AST 2 Pain

PGE2

Enhance transmission of pain signals in spinal cord centrally; increased excitability of spinal dorsal horn neurons (PGE2)

Lipoxygenase

Enzyme that changes arachidonic acid to leukotrienes in granulocytes

Anticonvulsants

Gabapentin and pregabalin bind voltage-gated N-type Ca 2+ channels. decreasing Ca 2+ entry, with a predominant effect on presynaptic channels, and modify the synaptic or nonsynaptic release of GABA

Windup

Progressive increase in the frequency and magnitude of firing of dorsal horn neurons produced by repetitive activation of C fibers above a critical threshold, leading to a perceived increase in pain intensity, a phenomenon that requires glutamatergic NMDA receptor activity.

PGD2 , PGI2 , PGE2

Prostaglandin inflammatory mediators forms. increased local blood flow in inflamed region; vasodilatation; leading to => => edema formation erythema (long-lasting up to 10 hrs) Increased vascular permeability; leukocyte infiltration tissue-damaging free radical formation during endoperoxide synthesis ================= potentiate effect of histamine and bradykinin on permeability increase, vasodilation, and pain Get redness, increased blood flow, swelling, etc

PGE2

Prostaglandin involved with fever

PGI2,PGE2

Prostaglandins involved in pain. Increase nociceptor sensitivity peripherally (lower the threshold) hyperalgesic response by potentiating pain-producing activity of bradykinin and other autocoids via sensitization of afferent nerve endings (C-fibers) to chemical and mechanical stimulation

PGI2 and TXA2

Prostaglandins involved with Platelet Activity. PGI2 (also PGD2) - causes disaggregation via increased cAMP levels 3. TXA2 - causes aggregation via increased IP3 levels and mobilization of intracellular calcium; also - amplification of other platelet agonists, e.g. thrombin & ADP

Opioid responsiveness

The degree of analgesia achieved as the dose of opioid is titrated to an endpoint defined either by intolerable side effects or the occurrence of acceptable analgesia

Unidimensional

Type of Pain assessment. Consist of a single item Usually relates to pain intensity alone Scales are usually easy to administer Requires little time to train practitioners to use

Multidimensional

Type of pain scale. Multiple items that evaluate pain in several domains Captures information about the pain such as intensity, affect, sensation, location, impact on activities of daily living Can be long to administer Includes:Initial Pain Assessment Tool and the Brief Pain Inventory

Unidimensional pain scales

Visual Analog Scale Numeric Rating Scale Verbal Descriptor Scale Faces Scale

Reasons for Changing Opioid

What to do if patient on an opioid is: Lack of therapeutic response Development of adverse effects Change in patient status Other considerations Opioid/formulation availability Formulary issues Patient/family health care beliefs

Transduction

begins when imminent or real injury from a thermal, chemical, or mechanical source stimulates peripheral endings of sensory neurons (nociceptors). Nociceptors translate (transduce) the physical stimulus into an electrical signal which, if strong enough, triggers an action potential.

Cannabinoids

bind at presynaptic CB 1 receptors, where they inhibit the release of either glutamate or GABA.

Capsaicin

binds to TRPV1, it causes the heat channel to open below 37oC Prolonged activation of neurons that contain TRPV1 by capsaicin depletes presynaptic substance P

Antidepressants and SSRIs

block the reuptake of neurotransmitters such as epinephrine and norepinephrine, thereby altering neurotransmission along pain pathways

Leukotriene Effect

increased vascular permeability bronchoconstriction chemotactic (leukotactic)

Corticosteroids

inhibit phospholipase A 2 thereby reducing the synthesis of arachidonic acid reduce expression of cyclooxygenase-2, cause vasoconstriction when applied directly to the skin, possibly by suppressing mast cell degranulation. decrease capillary permeability by reducing the amount of histamine released by basophils and mast cells.

Bisphosphonates

inhibit the digestion of bone by causing osteoclasts to undergo apoptosis, or cell death, thereby slowing bone loss. uses include the prevention and treatment of osteoporosis, bone pain caused by cancer metastasis

Allodynia

is a clinical condition in which a person experiences normal stimuli as painful.

Neuropathic Pain

tissue damage directly affects the nervous system, resulting in the generation of ectopic discharges that bypass transduction and stimulate the nerve directly

Nonselective NSAIDS

Can cause ulcers in stomach and promote bleeding

COX-1

Cyclooxygenase Isoforms: Constitutively active (present in most cells) Activation is physiological (2-4- fold increase in activity); "housekeeping activities" Leads to homeostasis via: platelet aggregation/ disaggregation cytoprotection (gastric epithelia) vascular responses renal protection

COX-2

Cyclooxygenase Isoforms: Inducible form; usually inflammatory stimulus, e.g. induction by growth factors, tumor promotors, endotoxin (LPS) or cytokines (interleukin-1 or TNF-alpha) Activation is pathological (10 20 -fold increase) Leads to: Inflammation Pain Fever Also involved in normal renal activity and vascular PGI2 production

Neuropathic Pain Causes

Abnormal nerve regeneration - damage to a healing nerve may lead to neuroma formation Increased expression of membrane sodium channels - chronic pain is frequently accompanied by upregulation of these channels in the periphery Disinhibition of modulatory processes Decreased expression of (mu)-opioid receptors - dependence (from coop)

Breaking of Fever

Healing tissue cells stop releasing chemicals -> set-point returns to normal -> activation of "cooling mechanisms"

Inflammation Mediators

Histamine Bradykinins Leukotrienes Prostaglandins Interleukin-1 ("leukocytic pyrogen")

Fever Onset

Injured tissue cells release chemicals (interleukins and prostaglandins) -> increase in temp set point -> activation of "heat generating mechanisms"

NNT

Method of expressing analgesic efficacy. It relates the numer of patients who need to receive the active drug for 1 patient to achieve at least 50% relief of pain compared to placebo

Acute Pain

Occurs suddenly due to illness, injury or surgery. Short-lived, resolves as acute illness heals.

Chronic Pain

Pain that lasts longer than the expected healing process (or three months) Affects a person's activities of daily living Frequently caused by inadequately treated acute pain

Prostaglandin Effects

Pathological i. Inflammation ii. Fever iii. Pain (hyperalgesia synergism) -- peripherally, increased nociceptor sensitivity -- centrally, enhance transmission of pain signals in spinal cord

Prostaglandin Effects

Physiological (protective) i. cytoprotective; maintain gastric lining ii. Vasodilatory; maintains adequate renal blood flow, and water balance within body iii. platelet aggregation and disaggregation iv.increase tone and uterine contractions

Inflammation

Redness and Warmth: Histamine causes local vasodilation, increasing blood flow to the injured area. Swelling: These chemicals also cause capillaries to be more permeable or leaky. Pain: Some of these chemicals, specifically the prostaglandins and bradykinins, activate the pain sensory neurons. Chemotaxis: Some of the chemicals released by injured cells atract white blood cells (neutrophils are small phagocytes and monocytes are macrophages; Macrophages are king of the phagocytes) to the injured tissue and this is called chemotaxis. Fever: Chemicals are being released from injured cells, carried from the blood stream into brain and raising the thermostatic set point to a higher level.

COX-2

Selective Inhibitor of this enzyme provide pain relief without the gastrointestinal side effects, but increase the rate of vascular events

The Gate control Theory

Stimulation of the fibers that transmit nonpainful stimuli can block pain impulses at the gate in the dorsal horn.

C fibers

These smaller fibers transmit dull burning or aching sensations, known as "second pain." The fibers transmit pain more slowly than the A fibers do because they are smaller and lack a myelin sheath and hence are more prone to injury. These fibers are also responsible for producing constant pain.

Lidocaine

Topical that blocks voltage-gated sodium channels

Conduction

When pain signals are conducted along nerve fibers via the passage of action potentials along neurons. Step 2 of pain response

Perception

When pain signals ultimately enter the brain through the thalamus—the brain's "master switchboard"—these signals are then routed to regions of the brain involved with sensation, autonomic nervous system, motor response, emotion, stress, and behavior. The complex interactions of all these areas define the patient's perception of pain. Step 5

Transmission

Wherever one nerve conduction pathway ends and another begins, neurotransmitters—including glutamate, substance P, norepinephrine, dopamine, and serotonin—transmit the signal across the synapses at three junctions. Step 3 of Pain response

Prostaglandin MOA

act on specific cell surface receptors. coupled by G proteins to adenylyl cyclase (to form cAMP) or to the phosphotidylinositol system (producing IP3 and DAG) --PGI2 activates adenylyl cyclase to increase cAMP and decrease intracellular calcium (+ DP, EP2) --TXA2 activates phosphatidylinositol metabolism, giving increased IP3 and intracellular calcium (+ FP, EP1)

Modulation

adjustment of pain intensity. —is performed by an extensive antinociceptive (antipain) system. Step 4 of pain response

A delta fibers

large fibers that produce sharp well-defined pain, called "fast pain" or "first pain," typically stimulated by a cut, an electrical shock, or a physical blow. Transmission through these fibers is so fast that the body's reflexes can actually respond faster than the pain stimulus, resulting in retraction of the affected body part even before the person perceives the pain.

Rate-limiting step of Prostagladin synthesis

liberation of arachidonic acid from phospholipids (AA is esterified in phospholipids) in membranes by phospholipase A2 [can be stimulated by cytokines, cell damage, antigen-antibody reactions on mast cells; inhibited by glucocorticoids]

Central Sensitization

neurons with the CNS become increasingly excitable and magnify pain signals being transmitted/received. The result is that a normal stimulus or a mild pain becomes amplified within the neural network to the point that the subject perceives moderate or even severe pain

Transmission Sites

occurs at three junctions: first, between nociceptor and dorsal horn of the spinal cord; second, between the spinal cord and the thalamus and brainstem; and third, from the thalamus into the cerebral cortex.

Hyperalgesia

occurs when the patient has a heightened experience of pain or lowered pain threshold. The signals are transmitted but the presynaptic inputs are vastly Magnified.

Peripheral Sensitization

peripheral nociceptors become increasingly excitable and magnify pain signals being transmitted to the CNS. is often found at the site of tissue damage or inflammation