The document provides a detailed overview of pain management, categorizing pain into various types such as nociceptive, neuropathic, acute, and chronic pain. It discusses the physiological processes involved in pain perception, classification, and mechanisms, including the roles of different nerve fibers and pathways. Additionally, it covers concepts like referred pain, various pain syndromes, and the neurobiological underpinnings of pain signaling and sensation.

1. CHRONIC PAIN MANAGEMENT
MONGERA MWAMBA

2. Sensation :
 Protopathic (noxious e.g pain)
 Epicritic (non-noxious e.g temperature )
Epicritic sensations
 Characterized by low threshold receptors
 Conducted by large myelinated nerve fibres
 Examples :
- light touch
- pressure
- proprioception
- temperature discrimination

3. Protopathic sensation (noxious)
 Detected by high threshold receptors
 Conducted by smaller, lightly myelinated (Aδ)
and unmyelinated (C) nerve fibers.
 Example : pain

4. Pain
 an unpleasant sensory and emotional
experience associated with actual or potential
tissue damage, or described in terms of such
damage.

5. Terms used in the management of pain
 Allodynia : Perception of an ordinarily nonnoxious
stimulus as pain (painful sensation from a warm
shower when the skin is damaged by sunburn)
 Analgesia : Absence of pain perception
 Anesthesia Absence of all sensation

6.  Anesthesia dolorosa : Pain in an area that lacks
sensation
 Dysesthesia : Unpleasant or abnormal sensation
with or without a stimulus
 Hypalgesia (hypoalgesia) : Diminished response
to noxious stimulation (eg, pinprick)

7.  Hyperalgesia : Increased response to noxious
stimulation
 Hyperesthesia : Increased response to mild
stimulation
 Hyperpathia : Presence of hyperesthesia,
allodynia, and hyperalgesia usually associated
with overreaction, and persistence of the
sensation after the stimulus

8.  Hypesthesia (hypoesthesia) Reduced cutaneous
sensation (eg, light touch, pressure, or
temperature)
 Neuralgia : Pain in the distribution of a nerve or a
group of nerves
 Paresthesia : Abnormal sensation perceived
without an apparent stimulus
 Radiculopathy : Functional abnormality of one or
more nerve roots

9. Classification of pain
a) Acute or chronic pain
b) Pathophysiology (e.g nociceptive or neuropathic
pain)
c) Etiology (e.g arthritis or cancer pain)
d) Affected area (e.g headache or low back pain)

10. Nociceptive pain
 Caused by activation or sensitization of peripheral
nociceptors
 Nociceptors are specialized receptors that
transduce noxious stimuli
Neuropathic pain
 Result from injury or acquired abnormalities of
peripheral or central neural structures.

11. ACUTE PAIN
 Caused by noxious stimulation due to injury, a
disease process, or abnormal function of muscle
or viscera
 Usually nociceptive
 Nociceptive pain serves to detect, localize, and
limit tissue damage

12.  Four physiological processes are involved:
transduction, transmission, modulation, and
perception
 Associated with neuroendocrine stress response
proportional to the pain’s intensity.
 Most common forms include post-traumatic,
postoperative, and obstetric pain ,myocardial infarction,
pancreatitis, and renal calculi.
 Most forms are self-limited or resolve with treatment
in a few days or weeks.

13. Types of acute (nociceptive) pain
1. Somatic pain
 Superficial somatic pain
 Deep somatic pain
2. Visceral pain
 True localized visceral pain
 Localized parietal pain
 Referred visceral pain
 Referred parietal pain

14. Somatic pain
a) superficial somatic pain :
 due to nociceptive input arising from skin,
subcutaneous tissues, and mucous membranes
 well localized
 described as a sharp, pricking, throbbing, or
burning sensation

15. b) Deep somatic pain
 arises from muscles, tendons, joints, or bones.
 dull, aching quality
 Poorly localized
 Both the intensity and duration of the stimulus
affect the degree of localization

16. Visceral pain
 Visceral acute pain is due to a disease process or
abnormal function involving an internal organ or its
covering (eg, parietal pleura, pericardium, or
peritoneum)
 Four subtypes :
a) true localized visceral pain
b) localized parietal pain
c) Referred visceral pain
d) Referred parietal pain.

17. True visceral pain
 dull, diffuse, and usually midline
 associated with abnormal sympathetic or
parasympathetic activity causing nausea,
vomiting, sweating, and changes in blood
pressure and heart rate.

18. Parietal pain
 Sharp
 stabbing sensation localized to the area around
the organ or referred to a distant site

19. REFERRED PAIN
Dermatomal rule:
 Pain is usually referred to a structure that
developed from the same embryonic segment or
dermatome as the structure in which the pain
originates.
 For example, the heart and the arm have the
same segmental origin, and the testicle has
migrated with its nerve supply from the primitive
urogenital ridge from which the kidney and ureter
have developed.

20. Convergence - projection theory.
 The basis for referred pain may be convergence of somatic and visceral pain fibers
on the same second-order neurons in the dorsal horn that project to the thalamus
and then to the somatosensory cortex.
 Somatic and visceral neurons converge in lamina I–VI of the ipsilateral dorsal horn
 Neurons in lamina VII receive afferents from both sides of the body—a
requirement if convergence is to explain referral to the side opposite that of the
source of pain
 The somatic nociceptive fibers normally do not activate the second-order neurons,
but when the visceral stimulus is prolonged, facilitation of the somatic fiber
endings occurs
 They now stimulate the second order neurons, and of course the brain cannot
determine whether the stimulus came from the viscera or from the area of
referral.

21. Patterns of referred pain
Location Cutaneous dermatome
Central diaphragm C4
Lungs T2 – T6
Aorta T1 – L2
Heart T1 – T4
Esophagus T3–T8
Pancreas and spleen T5–T10
Stomach, liver, and gallbladder T6–T9
Adrenals T8–L1
Small intestine T9–T11
Colon T10–L1
Kidney, ovaries, and testes T10–L1
Ureters T10–T12
Uterus T11–L2
Bladder and prostate S2–S4
Urethra and rectum S2–S4

22. CHRONIC PAIN
 Pain that persists beyond the usual course of an
acute disease or after a reasonable time for healing
to occur, this healing period typically can vary from
1 to 6 months.
 Nociceptive, neuropathic, or mixed
 Psychological mechanisms or environmental factors
frequently play a major role
 attenuated or absent neuroendocrine stress
responses
 Prominent sleep and affective (mood) disturbances

23.  Neuropathic pain :
- paroxysmal and lancinating
- has a burning quality
- associated with hyperpathia
 When it is also associated with loss of sensory input (eg,
amputation) into the central nervous system, it is
termed deafferentation pain
 When the sympathetic system plays a major role, it is
oft en termed sympathetically maintained pain .

24. common forms of chronic pain
 Pain associated with musculoskeletal disorders
 Chronic visceral disorders
 Lesions of peripheral nerves, nerve roots, or dorsal root ganglia
(including diabetic neuropathy, causalgia, phantom limb pain,
and postherpetic neuralgia)
 Lesions of the central nervous system (stroke, spinal cord injury,
and multiple sclerosis)
 Cancer pain
 Pain of most musculoskeletal disorders (eg, rheumatoid arthritis
and osteoarthritis) is primarily nociceptive
 Pain associated with peripheral or central neural disorders is
primarily neuropathic
 The pain associated with some disorders, eg, cancer and chronic
back pain (particularly after surgery), is oft en mixed.

25. PAIN PATHWAYS
 First order neurons
 Second order neurons
 Third order neurons

27. First order neurons
 first-order neurons send the proximal end of their
axons into the spinal cord via the dorsal (sensory)
spinal root at each cervical, thoracic, lumbar, and
sacral level.
 Some unmyelinated afferent (C) fibers enter the
spinal cord via the ventral nerve (motor) root
 In the dorsal horn : synapse with second-order
neurons, interneurons, sympathetic neurons, and
ventral horn motor neurons.

28. Pain fibres from the head are carried by :
 Trigeminal nerve (gaserian ganglion:V1,V2,V3)
 Facial nerve (geniculate ganglion)
 Glossopharyngeal nerve (superior and petrosal
ganglia)
 Vagus nerve :
- somatic – jugular ganglion
- Visceral – ganglion nodosum
 proximal axonal processes of the first-order neurons
in these ganglia reach the brainstem nuclei via their
respective cranial nerves and synapse with second-
order neurons in brainstem nuclei.

29. Second order neurons
 In spinal cord afferent segregate according to size, with
large, myelinated fibers becoming medial, and small,
unmyelinated fibers becoming lateral
 Pain fibers descend or ascend 1 – 3 spinal cord segments
in Lissauers tract before synapsing with second order
neurons in gray matter of the ipsilateral dorsal horn
 First order neurons also communicate with interneurons
before synapsing with second order neurons

31. Rexed spinal cord lamina
Lamina Predominant function Input Name
I Somatic nociception
thermoreception
Aδ, C Marginal layer
II Somatic nociception
thermoreception
C, Aδ Substantia gelatinosa
III Somatic mechanoreception Aβ, Aδ Nucleus proprius
IV Mechanoreception Aβ, Aδ Nucleus proprius
V Visceral and somatic nociception
and mechanoreception
Aβ, Aδ, C Nucleus proprius WDR neurons
VI Mechanoreception Aβ Nucleus proprius
VII Sympathetic Intermediolateral column
VIII Aβ Motor horn
IX Motor Aβ Motor horn
X Aβ, (Aδ) Central canal

32. Lamina I – VI (dorsal horn ) :
 Receive all afferent neural activity
 Principal site of modulation of pain by ascending and
descending neural pathways
Classification of Second order neurons :
 Nociceptive specific
 Wide dynamic range (WDR)neurons

33. Nociceptive –specific neurons :
 Serve only noxious stimuli
 Arranged somatotopically on lamina I
 Have discrete , somatic receptive fields
 are normally silent and respond only to high-
threshold noxious stimulation, poorly encoding
stimulus intensity

36. Wide Dynamic Range (WDR) neurons :
 Most prevalent cell type in the dorsal horn
 WDR neurons are most abundant in lamina V
 WDR neurons receive noxious, and nonnoxious
afferent input from Aβ, Aδ, and C fibers
 Large receptive fields
 With repeated stimulation, WDR neurons
increase their firing rate exponentially in a graded
fashion (“wind-up”), even with the same stimulus
intensity

38.  Most nociceptive C fibers send collaterals to, or
terminate on, second-order neurons in laminae I
and II, and, to a lesser extent, in lamina V
 Nociceptive Aδ fibers synapse mainly in laminae I
and V, and, to a lesser degree, in lamina X
 Lamina I responds primarily to noxious
(nociceptive) stimuli from cutaneous and deep
somatic tissues

39.  Lamina II (substantia gelatinosa ) :
- contains many interneurons and play a major role
in processing and modulating nociceptive input
from cutaneous nociceptors
- major site of action for opioids
 Laminae III and IV – receive nonnociceptive
sensory input
 Laminae VIII and IX make up the anterior (motor)
horn.
 Lamina VII is the Intermediolateral column and
contains the cell bodies of preganglionic
sympathetic neurons

40.  Visceral afferents terminate primarily in lamina V,
and, to a lesser extent, in lamina I.
 These two lamina represent points of central
convergence between somatic and visceral
inputs (˟referred pain)
 Lamina V responds to both noxious and
nonnoxious sensory input and receives both
visceral and somatic pain afferents.

41. visceral nociceptive fibers :
- are fewer in number
- more widely distributed
- Proportionately activate a larger number of spinal
neurons
- Are not organized somatotopically

42. Spinothalamic tract
 axons of most second-order neurons cross the
midline close to their dermatomal level of origin to
the contralateral side of the spinal cord before they
form the Spinothalamic tract and send their fibers to
the :
- Thalamus
- Reticular formation
- Nucleus raphe magnus
- Periaqueductal gray
 The Spinothalamic tract, which is classically
considered the major pain pathway, lies
anterolaterally in the white matter of the spinal cord

45. Divisions of the (ascending) spinothalamic tract
a) Lateral spinothalamic (neospinothalamic) tract :
- projects mainly to the ventral posterolateral
nucleus of the thalamus
- carries discriminative aspects of pain : location,
intensity, and duration

46. b) Medial spinothalamic (paleospinothalamic) tract
- projects to the medial thalamus
- mediates autonomic and unpleasant emotional
perceptions of pain
 Spinothalamic tracts to the Periaqueductal gray link
ascending and descending pathways
 Spinothalamic tracts to the RAS and hypothalamus
are responsible for the arousal response of pain

47. Alternate Pain Pathways
 Pain fibers ascend diffusely, ipsilaterally, and
contralaterally ;
 some patients continue to perceive pain following
ablation of the contralateral spinothalamic tract, and
therefore other ascending pain pathways are also
important:
 Spinoreticular tract mediate arousal and autonomic
responses to pain
 Spinomesencephalic tract with its projections to the
periaqueductal gray activate antinociception
 spinohypothalamic and spinotelencephalic tracts activate
the hypothalamus and evoke emotional behavior.

48.  Spinocervical tract ascends uncrossed to the
lateral cervical nucleus, and relays the fibers to
the contralateral thalamus; this tract is likely a
major alternative pathway for pain
 some fibers in the dorsal columns ,which mainly
carry light touch and proprioception , are
responsive to pain; they ascend medially and
ipsilaterally.

49. Integration with the Sympathetic and Motor Systems
 Somatic and visceral afferents are fully integrated with the skeletal
motor and sympathetic systems in the spinal cord, brainstem, and
higher centers.
 Afferent dorsal horn neurons synapse both directly and indirectly with
anterior horn motor neurons.
 These synapses are responsible for normal/ abnormal reflex muscle
activity associated with pain
 Synapses between afferent nociceptive neurons and sympathetic
neurons in the intermediolateral column result in reflex sympathetically
mediated vasoconstriction, smooth muscle spasm, and the release of
catecholamines, both locally and from the adrenal medulla.

50. Third-Order Neurons
 Located in the thalamus
 Send fibers to somatosensory areas I and II in the postcentral gyrus of
the parietal cortex and the superior wall of the sylvian fissure,
respectively
 Perception and discrete localization of pain take place in these cortical
areas
 Most neurons from the lateral thalamic nuclei project to the primary
somatosensory cortex
 Neurons from the intralaminar and medial nuclei project to the
anterior cingulate gyrus and are likely involved in mediating the
suffering and emotional components of pain.

51. Physiology of nociception
Nociceptors
 High threshold for activation
 Encode intensity of stimulation by increasing their
discharge rates in a graded fashion
 With repeated stimulation they display delayed
adaptation, sensitization and afterdischarges

52. Components of noxious sensations:
a) First pain
 Fast, sharp and well localized
 Conducted within 0.1 s by Aδ fibers
 Aδ fibers secrete and release glutamate as neurotransmitter
at presynaptic membrane
 Tested by pinprick
b) Second pain :
 slower onset
 Dull, and often poorly localized
 Conducted by C fibers.
 C fibers release substance P at presynaptic membrane

53.  Most nociceptors are free nerve endings that sense
heat and mechanical and chemical tissue damage.
 Types of nociceptors :
(1) mechanonociceptors – respond to pinch and
pinprick
(2) Silent nociceptors – respond only in the presence of
inflammation
(3) Polymodal mechanoheat nociceptors

54. Polymodal mechanoheat nociceptors
 Most prevalent
 Respond to :
- excessive pressure
- extremes of temperature (>42°C and <40°C)
- noxious substances (bradykinin, histamine, serotonin (5-
HT), H + , K + , some prostaglandins, capsaicin and
adenosine triphosphate)

55.  Polymodal nociceptors are slow to adapt to strong pressure
 They display heat sensitization
 TRPV1 and TRPV2 :
 Contain ion channels in nerve endings
 Both respond to high temperatures
 Capsaicin stimulates the TRPV1 receptor
(TRPV1 : Transient Receptor Potential cation channel subfamily V
member 1/ capsaisin receptor/ vanilloid receptor 1)

56. Cutaneous Nociceptors
 Present in both somatic and visceral tissues
 Primary afferent neurons reach tissues by traveling along
spinal somatic, sympathetic, or parasympathetic nerves
 Somatic nociceptors : skin (cutaneous) and deep tissues
(muscle, tendons, fascia, and bone)
 Visceral nociceptors – internal organs.
 cornea and tooth pulp are exclusively innervated by
nociceptive Aδ and C fibers.

57. Deep Somatic Nociceptors
 less sensitive to noxious stimuli than cutaneous
nociceptors
 easily sensitized by inflammation
 Pain arising from them is dull and poorly localized
 Specific nociceptors in muscles and joint capsules,
respond to mechanical, thermal, and chemical stimuli.

58. Visceral Nociceptors
 Visceral organs are generally insensitive tissues that
mostly contain silent nociceptors
 Heart ,lung, testis, and bile ducts have specific nociceptors
 Most other organs, e.g intestines, are innervated by
polymodal nociceptors that respond to smooth muscle
spasm, ischemia, and inflammation :
 These receptors generally do not respond to the cutting,
burning, or crushing that occurs during surgery.

59.  Brain - lack nociceptors
 Meningeal coverings – have nociceptors
 nociceptors are free nerve endings of primary afferent
neurons whose cell bodies lie in the dorsal horn.
 These afferent nerve fibers, travel with efferent
sympathetic nerve fibers to reach the viscera
 Afferent activity from these neurons enters the spinal
cord between T1 and L2

60.  Nociceptive C fibers from the esophagus, larynx, and
trachea travel with the vagus nerve to enter the
nucleus solitarius in the brainstem
 Afferent pain fibers from the bladder, prostate,
rectum, cervix and urethra, and genitalia are
transmitted into the spinal cord via parasympathetic
nerves at the level of the S2–S4 nerve roots.
 Fibers from primary visceral afferent neurons enter the
cord and synapse more diffusely with single fibers,
often synapsing with multiple dermatomal levels and
often crossing to the contralateral dorsal horn.

61. Chemical mediators of pain
 Neuropeptides and excitatory amino acids
 Most important Neuropeptides :
- substance P
- Calcitonin - gene related peptide (CGRP)
 Most important Excitatory amino acids
- Glutamate

62. Chemical mediators of pain
Neurotransmitter Receptor Effect of nociception
Substance P Neurokinin–1 Excitatory
Calcitonin gene-related peptide Excitatory
Glutamate NMDA, AMPA, kainate,
quisqualate
Excitatory
Aspartate NMDA, AMPA, kainate,
quisqualate
Excitatory
Adenosine triphosphate (ATP) P 1 , P 2 Excitatory
Somatostatin Inhibitory
Acetylcholine Muscarinic Inhibitory
Enkephalins μ, δ, κ Inhibitory
β-Endorphin μ, δ, κ Inhibitory
Norepinephrine α 2 Inhibitory
Adenosine A 1 Inhibitory
Serotonin 5-HT 1 (5-HT 3 ) Inhibitory
γ-Aminobutyric acid (GABA) A, B Inhibitory
Glycine Inhibitory

63. Substance P
 11 amino acid peptide
 Synthesized and released by first-order neurons
peripherally and in the dorsal horn
 Also found in intestines
 Facilitates transmission in pain pathways via
neurokinin-1 receptor activation

64.  Peripherally , substance P neurons send collaterals
that are closely associated with blood vessels,
sweat glands, hair follicles, and mast cells in the
dermis.
Physiologic effects of Substance P
 Sensitizes nociceptors
 Degranulates histamine from mast cells
 Degranulates 5-HT from platelets
 Potent vasodilator
 Chemoattractant for leukocytes.

65.  Substance P–releasing neurons also innervate
the viscera and send collateral fibers to
Paravertebral sympathetic ganglia
 Intense stimulation of viscera, therefore, can
cause direct postganglionic sympathetic
discharge

66. PAIN MODULATION
 Nociceptors
 Spinal cord
 Supraspinal structures
 Modulation can either inhibit (suppress) or
facilitate (intensify) pain.

67. Peripheral Modulation of Pain
 Nociceptors and their neurons display
sensitization following repeated stimulation
 Sensitization may be manifested as :
- an enhanced response to noxious stimulation
or
- a newly acquired responsiveness to a wider range
of stimuli, including nonnoxious stimuli.

68. Primary Hyperalgesia
 Sensitization of nociceptors results in :
a) a decrease in threshold
b) an increase in the frequency response to the same
stimulus intensity
c) a decrease in response latency , and
d) spontaneous firing even after cessation of the stimulus
( afterdischarges )

69.  Primary hyperalgesia is mediated by the release
of noxious substances from damaged tissues:
Histamine – mast cells, basophils, and platelets
Serotonin – mast cells and platelets
Bradykinin is released from tissues following
activation of factor XII and activates free nerve
endings via specific B1 and B2 receptors

70. Prostaglandins :
Prostaglandin E2 (PGE2) – directly activates free nerve
endings
Prostacyclin – potentiates edema from bradykinin
Leukotrienes – potentiates certain types of pain
 Aspirin(ASA) and NSAIDS inhibit COX
 Corticosteroids – inhibit prostaglandin production by
blockade of phospholipase A2 activation

71. Secondary hyperalgesia
 Neurogenic inflammation
 Manifested by the “triple response (of Lewis)” :
a) A red flush around the site of injury (flare)
b) Local tissue edema
c) Sensitization to noxious stimuli
 Secondary hyperalgesia is primarily due to
antidromic release of substance P and CGRP)

72.  Substance P degranulates histamine and 5-HT,
vasodilates blood vessels, causes tissue edema,
and induces the formation of leukotrienes
 Findings that support neural origin of this
response :
(1) it can be produced by electrical stimulation of a
sensory nerve
(2) it is not observed in denervated skin
(3) it is diminished by injection of a local anesthetic.

73. CENTRAL MODULATION OF PAIN
A. FACILITATION
 Three mechanisms are responsible for central sensitization in the spinal cord:
1. Wind-up and sensitization of second-order neurons
 WDR neurons increase their frequency of discharge with the same repetitive
stimuli and exhibit prolonged discharge, even after afferent C fiber input has
stopped.
2. Receptor field expansion
 Dorsal horn neurons increase their receptive fields such that adjacent neurons
become responsive to stimuli (whether noxious or not) to which they were
previously unresponsive.
3. Hyperexcitability of flexion reflexes.
 Enhancement of flexion reflexes is observed both ipsilaterally and
contralaterally.

74. Neurochemical mediators of central sensitization
 substance P
 CGRP
 vasoactive intestinal peptide (VIP)
 cholecystokinin (CCK)
 Angiotensin
 Galanin
 Excitatory A.A : l-glutamate and l-aspartate
 These substances trigger changes in membrane excitability by
interacting with G protein–coupled membrane receptors on
neurons

75. Aspartate and glutamate
 Plays a role in windup by activating NMDA
receptor ,and ,induction and maintenance of central
sensitization
 Activation of NMDA receptors also induces nitric
oxide synthetase, increasing formation of nitric oxide
 Both prostaglandins and nitric oxide facilitate the
release of excitatory amino acids in the spinal cord.

76. B. INHIBITION
a) segmental activity in the spinal cord
b) Descending neural activity from supraspinal
centers.

77. 1. Segmental inhibition
 Activation of large afferent fibers subserving
sensation inhibits WDR neuron and spinothalamic
tract activity
 Additionally activation of noxious stimuli in
noncontiguous parts of the body inhibits WDR
neurons at other levels :
 This may explain why pain in one part of the body
inhibits pain in other parts.

78. Segmental Inhibitory neurotransmitters :
 Glycine – increases Cl − conductance across
neuronal cell membranes
 γ-aminobutyric acid (GABA) – activation of GABA B
receptors
 Adenosine mediates antinociception by acting on A
1 , which inhibits adenyl cyclase :
-Methylxanthines reverse this effect through
phosphodiesterase inhibition.

79. Gate control theory (Melzack n Wall 1965)
 Proposes a mechanism for how pain is reduced by activating a non-painful
sensation
 For example deep touch activates pacinian corpuscle that transmit a signal via the
Dorsal Colum Medial Leminiscus (DCML)
 DCML sends collaterals to the substantia gelatinosa
 DCML ascends ipsilaterally to the medula where it crosses over in the medial
leminiscus of the brain stem
 When DCML is activated by deep touch, it activates the inhibitory
neurons(interneurons)
 Inhibitory neurons release inhibitory neurotransmitters e.g enkephalins which :
 Bind to opioid receptors in the presynaptic membrane and cause clossure of Ca2+
channels , leading to less release of excitatory neurotransmitters e.g substance P
and glutamate, hence less excitation of the secondary neuron, hyperpolarization
and a decreased action potential frequency decreasing pain signals to the brain
 Bind to opioid receptors on the dendrites of secondary neuron and cause opening
of K+ channels leading to hyperpolarization of the second order neuron ,
decreasing action potential frequency ,hence less pain signal transmission to the
brain

82. 2. Supraspinal inhibition
 Several supraspinal structures send descending
fibres to inhibit pain in the dorsal column :
a) periaqueductal gray
b) reticular formation
c) nucleus raphe magnus (NRM)

83. Periaqueductal gray (PAG)
 Stimulation of the periaqueductal gray area in the midbrain
produces widespread analgesia in humans
 Axons from these tracts act presynaptically on primary afferent
neurons and postsynaptically on second-order neurons and/or
interneurons.
 These pathways mediate their antinociceptive action via α 2 -
adrenergic, serotonergic, and opiate (μ, δ, and κ) receptor
mechanisms
 MAOi block reuptake of catecholamines and serotonin hence
express analgesic efficacy

84.  Inhibitory adrenergic pathways originate in the PAG and
reticular formation
 Norepinephrine mediates this action via presynaptic or
postsynaptic α2 receptors
 Part of the descending inhibition from the periaqueductal
gray is relayed first to the NRM and medullary reticular
formation
 Serotonergic fibers from the NRM then relay the inhibition
to dorsal horn neurons via the dorsolateral funiculus

85. Effects of noradrenergic/serotonergic fibres
 N.E/5-HTbind on presynaptic receptors inhibiting release
of substance P
 Stimulates an opioid interneuron in substantia gelatinosa.
The interneuron release endogenous opioids (enkephalins
/β-endorphins/ dynorphins ) which :
i) inhibit presynaptic release substance P
ii) prevents depolarization of the postsynaptic membrane

86.  Endogenous opiate system : NRM and reticular
formation acts via methionine enkephalin, leucine
enkephalin, and β-endorphin (antidote – naloxone
 These opioids act presynaptically to hyperpolarize
primary afferent neurons and inhibit the release of
substance P.
 Exogenous opioids preferentially act
postsynaptically on the second-order neurons or
interneurons in the substantia gelatinosa.

87. Pathophysiology of chronic Pain
 Caused by peripheral, central, and psychological
mechanisms
 Sensitization of peripheral nociceptors plays a role
 Neuropathic pain involves complex peripheral–central and
central neural mechanisms associated with partial or
complete lesions of peripheral nerves, dorsal root ganglia,
nerve roots, or more central structures
 Peripheral mechanisms :
- spontaneous discharge
- sensitization of receptors to mechanical, thermal, and
chemical stimuli
- up-regulation of adrenergic receptors
- Neural inflammation

88.  Central mechanisms :
Loss of segmental inhibition
wind-up of WDR neurons
spontaneous discharges in deafferentated
neurons
reorganization of neural connections.

89. Mechanisms of neuropathic pain
 Spontaneous self-sustaining neuronal activity in the primary
afferent neuron (such as a neuroma)
 Marked mechanosensitivity associated with chronic nerve
compression
 Short-circuits between pain fibers and other types of fibers
following demyelination, resulting in activation of nociceptive fibers
by nonnoxious stimuli at the site of injury (ephaptic transmission)
 Functional reorganization of receptive fields in dorsal horn neurons
such that sensory input from surrounding intact nerves emphasizes
or intensifies any input from the area of injury.

90.  Spontaneous electrical activity in dorsal horn cells or
thalamic nuclei
 Release of segmental inhibition in the spinal cord
 Loss of descending inhibitory influences that are
dependent on normal sensory input
 Lesions of the thalamus or other supraspinal structures.

91.  Psychological mechanisms or environmental factors associated with
chronic pain:
 Psychophysiological mechanisms in which emotional factors act as the
initiating cause (eg, tension headaches)
 Learned or operant behavior in which chronic behavior patterns are
rewarded (eg, by attention of a spouse) following an often minor injury
 Psychopathology such as major affective disorders (depression),
schizophrenia, and somatization disorders (conversion hysteria) in
which the patient has an abnormal preoccupation with bodily functions
 Pure psychogenic mechanisms (somatoform pain disorder), in which
suffering is experienced despite absence of nociceptive input.

92. SYSTEMIC RESPONSE TO ACUTE PAIN
 Triggers a neuroendocrine response proportionate to the
pain intensity
 Hormonal response results from increased sympathetic
tone and hypothalamically mediated reflexes
 moderate – severe acute pain adversely affect
perioperative morbidity and mortality

93. Cardiovascular Effects
 Hypertension
 Tachycardia
 Enhanced myocardial irritability
 Increased systemic vascular resistance
 ↑ C.O in normal patients but may
 ↓ C.O in patients with compromised ventricular
function
 ↑ myocardial oxygen demand can worsen or
precipitate myocardial ischemia

94. Respiratory Effects
 ↑O2 consumption
 ↑ CO2 production
 ↑ minute ventilation
 ↑ increased work of breathing
 Pain due to abdominal or thoracic incisions reduce
pulmonary function due to guarding (splinting) :
↓TV ↓FRC
promotes atelectasis, intrapulmonary shunting,
hypoxemia, and hypoventilation
 Reductions in vital capacity impair coughing and clearing
of secretions

95. Gastrointestinal and Urinary Effects
 Enhanced sympathetic tone increases sphincter tone
and decreases intestinal and urinary motility, promoting
ileus and urinary retention, respectively.
 Hypersecretion of gastric acid can promote stress
ulceration and worsen the consequences of pulmonary
aspiration
 Nausea, vomiting, and constipation

96. Endocrine Effects
 Increased catabolic hormones (catecholamines, cortisol,
and glucagon)
 Decreased anabolic hormones (insulin and testosterone)
 Negative nitrogen balance, carbohydrate intolerance, and
increased lipolysis
 ↑ : cortisol, renin, angiotensin, aldosterone, and ADH
results in sodium retention, water retention, and
secondary expansion of the extracellular space.

97. Hematological Effects
 Increased platelet adhesiveness
 Reduced fibrinolysis
 Hypercoagulability

98. Immune Effects
 Leukocytosis
 Depresses reticuloendothelial system and
predisposing patients to infection
 Stress-induced immunodepression enhance
tumor growth and metastasis.

99. Psychological Effects
 Anxiety
 sleep disturbances
 Depression
 Frustration and anger that may be directed at
family, friends, or the medical staff .

100. Systemic Responses to Chronic Pain
 Absent or attenuated neuroendocrine response
 Sleep and affective disturbances (depression)
 Changes in appetite (decease/increase)
 Stresses on social relationships

101. Evaluation of a patient with chronic pain
 Location ,onset and quality of pain
 Alleviating and exacerbating factors
 Pain history including therapies and changes in
symptoms over time
 Psychological factors
 X-rays/CT-scans/MRIs : physiological causes

102. Measurement of pain
 Reliable quantitation of pain severity helps determine
therapeutic interventions and evaluate the efficacy of
treatments
 Pain is a subjective experience that is influenced by
psychological, cultural, and other variables
 Scales :
• Numerical rating scale
• Wong-Baker FACES rating scale (paeds > 3years)
• Visual Analog scale (VAS)
• McGill Pain Questionnaire (MPQ)

103. PSYCHOLOGICAL EVALUATION
Indications :
 Medical evaluation can not reveal cause of pain
 Pain intensity, characteristic and duration are
disproportionate to disease /injury
 Depression/psychological issues are apparent

104.  Emotional and related disorders commonly
associated with chronic pain:
a) Somatization disorder:
Physical symptoms of a medical condition that
cannot be explained, resulting in involuntary
distress and physical impairment.
b) Conversion disorder
Symptoms of voluntary motor or sensory deficits
that suggest a medical condition; symptoms cannot
be medically explained but are associated with
psychological factors and are not intentionally
feigned.

105. c) Hypochondriasis
Prolonged (>6 months) preoccupation with the fear of
having a serious illness despite adequate medical
evaluation and reassurance.
d) Malingering
Intentional production of physical or psychological
symptoms that is motivated by external incentives (eg,
avoiding work or financial compensation)
e) Substance related disorders
Habitual misuse of prescribed or illicit substances that
often precedes and drives complaints of pain and drug
seeking behavior.

106. Entrapment syndromes
• Nerve courses through anatomically narrowed passages
• Sensory, motor, or mixed nerves
• Genetic factors and repetitive macrotrauma or
microtrauma and adjucent tenosynovitis
• Sensory nerve : pain and numbness in its distribution distal
to the site of entrapment ;pain may be referred proximal to
site of entrapment
• Motor nerve :weakness in the muscle(s) it innervates.

107. Common Entrapment neuropathies
Nerve Entrapment Location of pain
Cranial nerves VII, IX,
and X
Styloid process or stylohyoid
ligament
Ipsilateral tonsil, base of
tongue, temporomandibular
joint, and ear (Eagle’s
syndrome)
Brachial plexus Scalenus anticus muscle or a
cervical rib
Ulnar side of arm and
forearm
(scalenus anticus syndrome)
Suprascapular nerve Suprascapular notch Posterior and lateral shoulder
Median nerve Pronator teres muscle Proximal forearm and palmar
surface of the first
three digits (pronator
syndrome)
Interdigital nerve Deep transverse tarsal
ligament
Between toes and foot
(Morton’s neuroma)

108. Ulnar nerve Cubital fossa (elbow) Fourth and fifth digits of the
hand (cubital
tunnel syndrome)
Ulnar nerve Guyon’s canal (wrist) Fourth and fifth digits of the
hand
Lateral femoral
cutaneous nerve
Anterior iliac spine under the
inguinal ligament
Anterolateral thigh (meralgia
paresthetica)
Obturator nerve Obturator canal Upper medial thigh
Saphenous nerve Subsartorial tunnel (adductor
canal)
Medial calf
Sciatic nerve Sciatic notch Buttock and leg (piriformis
syndrome)
Common peroneal nerve Fibular neck Lateral distal leg and foot
Deep peroneal nerve Anterior tarsal tunnel Big toe or foot
Superficial peroneal nerve Deep fascia above the ankle Anterior ankle and dorsum of
foot
Posterior tibial nerve Posterior tarsal tunnel Undersurface of foot (tarsal
tunnel syndrome)

109. Myofascial pain
• pain syndromes characterized by aching muscle pain, muscle
spasm, stiffness, weakness, and, occasionally, autonomic
dysfunction(vasoconstriction or piloerection)
• Discrete trigger points of marked tenderness in one or more
muscles or the associated connective tissue
• Palpation of involved muscles reveal tight, ropy bands over trigger
points
• Pain radiates in a fixed pattern that does not follow dermatomes
• Caused by gross trauma or repetitive microtrauma

110. FIBROMYALGIA
 American College of Rheumatology criteria for
fibromyalgia :
1. Widespread Pain Index (WPI) score of 7 or higher, and
Symptom Severity (SS) scale score of 5 or higher, or WPI
of 3–6 and SS scale score of 9 or higher
2. Symptoms present at a similar level for at least 3 months
3. Absence of another disorder that would otherwise
explain the pain.

111. Treatment of fibromyalgia :
• Cardiovascular conditioning
• strength training
• Improving sleep hygiene
• cognitive–behavioral therapy
• Patient education
• Pharmacotherapy:
Pregabalin (gabapentinoid)
Duloxetine (serotonin-norepinephrine reuptake
inhihibitor - SNRIs)
Milnacipran (SNRIs)

112. Low Back Pain and Associated Syndromes
Causes of low back pain:
• Lumbosacral strain
• Degenerative disc disease
• Myofascial syndromes
• Congenital
• Trauma
• Inflammatory process
• Infectious process
• Metabolic disorder
• Psychological disorder
• Neoplastic process

113. a) Paravertebral Muscle & Lumbosacral Joint Sprain/Strain
 Sprain/strain cause 80 – 90 % of low back pain
 Associated with :
- lifting heavy objects
- falls
- sudden abnormal movements of the spine
 Sprain : generally used when the pain is related to a well-defined
acute injury :
-self limiting benign process
-resolves in 1-2 weeks
-symptomatic treatment : bed rest and oral analgesics

114.  Strain : used when pain is more chronic and is likely related to
repetitive minor injuries
 Injury to paravertebral muscles and ligaments results in reflex
muscle spasm ,produces dull and aching pain that radiates to
buttocks or hips
 Sacroiliac joint :
 Rotational injuries ; slippage or subluxation of the joint
 Pain along posterior ilium, and radiates to the hip, posterior thigh
and knee
 L.A intra-articular injection : diagnostic and therapeautic

115. b) Buttock Pain
• Coccydynia (coccygodynia) : trauma to the coccyx or surrounding
ligaments
Treatment :
• Physical therapy
• Coccygeal nerve blocks to the lateral aspects of the coccyx
• Ablative or neuromodulatory techniques
Piriformies syndrome :
 Pain in the buttock
 Numbness and tingling in the distribution of sciatic nerve

116. c) Degenerative disease
• Intervertebral discs bear 1/3 of the wt of
spinal colum
• Structure of intervertebral disc:
Nucleus pulposus
Annulus fibrosus

117. nucleus pulposus :
• Central portion of the intervertebral disc
• composed of gelatinous material early in life
• This material degenerates and becomes fibrotic with advancing
age and following trauma.
annulus fibrosus :
• Surrounds nucleus pulposus
• Thinnest posteriorly
• bounded superiorly and inferiorly by cartilaginous plates.

121. Mechanisms of Disc (discogenic) pain :
(1) protrusion or extrusion of the nucleus pulposus
posteriorly
(2) Loss of disc height, resulting in the reactive
formation of bony spurs (osteophytes) from the
rims of the vertebral bodies above and below the
disc.

122. • Why lumbar spine is most vulnerable to Degenerative
disc disease :
1. It is subjected to the greatest motion
2. Posterior longitudinal ligament is thinnest at L2–L5
Factors predisposing to lumber spine disc disease :
3. Increased body weight
4. Cigarette smocking

123. Treatment of discogenic pain:
• Conservative therapy
• Steroid injections into the disc
• Intradiscal biacplasty, involving heating the posterior
annulus of the disc by way of radiofrequency ablation
• Surgical fusion with bone graft or hardware
placement

124. d) Herniated (Prolapsed) Intervertebral Disc
• Weakness and degeneration of the annulus fibrosus and
posterior longitudinal ligament can cause herniation of the
nucleus pulposus posteriorly into the spinal canal
• 90% of disc herniations occur at L5–S1 or L4–L5
• Symptoms develop following flexion injuries and heavy lifting ,
and is associated with bulging, protrusion, or extrusion of the
disc
• Disc herniations usually occur posterolaterally and often result
in compression of adjacent nerve roots, producing pain that
radiates along that dermatome ( radiculopathy ).

125. • When disc material is extruded through the annulus fibrosus
and posterior longitudinal ligament, free fragments can become
wedged in the spinal canal or the intervertebral foramina.
• Less commonly a large disc bulges or large fragments extrude
posteriorly, compressing the cauda equina in the dural sac
producing :
 Bilateral pain
 Urinary retention
 fecal incontinence.

126.  Factors aggravating disc disease pain :
• Bending
• Lifting
• Prolonged sitting
• Increased intraabdominal pressure (sneezing, coughing,
or straining)
 Factors relieving disc disease pain:
• lying down
 Numbness /weakness – indicate radiculopathy

127. • A centrally herniated disc will usually cause pain
at the lower level
• Laterally protruded disc cause pain at the same
level as the disc

128. Lumbar disc radiculopathies :
Disk Level
L3–L4 (L4 Nerve) L4–L5 (L5 Nerve) L5–S1 (S1 Nerve)
Pain distribution Anterolateral thigh,
anteromedial calf to
the ankle
Lateral thigh,
anterolateral
calf, medial dorsum
of foot,
especially between
the first
and second toes
Gluteal region,
posterior thigh,
posterolateral calf,
lateral dorsum
and undersurface of
the foot,
particularly between
fourth
and fifth toes
Weakness Quadriceps femoris Dorsiflexion of the
foot
Plantar flexion of foot
Reflex affected Knee None Ankle

129.  Treatment of acute back pain due to herniated disc :
 Modification of activity
 NSAIDs
 Acetaminophen
 Opioids
 Stop smocking (nicotine compromises blood flow to the relatively
avascular intervertebral disc)
 Percutaneous disc decompression- extraction of a small amount
of nucleus pulposus to decompress the nerve root
 Surgical decompression
 Physical therapy
 NB : back supports should be discouraged because they may
weaken paraspinal muscles

130. Spinal Stenosis
• Spinal stenosis is a disease of advancing age
• Degeneration of nucleus pulposus reduces disc height
and leads to osteophyte formation ( spondylosis ) at the
endplates of adjoining vertebral bodies
• In conjunction with facet joint hypertrophy and with
ligamentum flavum hypertrophy and calcification, this
process leads to progressive narrowing of the neural
foramina and spinal canal.

131. • Neural compression may cause radiculopathy that
mimics a herniated disc.
• Extensive osteophyte formation may compress
multiple nerve roots and cause bilateral pain
• Back pain usually radiates into the buttocks,
thighs, and legs
• Back pain worse with exercise ; relieved by rest,
particularly sitting with the spine flexed
(“shopping cart sign”)

132. Treatment of mild-moderate spinal stenosis
• Epidural steroids
• Minimally invasive lumbar decompression (MILD)
procedure : percutaneously sculpting of lamina and
ligamentum flavum to reduce central canal
compression.

133. NEUROPATHIC PAIN
• diabetic neuropathy
• Causalgia (burning pain)
• phantom limbs
• postherpetic neuralgia
• Stroke
• spinal cord injury
• multiple sclerosis
Cancer pain
chronic low back pain

134. Characteristics of neuropathic pain:
 Paroxysmal
 Lancinating (sharp and stabbing)
 Burning quality
 Associated with hyperpathia

135. Treatment options for neuropathic pain :
• Anticonvulsants :eg, gabapentin, pregabalin
• TCAs : e.g nortriptyline or desipramine, amitryptyline, etc
• SNRIs : e.g duloxetin ,milnacipran
• antiarrhythmics : e.g mexiletine
• α 2 -adrenergic agonists : e.g clonidine
• topical agents : lidocaine or capsaicin
• analgesics : NSAIDs and opioids
• Sympathetic blocks
• Spinal cord stimulation

136. Sympathetically Maintained & Sympathetically Independent Pain
• Complex regional pain syndrome (CRPS) is a neuropathic pain
disorder with significant autonomic features
• Divided into two :
a) CRPS 1(reflex sympathetic dystrophy- RSD) – no nerve injury
b) CRPS 2, formerly known as causalgia – documented nerve
injury

137. Signs and symptoms of CRPS:
• Burning neuropathic pain
• Hyperalgesia
• Allodynia
• Autonomic dysfunction :
- alterations in sweating(sudomotor changes)
- changes in color and skin temperature
- trophic changes in skin, hair, or nails.
• Decreased strength and ROM of affected
extremity

138. Causalgia (burning pain)
• Typically follows gunshot injuries and major trauma to large nerves
• immediate onset
• associated with allodynia, hyperpathia, and vasomotor and sudomotor
dysfunction
• Exacerbated by increased sympathetic tone : fear, anxiety, light, noise, or
touch
• Most Commonly affected nerves :
- brachial plexus, particularly the median nerve
- tibial division of the sciatic nerve

139. Treatment of CRPS
• Sympathetic blockade :
- non-selective α blocker : phenoxybenzamine
- α 1 Selective Prazosin
• Physiotherapy
• Transcutaneous electrical nerve stimulation (TENS) therapy
• Intravenous ketamine

140. ACUTE HERPES ZOSTER & POSTHERPETIC NEURALGIA (PHN)
• During an initial childhood infection (chickenpox), the varicella-
zoster virus (VZV) infects dorsal root ganglia, where it remains latent
until reactivation
• Acute herpes zoster, represents VZV reactivation, and manifests as
an erythematous vesicular rash in a dermatomal distribution ,
usually associated with severe pain
• Pain often precedes the rash by 48–72 h
• Rash lasts1–2 weeks
• T3–L3 : most commonly affected dermatomes

141. • Common in elderly and immunocompromised patients
• Self-limited in young healthy patients <50 years
Treatment of PHN:
• Oral analgesics
• ARVs: oral acyclovir, famciclovir, ganciclovir, or
valacyclovir
NB : Antiviral therapy reduces the duration of the rash and
speeds healing

142. • Sympathetic blockade in acute episodes provides
excellent analgesia
• Antidepressants, anticonvulsants, opioids, and TENS
may be useful
• Transdermal lidocaine 5% patch decrease peripheral
sensitization of nerve endings and receptors.
• Capsaicin cream or a transdermal capsaicin 8%
patch

143. Classification of headaches.
Classic headache syndromes
• Migraine
• Tension
• Cluster
Vascular disorders
• Temporal arteritis
• Stroke
• Venous thrombosis
Neuralgias
• Trigeminal
• Glossopharyngeal
• Occipital
Intracranial pathology
• Tumor
• Cerebrospinal fluid leak
• Pseudomotor cerebri
• Meningitis
• Aneurysm
Eye disorders
• Glaucoma
• Optic neuritis
Sinus disease
• Allergic
• Bacterial

144. Classification of headaches
• Temporomandibular joint
disease
• Dental disorders
• Trauma
• Miscellaneous : Cold stimulus
(swallowing cold liquid)
Drug-induced
• Acute ingestion
• Withdrawal (eg, caffeine and
alcohol)
Systemic disorders
a) Infections
• Viral (eg, influenza)
• Bacterial
• Fungal
b) Metabolic
• Hypoglycemia
• Hypoxemia
• Hypercarbia

145. Tension Headache
• Tight bandlike pain or discomfort that is often associated with tightness
in the neck muscles
• may be frontal, temporal, or occipital
• more often bilateral than unilateral
• Intensity typically builds
• Gradually, fluctuating intensity lasting hours to days
• Associated with emotional stress or depression.
• Symptomatic treatment : NSAIDs.

146. MIGRAINE HEADACHES
• Throbbing or pounding
• often associated with photophobia, scotoma, nausea and
vomiting.
• Classic migraines are preceded by an aura (localized transient
neurological dysfunction : sensory, motor, visual, or olfactory)
• Pain is unilateral ; can be bilateral
• Location – frontotemporal

147. • lasts 4–72 h
• Primarily affect children (both sexes equally) and young adults
(predominantly females)
• Familial tendency
• Precipitants : odors, certain foods (eg, red wine), menses, and sleep
deprivation
• Sleep relieves the headache
• Complex mechanism involving vasomotor, autonomic (serotonergic
brainstem systems), and trigeminal nucleus dysfunction

148. Abortive treatment for migraines
• Oxygen
• Sumatriptan (6 mg subcutaneously)
• Dihydroergotamine (1 mg intramuscularly or
subcutaneously)
• Intravenous lidocaine (100 mg)
• nasal butarphanol (1–2 mg)
• Sphenopalatine ganglion block.
• Zolmitriptan nasal spray
• Dihydroergotamine nasal spray
• oral serotonin 5-HT 1B/1D –receptor agonist
(almotriptan, frovatriptan, naratriptan, rizatriptan,
eletriptan, or sumatriptan).

149. Prophylactic treatment for migraines
 β-adrenergic blockers
 Calcium channel blockers
 Valproic acid
 Amitryptyline
 Botulinum toxin A (Botox) injections.

150. Cluster Headache
• classically unilateral and periorbital
• Occur in clusters of one to three attacks a day over a 4 – 8
week period
• Painful burning or drilling sensation that may awaken the
patient from sleep
• Each episode lasts 30 –120 min
• headaches are typically episodic but can become chronic
without remissions

151. • Remissions may last a year
• Primarily affect males (90%)
Signs and symptoms
 Red eye
 Tearing
 Nasal stuffiness
 Ptosis
 Horner’s syndrome

152. Horner's syndrome (oculosympathetic paresis)
Miosis
Hemifacial
anhidrosis
Partial Ptosis
Enophthalmos

153. Abortive treatments for Cluster headaches
 Oxygen
 sphenopalatine ganglion block
Prophylaxis :
 Lithium
 Steroid
 Verapamil

154. Temporal Arteritis
 Inflammatory disorder of extracranial arteries
 headache can be bilateral or unilateral
 Location : temporal area in at least 50% of patients.
 Pain develops over a few hours, is dull and lancinating
 Pain is worse at night and in cold weather
 Scalp tenderness
 Often accompanied by polymyalgia rheumatica, fever, and weight
loss
• Commonly affects older patients (>55 years) ; incidence 1 : 10,000
per year
• Female predominance.
• Complications : blindness (ophthalmic artery) ; early steroid
therapy ameliorates ophthalmic artery involvement

155. Trigeminal Neuralgia
• Also called tic douloureux
• Unilateral
• usually located in the V2 or V3 distribution of the trigeminal nerve
• has an electric shock quality lasting from seconds to minutes at a
time
• often provoked by contact with a discrete trigger
• Facial muscle spasm may be present
• common in middle-aged and elderly with a 2:1, F : M ratio
• Common causes :
- compression of the nerve by the superior cerebellar artery as it
exits the brainstem
- cerebellopontine angle tumor
- Multiple sclerosis.

156. Treatment :
a) Carbamazepine (DOC) ; S/E agranulocytosis.
b) Phenytoin
c) Baclofen
d) Glycerol injection
e) Radiofrequency ablation
f) Balloon compression of the gasserian ganglion
g) Microvascular decompression of the trigeminal
nerve.

157. Cancer Related Pain
Causes :
• Cancerous lesion itself
• Metastatic disease
• Complications such as neural compression or infection
• Treatment such as chemotherapy or radiation therapy
 Patient may have acute/chronic pain that is unrelated
to cancer

158. WHO Analgesic Ladder
STRONG
OPIOIDS
(morphine
hydromorph
one)
WEAK ORAL OPIOIDS
(codeine,oxycodone)
NONOPIOID
(Acetaminophen,NSAIDs)

159. Indications for Parenteral therapy :
 Refractory pain
 cannot take medication orally
 Poor enteral absorption
• Regardless of the agent selected, drug therapy
should be provided on a fixed time schedule
rather than as needed
• Use adjuvant e.g antidepressants liberally in
patients with cancer-related pain

160. Ziconotide
 Direct acting N-type calcium channel blocker
 Treats refractory pain ; may be used as a first-line
agent
 MOA : decreases release of substance P from the
presynaptic nerve terminal in the dorsal horn of
the spinal cord
 Rout : Intrathecal
 S/E : dose dependent :
Auditory hallucinations
worsening of depression or psychosis

161. INTERVENTIONAL PAIN THERAPIES
• Pharmacological treatment
• Nerve blocks with local anesthetics and steroid or a neurolytic solution
• Radiofrequency ablation
• Neuromodulatory techniques
• Psychological interventions
• Physical or occupational therapy
• Acupuncture

162. PHARMACOLOGICAL INTERVENTIONS
• Acetaminophen
• Cyclooxygenase (COX) inhibitors
• Opioids
• Antidepressants
• Neuroleptic agents
• Anticonvulsants
• Corticosteroids
• Systemic administration of local anesthetics.

163. Acetaminophen
• Paracetamol
• Analgesic /antipyretic
• It inhibits prostaglandin synthesis but lacks
significant anti-inflammatory activity
• Hepatotoxic at high doses
• Recommended adult maximum daily limit is 3000
mg/d
• Isoniazid, zidovudine, and barbiturates potentiate
acetaminophen toxicity.

164. Children
 <12yrs 10-15mg/kg/dose q 4hrs : do not to
exceed 2.6gm/24hrs
 Weight ≤10 kg: 7.5 mg kg−1
 Weight >10 kg: 15 mg kg−1
Adult
• 325-650mg q 4hrs : do not to exceed 3gm/24hrs.
• Onset 30 min
• Duration is 3 – 4 hr

165. Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
• inhibit prostaglandin synthesis
• Prostaglandins sensitize and amplify nociceptive
input
• analgesic, antipyretic, and anti-inflammatory
effects
• COX 1 and COX 2
• COX-1 is constitutive and widespread throughout
the body.
• COX-2 is expressed primarily with inflammation.

166. • COX-2 inhibitors do not interfere with platelet
aggregation
• Well absorbed enterally
• Food delays absorption but has no effect on
bioavailability
• Highly protein binding >80% ; displaces Wafarin
• Hepatic metabolism ; renal excretion

167. Side effects of NSAIDs
• Stomach upset
• Heartburn
• Nausea
• Dyspepsia
• dizziness,
• Headache
• Drowsiness
• Gastric ulceration due to inhibition of
prostaglandin-mediated mucus and bicarbonate
secretion.

168. • Except selective COX-2 inhibitors, all other COX inhibitors induce
platelet dysfunction
• Aspirin irreversibly acetylates platelets, inhibiting platelet
adhesiveness for 1–2 weeks
• Antiplatelet effect of other NSAIDs is reversible and lasts
approximately five elimination half-lives (24–96 h)
• NSAIDs can exacerbate bronchospasm in patients with the triad of
nasal polyps, rhinitis, and asthma
• ASA can precipitate Reye’s syndrome in children with varicella or
influenza.
• NSAIDs can cause acute renal insufficiency and renal papillary necrosis

169. Antidepressants
• Lower doses than for antidepressant activity
• Useful for neuropathic pain
• MOA : blockade of presynaptic reuptake of serotonin,
norepinephrine, or both : SSRIs and SNRIs
• Antidepressants potentiate the action of opioids
• Normalize sleep patterns
• All undergo first pass metabolism
• Highly protein bound
• Large volume of distribution
• Elimination half-lives vary between 1 – 4 days
• Many have active metabolites

170. Side effects of antidepressants
 antimuscarinic effects:
 dry mouth
 impaired visual accommodation
 urinary retention
 constipation
 antihistaminic effects :
 Sedation
 increased gastric pH
 α-adrenergic blockade:
 orthostatic hypotension
 quinidine-like effect
 atrioventricular block
 QT prolongation
 Torsades de pointes

171. Serotonin & Norepinephrine Reuptake Inhibitors (SNRIs)
a) Milnacipran :
 Indications : fibromyalgia
 elimination half-life : 8 h
 minimally metabolized by the liver
 Primarily excreted unchanged in urine
b) Duloxetine :
 Indications : neuropathic pain, depression, and
 half-life : 12 h
 metabolized by the liver
 metabolites are excreted in urine.

172. Absolute and relative contraindications to SNRIs
• Hypersensitivity
• Usage of other drugs that act on the central nervous
system e.g MAOIs
• Hepatic and renal impairment
• Uncontrolled narrow-angle glaucoma
• Suicidal ideation.

173. Side effects
 Nausea
 Headache
 Dizziness
 Constipation
 Insomnia
 Hyperhydrosis
 Hot flashes
 Vomiting
 Palpitations
 Dry mouth
 Hypertension

174. Neuroleptics
• Indications : refractory neuropathic pain especially
with marked agitation or psychotic symptoms.
• Commonly used agents
- Fluphenazine
- Haloperidol
- Chlorpromazine
- perphenazine.
 MOA : blockade of dopaminergic receptors in
mesolimbic sites.

175.  Blockade of dopiaminergic neurons in nigrostriatal pathways
produce undesirable extrapyramidal side effects :
• Masklike facies
• Festinating gait
• Cogwheel rigidity
• Bradykinesia
• Acute dystonic reactions e.g oculogyric crisis and torticollis
• Akathisia (extreme restlessness)
• Tardive dyskinesia (involuntary choreoathetoid movements
of the tongue, lip smacking, and truncal instability)
 Antihistaminic , antimuscarinic, and α-adrenergic–blocking
effects

176. Antispasmodics & Muscle Relaxants
Indications :
 musculoskeletal sprain
 Pain associated with spasm or contractures
a) Tizanidine
• centrally acting α 2 -adrenergic agonist.
• Indications :muscle spasm in multiple sclerosis, low back pain, and
spastic diplegia.

177. b) Cyclobenzaprine :
 MOA : unknown
 Indications :muscle spasm in multiple sclerosis, low back pain,
and spastic diplegia.
c) Baclofen :
• GABA B agonist
• Indications : muscle spasm associated with multiple sclerosis or
spinal cord injury

178. Effects of Abrupt discontinuation of Baclofen
• Fever
• Altered mental status
• Pronounced muscle spasticity or rigidity
• Rhabdomyolysis
• Death

179. Corticosteroids
• Anti-inflammatory and possibly analgesic actions
• Agents differ in potency, relative glucocorticoid and
mineralocorticoid activities, and duration or action
Excess glucocorticoid activity :
Hypertension
Hyperglycemia
increased susceptibility to infection
peptic ulcers
Osteoporosis

180. Excess glucocorticoid activity :
aseptic necrosis of the femoral head
proximal myopathy
Cataracts
Psychosis (rare)
Cushings syndrome
Excess mineralocorticoid activity :
• Sodium retention
• Hypokalemia
 Can precipitate congestive heart failure.

181. Anticonvulsants
 neuropathic pain, especially trigeminal neuralgia and diabetic neuropathy.
 MOA : block voltage-gated calcium or sodium channels and suppress the spontaneous neural
discharges
commonly used agents :
• Phenytoin (gum hyperplasia)
• Carbamazepine (slow and unpredictable absorption - monitor serum levels)
• Valproic acid
• Clonazepam
• Gabapentin
• Pregabalin
• Lamotrigine
• Topiramate
• All are highly protein bound
• Long half-lives.
• Levetiracetam
• Oxcarbazepine
 Gabapentin and pregabalin are effective adjuvants for acute postoperative pain.

182. Local anesthetics
 Systemic infusion produce sedation and central
analgesia
 Slow bolus or continuous infusion
Agents:
 Lidocaine : infuse over 5–30 min for a total of 1–5
mg/kg.
 Procaine : 200–400mg, over 1–2 h
 Chlorprocaine : 1 mg/kg/min for a total of 10–20
mg/kg.

183. Monitoring :
• electrocardiographic data
• blood pressure
• Respiration
• pulse oximetry
• mental status
 full resuscitation equipment should be immediately
available
 Signs of toxicity: tinnitus, slurring of speech,
excessive sedation, or nystagmus.

184.  5% lidocaine transdermal patch (Lidoderm)
containing 700 mg of lidocaine has been
approved treats PHN :
 1- 3 patches applied alternating 12h on and 12h
off
 Patients who are unresponsive to anticonvulsants
but respond to L.A may benefit from chronic P.O
antiarrythmic agents e.g mexiletine 150 – 300mg
Q6 – 8 h

185. α 2 -Adrenergic Agonists
• MOA : Activation of descending inhibitory pathways in the dorsal
horn
• Epidural and Intrathecal α 2 –adrenergic agonists are particularly
effective in the treatment of neuropathic pain and opioid
tolerance
Clonidine :
• Effective adjuvant in treatment of severe pain
• P.O : 0.1 – 0.3 mg B.D
• Transdermal patch (0.1 – 0.3 mg/d) applied for 7 days
• Combined with Intrathecal/epidural L.A or opioid ; synergistic
/prolongs analgesic effect

186. Opioids
a) Oral opioids :
 Agents : codeine, oxycodone, and hydrocodone
 Readily absorbed
 hepatic first-pass metabolism limits systemic
delivery
 Hepatic biotransformation and conjugation ; renal
elimination
 Codeine is transformed by liver into morphine.
 When prescribed on a fixed schedule, stool
softeners or laxatives are oft en indicated.

187.  Tramadol
- synthetic oral opioid that also blocks neuronal
reuptake of norepinephrine and serotonin.
- same efficacy as the combination of codeine and
acetaminophen
- significantly less respiratory depression
- little effect on gastric emptying.

188.  Moderate to severe cancer pain :
immediate-release morphine preparation (eg, liquid
morphine, Roxanol, 10–30mg1–4 h) ; t1/2 : 2–4 h
sustained-release morphine preparation (MS Contin
or Oramorph SR) 10– 30 mg , Q 8–12 h
Immediate release morphine or oral transmucosal
fentanyl lozenges 200 – 1600 mcg can be used for
breakthrough pain(PRN)

189. Excessive sedation : Rx - dextroamphetamine or
methylphenidate 5 mg in the morning and 5 mg
the early afternoon
Nausia /vomiting : Rx - transdermal scopolamine,
oral meclizine, or metoclopramide
Hydromorphone : excellent alternative to
morphine,in elderly (fewer S/E) and patients with
impaired renal function.

190.  Methadone : half-life 15 – 30h; clinical duration 6 – 8h
 Opioid tolerance: escalate doses of opioid to maintain the same
analgesic effect
 Physical dependence :
- manifests in opioid withdrawal when the opioid medication is
either abruptly discontinued or the dose is abruptly and
significantly decreased
- occurs in all patients receiving large doses of opioids for extended
periods
- Results in decreased opioid-related sedation, nausea, and
respiratory depression

191.  Psychological dependence :
- characterized by behavioral changes focusing on
drug craving
- rare in cancer patients
 Tapentadol:
- μ-opioid receptor agonist
- Has norepinephrine reuptake inhibition properties
- less nausea and vomiting ; less constipation
- Indications: acute and chronic pain
- It should not be used concomitantly MAOIs
(↑norepinephrine)

192. Opioid antagonists :
 Naloxone
 Methylnatrexone
 Alvimopan

193. Botulinum Toxin (Botox)
• Treatment of conditions associated with involuntary
muscle contraction eg, focal dystonia and spasticity
• Prophylactic treatment of chronic migraine headache
• MOA : blocks acetylcholine released at the synapse in
motor nerve endings but not sensory nerve fibers
• Mechanisms of analgesia : improved local blood flow,
relief of muscle spasms, and release of muscular
compression of nerve fibers