PAIN: PHYSIOLOGY AND TREATMENT
May 26, 2015
PAIN: PHYSIOLOGY AND TREATMENT
Definitions
• Pain– “Unpleasant sensory and emotional experience
associated with actual or potential tissue damage or described in terms of such damage”.
• Nociceptor– is a receptor that is preferentially sensitive to a
noxious (damaging to tissue) stimulus or to a stimulus that would become noxious if prolonged.
Transduction
TransmissionModulation
Perception
Transduction
• Mechanical, chemical and thermal energy are converted into electrical energy/impulses by specialized nerve endings called “nociceptors”
• Nociceptors – free nerve endings of primary afferent fibers.– have high stimulus thresholds for activation.
Nociceptors
• A-fiber mechanoheat receptors
-signal “first” pain (sharp, stinging, pricking sensation), well localized pain, transient, lasts only as long as the stimulus activates the nociceptors
C-fiber mechanoheat (polymodal) receptors
-mediate “second” or “slow” pain, a diffuse, persistent sensation that exists past the termination of an acute painful stimulus.
Nociceptors
• Repeated stimulation produces:– reduction in receptor threshold – an enhanced magnitude of response.
Transmission
• occurs along 2 different types of afferent nerve fibers:A-delta fibers– large diameter– myelinated– rapid impulse conduction (6-30 m/sec)– stimulates immediate reaction
Transmission
• C fibers– small diameter– unmyelinated– slow conduction
• (0.5 – 2 m/sec)
– reinforces the immediate
response that is signaled by A-delta fibers
Transmission
• Spinothalamic tract– Most important tract in
transmission of nociceptive
information
• Spinoreticular tract
• Spinohypothalamic tract
Perception-Supraspinal Processing
• Reticular System
• Limbic System
• Thalamus
• Cortex
Transduction
TransmissionModulation
Perception
Descending Modulation
• Inhibitory influences at the
cortical and spinal cord levels
• Inhibitory neurotransmitters
include GABA, glycine,
serotonin, dopamine, NE,
endogenous opioids
Peripheral Sensitization
• arises as a result of the exposure of nociceptor to chemical mediators of inflammation: substance P, hydrogen ions, norepinephrine, bradydkinin, histamine, potassium, cytokines, serotonin, nitric oxide
• all of these mediators act together to lower the response threshold of both the A-delta and C fibers nociceptors
Central Sensitization• Produced by changes in the membrane
excitability of dorsal horn neurons. – Increase in receptive field of dorsal horn
neurons (zone of secondary hyperalgesia).– increased responsiveness to mechanical
stimulation that is normally innocuous (allodynia).
– Recruitment of non-nociceptive receptors (A-beta fibers)
Types of Pain
• Physiologic pain– transient stimulus, no tissue damage or
inflammation, neurophysiology associated with simple stimulus-response model.
Types of Pain
• Pathologic pain – pain that arises in the clinical setting
– involves dynamic changes in the processing of noxious input at both the peripheral and central levels
– stimulus is not transient
– usually associated with significant tissue inflammation.
– can be associated with damage to nervous tissue (neuropathic pain).
– recently occurring (acute) or long-lasting (chronic).
Acute Post-Operative Pain
• arises from soft tissue trauma or inflammation• plays a biologically adaptive role by facilitating
tissue repair– functions:
-hypersensitizes injured area (primary hyperalgesia)
-sensitizes surrounding tissues (secondary hyperalgesia)
– serves to facilitate avoidance of external stimuli
– doesn’t give license to allow pain to exist untreated
Chronic Pain:
• pain that persists beyond the expected time frame for a given disease, process or injury.
• may be associated with ongoing inflammation • may be autonomous with no temporal relation to
the inciting cause.• Maladaptive, offers no biologic advantage• examples of chronic pain:
– cancer pain– osteoarthritic pain– postamputation phantom limb pain
Visceral Pain
• nature of pain originating from viscera versus somatic tissues is significantly different.
• the viscera most sensitive to distention (hollow organs of GI tract), ischemia (myocardium) and inflammation (pancreatitis).
• poorly localized. • referred – pain response is localized to distant
structures
Neuropathic Pain• produced as a consequence of damage to the nervous
system.• characterized by altered sensory processing of stimuli• several manifestations of hypersensitivity:
– persistent burning sensations, partial or focal loss of sensitivity
• allodynia (an increased responsiveness to mechanical stimulation that is normally innocuous).
• may arise from an acute injury discharge in axotomized afferent fibers.
Systemic Response to Pain and Injury
• increased sympathetic tone– vasoconstriction– increased cardiac output through increases in
stroke volume and heart rate– decreased gastrointestinal and urinary tone– increased skeletal muscle tone
Systemic Response to Pain and Injury
• hormonal changes – increased secretion of cortisol, ADH, catecholamines,
renin, angiotensin II, aldosterone– decreases in insulin and testosterone
• endocrine changes result in a catabolic state:– hyperglycemia– increased protein catabolism and lipolysis, – renal retention of water and sodium, – increased potassium excretion– decreased GFR.
Stress Response Markers/Pain Assessment
• heart rate
• respiratory rate
• blood pressure
• posture
• attitude
• food and water intake
• patterns of defecation, urination
Stress Response Markers/Pain Assessment
• Change in activity levels
• Natural behaviors – inquisitive, grooming
• Provoked behavior
• Aggression
• Gait-/posture
• Vocalization
• Appearance of stereotypical behaviors
General Approaches to Pain Management
• minimize debilitating pathologic pain while maintaining the protective and adaptive aspects associated with physiologic pain.
• a single drug administered at a standard dose for different pain syndromes is not an effective pain management strategy.
General Approaches to Pain Management
• Pre-emptive analgesia-initiating treatment prior to acute insult helps to
limit the development of peripheral and central sensitization.
General Approaches to Pain Management
• Multimodal/balanced analgesia:– combining analgesic
drugs and techniques to achieve beneficial additive or synergistic analgesic effects.
– can use lower doses, fewer side effects.
General Classes of Analgesic Drugs
• 1. Opioids• 2. Local Anesthetics• 3. Non Steroidal Anti Inflammatory Drugs• 4. Alpha 2 adrenergic agonists• 5. NMDA Antagonists• 6. Others
• GABApentin• Tramadol
OPIOID ANALGESICS
USES
• 1. sedation• 2. analgesia• a. preoperatively• b. intraoperatively• c. postoperatively• 3. neuroleptanalgesia• a. in combination with a
tranquilizer/sedative• b. useful for minor procedures that do
not require general anesthesia
Opioid Classification
• Agonists– Stimulate receptor activity– Mu agonists
• most common group of opioid agonists used
• Include morphine, meperidine, oxymorphone, hydromorphone, fentanyl, carfentanil
Opioid Classification
• Agonists-Antagonists– Stimulate activity at some receptors and
antagonize others– Butorphanol – kappa agonist, mu antagonist
Opioid Classification
• Partial Agonists– Bind to receptor but only produce a partial
effect• Buprenorphine – partial mu agonist, kappa
antagonist
Opioid Classification
• Antagonists– Primary activity is mu receptor antagonism
• Naloxone
• Naltrexone
• Nalmefene
• Diprenorphine
• Classification:– Traditional:
• μ, κ, δ, ε, σ
– New (?) Classification: • OP1 (δ), OP2 (κ), OP3 (μ)
Opioid Receptor Pharmacology
Opioid Receptor Pharmacology
• Mu– Supraspinal, spinal, peripheral analgesia– Respiratory depression– Euphoria/Sedation– Physical dependence– Bradycardia
Opioid Receptor Pharmacology
• Kappa– Spinal analgesia
– Sedation
– Respiratory depression
• Sigma (opioid receptor?)– Dysphoria/hallucinations
– Hypertonia
– Respiratory stimulation
– tachycardia
Opioid Effects
• Cardiovascular– Bradycardia – vagally mediated– Negligible effect on myocardial contractility– Hypotension due to histamine release
• Seen with morphine, meperidine (particularly when administered IV)
• Not a problem with synthetic opioids
Opioid Effects
• Respiratory– Decrease in frequency and tidal volume– Blunts response to carbon dioxide– Cough suppressant
Opioid Effects
• CNS – Narcosis – sedation, euphoria, hypnosis, analgesia,
excitement, dysphoria– Medullary depression
• Respiratory center• Cough center• Vomiting center (delayed)
– Vomiting center (early)– Vagus nerve– Oculomotor nerve (miosis – dog; mydriasis – horse,
cat)
Opioid Effects
• Gastrointestinal– Salivation– Nausea– Vomiting– Nonpropulsive hypermotility– Defecation
Opioid Effects
• Species Specific Effects– Excitement in horses (u agonists;
agonists/antagonists)– Excitement in cats (dose related)– Panting in dogs – resets thermostat– Sweating in horses
Opioid Pharmacology:Distribution
Routes of Administration
• SC, IM, IV
• CRI
• Oral
• Epidural
• Transdermal
• Intra-articular
Epidural Catheter
Epidural Catheter
Commonly Used Opioids
Mu agonists
DRUG DOSE (MG/KG)
ROUTE
DURATION
COST (20 KG)
Morphine 0.5 – 1
IM/SC
4-6 0.27
Meperidine 2 –6
IM/SC
1-2 1.47
Fentanyl .004-0.008
IV/IM/SC
1-2 4.80
Oxymorphone 0.05-0.2
IV/IM/SC
4-6 14.00
Hydromorphone 0.1-0.2
IV/IM/SC
4-6 0.76
Commonly Used Opioids
Mixed agonists/antagonists
DRUG DOSE (MG/KG)
ROUTE
DURATION
Butorphanol 0.2-0.4
IV/IM/SC
3-4
Buprenorphine 0.01-0.02
IV/IM/SC/PO
8-12
Reversal of Opioid Effects
• Naloxone (1 ug/kg diluted in 5-10 ml normal)
• Butorphanol (0.1-0.2 mg/kg)
Which Opioid? Which Route of Administration?
• Nature of procedure – severity and expected duration of pain.
• Nature of patient
• Resources
Neuroleptanalgesia
• A state of quiescence, altered awareness and analgesia produced by the administration of an opioid analgesic and a tranquilizer or sedative
• Indications:– Minor surgical procedures
– Diagnostic procedures
– Premedication for General Anesthesia
– Induction of General Anesthesia
Neuroleptanalgesia
• Clinical Effects– Narcosis without unconsciousness– Hyper-responsive to auditory stimuli– Defecation– Respiratory depression– Bradycardia– Analgesia
Neuroleptanalgesia
• Combinations:
Acepromazine
Midazolam
Diazepam
Oxymorphone
Hydromorphone
Butorphanol
Morphine
Buprenorphine
Fentanyl