Pain management
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Introduction
Definition of pain
 Pain is a subjective, unpleasant, sensory, and
emotional experience associated with actual or
potential tissue damage or described in terms of
such damage.
 It may be classified as acute, chronic, or cancer pain.
 A persons reaction to pain is influenced by both
physiologic variables (e.g., tissue injury) and
psychological variables (e.g., anxiety).
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Introduction cont…..
 The pain sensation is therefore the net effect of
complicated interactions of ascending and
descending neural pathways with biochemical
and electrochemical processes.
 It can be physiologic and protective (adaptive) or
pathophysiologic and harmful (maladaptive).
 The pain experienced from touching something too
cold, hot, or sharp is called nociceptive pain.
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 Pain that occurs as a result of unavoidable tissue
damage (trauma or surgery) creates sensitization at and
adjacent to the site of tissue injury.
 This process also engages the immune system, and is
called inflammatory pain.
 Nociceptive and inflammatory pain are both adaptive
and protective.
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Pathophysiology
Nociceptive pain is typically classified as
either:
 Somatic (arising from skin, bone, joint, muscle, or
connective tissue) – often presents as throbbing
and well localized.
 Visceral (arising from internal organs such as the
large intestine or pancreas)__are referred pain or
as a more localized phenomenon.
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Pathophysiology
Stimulation or Transduction
stimulation of free nerve endings known as nociceptors
(both on somatic and visceral structures)
release of bradykinins, potassium ion (K+),
prostaglandins, histamine, leukotrienes, serotonin, and
substance P that sensitize and/or activate the
nociceptors.
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change the permeability of the membrane thereby
depolarizing neuronal membranes and leads to
development of action potentials.
Pathophysiology cont……
Conduction
 Receptor activation, involving voltage-gated sodium
channels, leads to the generation of action potentials
that are conducted along afferent A-δ and C-nerve
fibers to the spinal cord.
 Stimulation of large-diameter, sparsely myelinated A-δ
fibers evokes sharp, well-localized pain, whereas
stimulation of unmyelinated, small-diameter C fibers
produces aching, poorly localized pain
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Transmission
 These afferent, nociceptive pain fibers synapse in
various layers of the spinal cord’s dorsal horn,
releasing excitatory neurotransmitters, such as
glutamate and substance P.
 The thalamus acts as a relay station within the brain.
 As these pathways ascend and pass the impulses to
higher cortical structures, pain can be processed
further
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Perception
 At this point in transmission, pain is thought to
become a conscious experience that takes place in
higher cortical structures.
 Cognitive and behavioral functions can modify pain.
 Thus relaxation, distraction, meditation, and guided
mental imagery may strongly influence pain
perception and decrease pain.
 In contrast, conditions such as depression or anxiety
often worsens pain.
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Pathophysiology cont…
Modulation
 The brain and spinal cord modulate pain through a
number of intricate processes.
 Pain transmission may be facilitated by
neurotransmitters such as glutamate or substance P to
make the signals stronger and pain more intense.
 The signal can also be attenuated/inhibited by
descending pathways that consist of endogenous opioids
(eg, enkephalins, and β-endorphins) γ-aminobutyric acid
(GABA), norepinephrine, or serotonin.
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Peripheral and Central Sensitization
 Under normal homeostatic conditions, a balance exists
between excitatory and inhibitory neurotransmission.
 Changes in this balance lead to exaggerated
responses and sensitization.
 Examples often observed in chronic pain include:
– Hyperalgesia (enhanced pain to a given noxious
stimulus)
– Allodynia (pain in response to a normally nonnoxious mechanical stimulus, such as light touch).
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Neuropathic pain/functional pain
 It is distinctly different from nociceptive pain in that it
becomes disengaged from noxious stimuli or healing and
often is described in terms of chronic pain.
 Neuropathic pain – it is a result of nerve damage
e.g. post-herpetic neuralgia, diabetic neuropathy
 Functional pain - abnormal operation of the nervous
system
e.g. Fibromyalgia, irritable bowel syndrome,
sympathetic induced pain, tension-type headaches.
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Classification of pain
Acute pain
 It warning individuals of disease states and potentially
harmful situations.
 It is usually nociceptive, although it can be neuropathic.
 Common causes of acute pain include surgery, acute
illness, trauma, labor, and medical procedures.
Chronic pain
 Pain persists for months to years
 It can be nociceptive, neuropathic/ functional, or both.
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Cancer Pain
– Pain associated with potentially life-threatening
conditions is often called malignant pain or in the
case of cancer, cancer pain.
– This type of pain includes both chronic and acute
(e.g., breakthrough pain) components and often has
multiple etiologies.
– It is pain caused by the disease itself (e.g., tumor
invasion, organ obstruction), treatment (e.g.,
chemotherapy, radiation, and surgical incisions), or
diagnostic procedures (e.g., biopsy)
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Treatment - pharmacological management
Goal of pain therapy is:
 Rapid pain relief or reduction in pain intensity
 Improve or maintain day-to-day functioning,
 Decrease the rate of physical deterioration
 Decrease pain perception
 Improve the patient’s sense of well-being
 Improve family and social relationships
 Decrease dependency on drug therapy
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Pharmacologic Treatment
Non-opioid Agents
Acetaminophen, acetylsalicylic acid, and NSAIDs
 Mild-to-moderate pain - preferred over opiates.
 Prevent formation of prostaglandins produced in
response to noxious stimuli with exception of
acetaminophen, thereby decreasing the pain impulses
received by the CNS
 NSAIDs may be particularly useful in the management of
Cancer-related bone pain and
Short-term relief in the management of chronic low
back pain.
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 Choice of a particular agent often depends on
availability, cost, pharmacokinetics, pharmacologic
characteristics, and the side-effect profile.
 Chronic use of NSAIDs, including selective COX-2
inhibitors may be limited by adverse effects,
including GI, renal, and cardiac effects.
 Topical NSAIDs may offer similar efficacy as oral
NSAIDs in some patients with improved safety and
tolerability.
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 The salicylate salts cause fewer gastrointestinal (GI) side
effects than aspirin and do not inhibit platelet
aggregation.
 Do not give aspirin-like compounds to children or
teenagers with viral illnesses (eg, influenza or
chickenpox), as Reye syndrome may result.
 Acetaminophen has analgesic and antipyretic activity
but little anti-inflammatory action.
 It is highly hepatotoxic on overdose.
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Adult Dosing of FDA-Approved Non-opioid Analgesics
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Opiates
 Opiates can attach to one or more of five opioid
receptors: the μ-, δ-, ε-, κ-, and σ -receptors.
μ-opioid receptors (MOR) - 70% of the total
receptor
κ (kappa, KOR), and δ (delta, DOR) _ 24% and
6% of the population, respectively.
 Because morphine has a 50 times higher affinity for the
μ-receptor than for the δ- or κ-receptors, it is a very
effective analgesic.
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Opiates …..
Opioids produce analgesia by three main mechanisms:
1. Presynaptically, reduce the release of
inflammatory transmitters (e.g., tachykinin, excitatory
amino acids, and peptides) from the terminals of afferent
C-fiber neurons after activation of opioid receptors.
2. Opioids also can reduce the activity of output neurons,
interneurons, and dendrites in the neuronal pathways by
means of postsynaptic hyperpolarization.
3. Opioids also inhibit neuronal activity via GABA and
enkephalin.
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Opioids are used for
 next step in the management of acute pain
 cancer-related chronic pain
 effective treatment option in the management of
chronic non-cancer pain.
 Opioid choice should be based on patient
acceptance; analgesic effectiveness; as well as
pharmacokinetic, pharmacodynamic, and side-effect
profiles.
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Opioid Analgesics, Central Analgesics, Opioid Antagonist
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 Opioids share related pharmacologic attributes and exert a
profound effect on the CNS and GI tract.
 Mood changes, sedation, nausea, vomiting, decreased GI
motility, constipation, respiratory depression,
dependence, and tolerance are evident in varying
degrees with all agents.
 Some differences exist between the opioids in regards to
incidence of side effects, which may assist in selection of
the most appropriate agent.
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 In the initial stages of acute pain, analgesics should be
given around the clock.
 This should commence after administering a typical
starting dose and titrating up or down, depending on
the patient’s degree of pain and demonstrated side
effects (e.g., sedation).
 As the painful state subsides and the need for
medication decreases, as-needed schedules may be
appropriate.
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 Patients with severe pain may receive high doses of
opioids with no unwanted side effects, but as pain
subsides, patients may not tolerate even low doses.
 Most opioid-related itching or rash is due to histamine
release and mast cell degranulation, and is not a true
allergic response.
 When opioid allergies occur, an opioid from a different
structural class may be cautiously tried.
 Naloxone is used to reverse respiratory depression,
but continuous infusion may be required.
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General treatment ……..
 When treating chronic pain,
– Use analgesics at fixed time intervals (“time-
contingent”) rather than on an as-needed basis.
– As-needed schedules create wide swings in pain and
sedation.
 As-needed schedules may be useful:
– when painful state subsides and the need for
medication decreases.
– Pain that is intermittent or sporadic in nature
– In conjunction with around-the-clock regimens
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 Identify pain source if possible; assess pain severity and
quality using consistent method such as numeric rating
scale (NRS); 0–10 out of 10).
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Algorithm for acute pain management
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Analgesic Selection
• The selection of an analgesic must be individualized
for each patient
• Age of patient
• Concomitant medical conditions.
• Clinical response of the patient dictates future
dose adjustment, route, and desired dosing interval.
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Treatment…..
1. NSAIDs
 Low to Moderate Potency (Mild) Analgesics.
 The NSAID in contrast with opoids analgesics
– Have a relatively flat dose-response
– Higher doses of NSAIDs do not produce greater
analgesia.
– But analgesic duration can be prolonged
– For example, ibuprofen given 600 mg every 6 hours
produces a similar analgesic effect as 400 mg given
every 4 hours.
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 All of the NSAIDs, including ibuprofen, naproxen,
naproxen sodium , diclofenac, diclofenac
potassium, nabumetone, ketoprofen , flurbiprofen,
ketorolac (Toradol), and others, provide analgesia
equivalent or superior to that of aspirin or
acetaminophen.
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Morphine and Congeners
Morphine – Morphine remains the prototype opiate analgesic.
– The first-line agent for moderate-to-severe pain
due to its relative low cost, broad clinical
experience, and abundant dosage forms/strengths.
– Morphine can be given parenterally, orally, or
rectally
– Response to morphine should be monitored carefully.
– Once the pain has been controlled, single-day
dosage adjustment should be sufficient
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Side effects:
 Nausea and vomiting - direct stimulation of the
CTZ.
 Respiratory depression –
– Increases as doses of morphine increased.
– reversed by pure opioid antagonists, such as
naloxone
 Decreases the propulsive contractions of the
gastrointestinal tract and reduces biliary and pancreatic
secretions, resulting in constipation.
 Tolerance, Dependence, and Addiction
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 Therapeutic doses of morphine have minimal effects on
blood pressure, cardiac rate, or cardiac rhythm when
patients are supine
 however, morphine does produce venous and
arteriolar vessel dilation, potentially resulting in
orthostatic hypotension
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Hydromorphone –
– more potent, has better oral absorption, and is more
soluble than morphine.
– Overall pharmacologic profile parallels that of
morphine.
Oxymorphone– Can be administered orally, rectally, and by injection.
– It offers no pharmacologic advantage over morphine.
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Levorphanol Has an extended half life, but its overall therapeutic
effects are similar to the other agents in this class.
Codeine –
 Commonly used in the treatment of mild-moderate
pain.
 It often is combined with other analgesic products
(e.g., acetaminophen).
 Unfortunately, it has the same propensity to produce side
effects as morphine and may produce more nausea and
constipation.
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Hydrocodone –
– Available for pain only in combination products with
other analgesic agents (e.g., acetaminophen,
ibuprofen).
– Its pharmacologic properties are similar to those of
morphine.
Oxycodone –
 It is a useful oral analgesic for moderate-to-severe
pain.
 This is especially true when the product is used in
combination with non-opioids.
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Meperidine and Congeners
Meperidine:
– Has a pharmacologic profile comparable with that of
morphine;
– Have less potency and has a shorter analgesic duration.
– Has greater toxicity (CNS hyperirritability caused by its
renally eliminated metabolite normeperidine), and
should be limited in use.
– In particular, avoid long-term usage, and use in patients at
greatest risk for toxicity (e.g., elderly patients and those
with renal dysfunction).
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Fentanyl
 It is a synthetic opioid structurally related to meperidine
that is used often used as an adjunct to general
anesthesia.
 This agent is more potent and faster acting than
meperidine
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Tramadol
– Centrally acting analgesic with weak opioid agonist
properties.
– Low tolerance and dependence potential
– Indicated for the treatment of moderate to severe
pain, but analgesia is not superior to other opiate
analgesics.
– Doses range from 50 to 100 mg orally every 4 to 6
hours and should not exceed 400 mg/day.
– Tramadol is well tolerated in short-term use.
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Adverse effects of tramadol
 Are sedation, dizziness, nausea, vomiting, dry mouth,
constipation, and sweating
 But, lower incidence of respiratory depression or
significant GI dys-motility than most traditional opioids.
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Opioid Antagonists
 The opioid antagonist naloxone binds competitively to
opioid receptors but does not produce an analgesic
or opioid side-effect response.
 Therefore, it is used most often to reverse the toxic
effects of agonist- and agonist–antagonist-derived
opioids.
 Other opioid antagonists exist, including naltrexone,
naloxegol, and methylnaltrexone
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Adjuvant Analgesics
 useful in the management of pain but that typically are not
classified as analgesics
 Chronic pain that has a maladaptive inflammatory (e.g., low
back pain) and/ or neuropathic component (e.g., diabetic
neuropathy) may require such agents.
 Anticonvulsants (e.g., gabapentin, which may decrease
neuronal excitability),
 tricyclic antidepressants, serotonin and norepinephrine
reuptake inhibitor antidepressants (which block the reuptake
of serotonin and norepinephrine, thus enhancing pain
inhibition).
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