned in others)
Diamorphine
3
6
Cleavage to 6-
acetylmorphine and
morphine occurs
rapidly in the CNS and
is required for effect
Morphine
3
6
Nb. In organic
chemistry, an
‘empty’
projection
indicates the
presence of a
methyl (CH3)
substituent

11.  Pethidine (meperidine in USA)
o used in acute pain, particularly labour
o rapid onset of action when given IV, IM, or SC, but
short duration of action and thus not suitable for
control of chronic pain
o should not be used in conjunction with MAO
inhibitors (excitement, convulsions, hyperthermia)
o norpethidine is a neurotoxic metabolite
Actions and Applications of Selected Opioids (2)
 Fentanyl
o given IV to provide analgesia in maintenance anaesthesia
o suitable for transdermal delivery in chronic pain states, but not in acute pain
 Buprenophine
o useful in chronic pain with patient-controlled injection systems
o partial agonist
o slow onset, but long duration of action
o can be given by injection, or sublingually
Codeine
 Codeine (3-methoxymorphine) and dihydrocodeine
o weaker opioids used in mild/moderate pain
o hepatic metabolism (in relatively small amounts)
produces active morphine and dihydromorphine
o given orally, not IV
Hepatic O-demethylation converts CH3
substituent to H, yielding morphine
(subject to genetic variation)

12. Actions and Applications of Selected Opioids (3)
Tramadol
o weak μ-receptor agonist. Probably exerts significant analgesic action by
potentiation of the descending serotonergic (from NRM) and adrenergic
(from LC) systems
o given orally, avoid in patients with epilepsy
 Methadone
o weak μ-agonist with additional actions at other
sites in the CNS, including potassium
channels, NMDA receptors and some 5-HT
receptors
o given orally, long duration of action (plasma
half-life˃24 h.)
o main use is to assist in withdrawal from
‘strong opioids’, such as heroin
As a generalisation, agents with
abuse potential that have a
short half-life are more addictive
than those with a long half-life.
Methadone (although hardly a
cure) helps by reducing the very
serious risks of self-injection
and the need to resort to illegal
activity to support ‘strong
opioid’ drug habit
 Etorphine (Immobilon ®)
o used in veterinary, not human, practice
o 1000-fold more potent than morphine!
o useful in sedation of large animals
o even incorporated into a dart, or pellet, can
‘down an elephant, or rhino’!
o diprenorphine (Revivon ®), weak partial
agonist, reverses the action of etorphine
What
hit me?

13.  Naloxone
o competitive antagonist at μ-receptors (to a lesser extent κ- and δ-receptors)
o used to reverse opioid toxicity (i.e. respiratory and/or neurological
depression) associated with ‘strong opioid’ overdosage
o given incrementally IV. IM and SC routes may also be employed if the IV
route is not practical
o short half-life – very important clinically since opioid toxicity can recur to
‘strong opioid’ agonists with a longer duration of action (clinically, you must
monitor the effect of naloxone very carefully, titrating the individual dose,
and frequency, to that required to reverse opioid toxicity)
o in opioid addicts (or those patients requiring high dose opioid analgesia on
a regular basis) the administration of naloxone may trigger an acute
withdrawal response
o may be given to a newborn displaying opioid toxicity (e.g. respiratory
depression) as a result of administration of pethidine to mother during
labour
 Naltrexone
o is similar to naloxone, but with the advantage of a much longer half-life
Actions and Applications of Selected Opioids (4)
 ANTAGONISTS:

14. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Diminish Nociceptor Sensitization
 NSAIDs, especially ibuprofen and naproxen, are very widely employed to
reduce mild/moderate inflammatory pain.
 Non-selective NSAIDs have analgesic, antipyretic and anti-inflammatory
actions, largely by inhibiting the synthesis and accumulation of
prostaglandins by cyclo-oxygenase (COX) enzymes COX-1 and COX-2
Prostaglandins
(e.g. PGE2, PGD2)
• hyperalgesia
Prostacyclin (PGI2)
• platelet disaggregation
• vasodilation
Cyclo-oxygenase-1
(COX-1)
Cyclo-oxygenase-2
(COX-2)
Arachidonic acid
Endoperoxides
Thromboxane-A2
• platelet aggregation
• vasoconstriction
PhospholipidsInhibited by non-
selective NSAIDs but not
COX-2 selective ‘coxibs’
Inhibited by non-
selective NSAIDs and
COX-2 selective ‘coxibs’Phospholipase A2
Thromboxane
synthase
Prostacyclin
synthase
Prostaglandin
isomerase
Non-selective
NSAIDs
• aspirin
• ibuprofen
• naproxen
• diclofenac
• indometacin
COX-2-
selective
inhibitors
• etoricoxib
• celecoxib
• lumiracoxib

15.  COX-1 is constitutively active, COX-2 is induced in inflammation, therapeutic
benefit derives from inhibition of COX-2. G.I. toxicity occurs through
inhibition of COX-1
 Most cells generate PGE2 in response to mechanical, thermal, or chemical
injury
 Paracetamol (acetaminophen) is not classed as an NSAID because it lacks
anti-inflammatory activity and only weakly inhibits COX isoenzymes (inhibition
of COX-3 and inhibition of COX-2 at low rates of enzyme activity have been suggested
but remain contentious). The analgesic effect of paracetamol may involve its
metabolites (e.g. N-acetyl-p-benzoquinoneimine, which is also responsible for
hepatotoxicity in overdosage). TRPA1 (an excitatory cation-selective ion channel) has
emerged as a recent, novel, target that is activated by such metabolites
 PGE2 sensitises nociceptive neurones and causes hyperalgesia
 NSAIDs have limited analgesic efficacy because multiple signalling
pathways, several of which do not involve arachidonic acid metabolism,
cause nociceptor sensitization
 Long term administration of non-selective NSAIDs may produce
gastrointestinal damage (PGE2 produced by COX-1 protects against the
acid/pepsin environment). Paracetamol does not have this adverse effect.
Nephrotoxicity can occur because of inhibition of COX-2 constitutively expressed by the kidney.
Inhibition can compromise renal haemodynamics in renal disease
 Selective COX-2 inhibitors are, unfortunately, prothrombotic, limiting their use

16. Drugs for Neuropathic Pain (1)
 Neuropathic pain is severe and debilitating occurring in conditions
such as:
 trigeminal neuralgia
 diabetic neuropathy
 post-herpetic neuralgia
 phantom limb pain
 Neuropathic pain does not respond to NSAIDs and appears to be
relatively insensitive to opioids (unless these are given at high doses)
 Treatment options are a diverse group of compounds including:
 Gabapentin and pregabalin (antiepileptics)
• these do not act via the GABAergic system but instead reduce the cell
surface expression of a subunit (α2δ) of some voltage-gated Ca2+
channels (high-voltage-activated subgroup) which are upregulated in
damaged sensory neurones
• this presumably causes a decrease of neurotransmitters, such as
glutamate and substance P, from the central terminals of nociceptive
neurones
• gabapentin is employed in migraine prophylaxis and neuropathic pain
• pregabalin is useful in painful diabetic neuropathy

17.  Amitriptyline, nortryptiline and desipramine (tricyclic antidepressants)
• act centrally by decreasing the reuptake of noradrenaline
• duloxetine and venlafaxine additionally decrease reuptake of 5-HT [but
selective serotonin reuptake inhibitors (SSRIs) do not provide analgesia]
 Carbamazepine
• blocks subtypes of voltage-activated Na+ channel that are upregulated in
damaged nerve cells - first-line treatment to control pain intensity and
frequency of attacks in trigeminal neuralgia
Drugs for Neuropathic Pain (2)