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tylenolol. Treatment of mild pain and minor febrile conditions. Lacks significant anti inflammatory effect, so not like NSAID. Also has protective cardiovascular effects.
- Lacks antiplatelet effect (so not lower blood pressure) and gastrointestinal toxicity but has hepatoxicity at greater than 4 gram.
- Max dose of 4000mg
What is nociceptive pain?
Pharmacologic approach to nociceptive pain primarily involves non-narcotic and opioid analgesia.
Nociceptor is a nerve fiber preferentially sensitive to a noxious stimulus or to a stimulus that would become noxious if prolonged. Nociceptive pain is the perception of nociceptive input, usually due to tissue damage
2 Classes of Nociceptor Pain
Somatic pain arises from injury to body tissues. It is well localized but variable in description and experience.
Visceral pain is pain arising from the viscera mediated by stretch receptors. It is poorly localized, deep, dull, and cramping. (cholecystitis, appendicitis)
3 classes of Nociceptor Pain.
by the Institute for Clinical Systems Improvement
musculoskeletal pain: pain that affects the muscles, ligaments and tendons, along with the bones
inflammatory pain: Inflammatory pain is precipitated by an insult to the integrity of tissues at a cellular level. This can happen with penetration wounds, burns, extreme cold, fractures, arthritis, autoimmune conditions, excessive stretching, infections and vasoconstriction. During inflammation a complex neuro-immune interaction results in primary hyperalgesia. (Rheumatoid and arthritis)
mechanical/compressive pain (using back pain): irritation or injury to the disc, the ligaments or the muscles/ nerve roots that leave the spine are either irritated or pinched
Abnormal neural activity secondary to disease, injury, or dysfunction of the nervous system. It commonly persists without ongoing disease (eg, diabetic neuropathy, trigeminal neuralgia, or thalamic pain syndrome)
3 classes of Neuropathic Pain
Sympathetically mediated pain (SMP) is pain arising from a peripheral neve lesion and associated with autonomic change
Peripheral neuropathic pain is due to damage to a peripheral nerve without autonomic change (eg, postherpetic neuralgia, neuroma formation)
Central pain arises from abnormal central nervous system (CNS) activity (eg, phantom limb pain, pain from spinal cord injuries, and post-stroke pain).
Pain Taxonomy by International Association for the Study of Pain (IASP)
- Axis I: Anatomic regions
- Axis II: Organ systems
- Axis III: Temporal characteristics, pattern of occurrence
- Axis IV: Intensity, time since onset of pain
- Axis V: Etiology
- Pain duration (eg acute, subacute, chronic) (see 'Chronic pain' above)
- Pain location (eg, low back pain, headache)
- Treatment responsiveness (eg, opioid-responsive pain, opioid poorly responsive pain)
- Pain origin (eg nociceptive or neuropathic) (see 'Types of pain' above)
- Body system (eg, myofascial, rheumatic, neurologic, vascular)
- Pain severity (eg, mild, moderate, or severe).
- Pain mechanism(s) (eg, peripheral sensitization, disinhibition, or central sensitization)
- Diagnosis (eg, cancer pain, sickle cell pain, postherpetic neuralgia)
PATHOGENESIS OF PAIN
Pain sensation begins in the periphery of the nervous system. Pain stimuli are sensed by specialized nociceptors that are the nerve terminals of the primary afferent fibers. The pain signal is then transmitted to the dorsal horn of the spinal column and transmitted through the central nervous system (CNS) where it is processed and interpreted in the somatosensory cerebral cortex
Four physiologic processes are associated with pain
Transduction refers to the conversion of a noxious stimulus (thermal, mechanical, or chemical) into electrical activity in the peripheral terminals of nociceptor sensory fibers.
Transmission refers to the passage of action potentials from the peripheral terminal along axons to the central terminal of nociceptors in the central nervous system. Conduction is the synaptic transfer of input from one neuron to another.
Modulation refers to the alteration (eg, augmentation or suppression) of sensory input.
Perception refers to the "decoding"/interpretation of afferent input in the brain that gives rise to the individual's specific sensory experience.
Peripheral sensitization (1. mechanism for persistent pain)
Tissue inflammation may result in changes in the chemical environment of the peripheral terminal of nociceptors.
- -The release of adenosine triphosphatase by injured cells, for example, causes immediate activation and results in immediate detection of tissue damage
- -Transient receptor potential V1 (TRPV1) channels expressed by nociceptors may produce pain some time after injury . These channels are calcium-permeable nonelective cation channels gated by heat, low pH, or chemical mediators (“endovanilloids”). Activation of mitogen-activated protein kinase (MAPK) signaling in TRPV1 may contribute to hyperresponsiveness of peripheral nociceptors (peripheral sensitization).
Central sensitization (2. mechanism for persistent pain)
Central sensitization amplifies the synaptic transfer from the nociceptor terminal to dorsal horn neurons.
- -The glutamate-activated N-methyl-D-aspartic acid (NMDA) receptor is integral to this central sensitization process. During central sensitization, the NMDA receptor is phosphorylated, which increases its distribution in the synaptic membrane and its responsiveness to glutamate. Increased responsiveness to glutamate occurs by removal of a normal voltage-dependent magnesium ion block of the NMDA channel, increasing the time the channel is open. The increase in excitability of the dorsal horn cell means that it can be activated by normally subthreshold inputs, with increased response to suprathreshold inputs.
- -Neuroimmune interaction resulting from the action of chemical signals produced by inflammatory cells on nerve fibers may contribute to peripheral and central sensitization. Transcription-dependent central sensitization has been studied in the context of peripheral inflammation where changes in brain derived neurotrophic factor (BDNF), substance P, neurokinin 1 (NK1), dynorphin and cyclooxygenase 2 (Cox 2) are well described
- -Neuron-glial interactions may also contribute to nociceptive processes . The macrophage-like glial cells, quiescent in the normal spinal cord, are rapidly activated after nerve injury. These cells are a likely source of cytokines and chemokines that then act on neurons and their supporting glia to alter patterns of gene transcription.
Ectopic excitability (3. mechanism for persistent pain)
Increased excitability of injured and neighboring uninjured sensory neurons can generate pacemaker-like ectopic action potential discharges, resulting in sensory inflow independent of a peripheral stimulus [38,39]. These changes may manifest at the site of the injury, at a neuroma, or in the dorsal root ganglion . These ectopic signals arise due to multiple factors including upregulation of voltage gated sodium channels, channel subunits, or signal receptors in myelinated neurons; or downregulation of potassium channels.
Structural reorganization/phenotypic switch (4. mechanism for persistent pain)
Nerve injury may result in an altered profile of sensory neurons. The central terminals of nociceptor sensory neurons terminate in the most superficial laminae of the dorsal horn in the spinal cord. In contrast, low threshold sensory fibers activated by touch, pressure, vibration, and normal ranges of movement of joints terminate in the deep laminae of the dorsal horn.Experiments in rodents have shown that physical rearrangement of this circuitry may occur after peripheral nerve injury, with new growth of the central terminals of the low-threshold afferents seen in the zone normally occupied exclusively by nociceptor terminals . Additionally, after peripheral nerve injury, the neuromodulators brain-derived neurotrophic factor (BDNF) and substance P, normally expressed only in C-fibers, may begin to be expressed in large-diameter A fiber neurons
Primary sensory degeneration (5. mechanism for persistent pain)
Loss of neurons (normally a source of growth factors) and the resulting imbalance of sensory inflow may contribute to the abnormal sensations . This paradoxical increase in pain perception with neurite dropout is not well understood. Conceivably, this may be related to changes in neurotrophic factors, compensatory local changes in the surrounding neurons or dorsal root ganglion/dorsal horn of the spinal cord, changes in related glia, and/or changes in cortical interpretation of afferent input
Disinhibition (6. mechanism for persitent pain)
A reduction in inhibition can have an effect similar to increased excitability. Pharmacologically blocking GABA or glycine-mediated inhibition produces a pattern of pain hypersensitivity similar to that of neuropathic pain, with prominent tactile allodynia . GABA blockade recruits previously absent ABeta fiber inputs to lamina II cells, effectively uncovering a previously silent synaptic pathway .Partial nerve injury also reduces inhibition in the superficial dorsal horn, with selective loss of GABAergic inhibitory synaptic currents due to apoptosis in GABAergic inhibitory interneurons . One week after nerve injury that produces hypersensitivity to pain, neurons begin to undergo apoptosis in the dorsal horn. The apoptosis may be due to excessive glutamate release or failure of glutamate uptake, or result from cell death-inducing signals, such as release of tumor necrosis factor-alpha from activated microglia.
- Aspirin (salicylate drug) ->more bleeding
- -suppress the production of prostaglandins and thromboxanes is due to its irreversible inactivation of the cyclooxygenase (PTGS) [COX-1] enzyme required for prostaglandin and thromboxane synthesis
- - used infrequently for treatment of chronic pain and inflammation due to its association with severe gastropathy
- -irreversibly inhibits platelet function for platelet life (7 to 10 days) and salicylism may occur with high doses or chronic use at analgesic doses
NSAID: Salicylates (non-acetylated)
- 1. Diflunisal [aka dolobid] 1500 (more potent than aspirin)
- 2. Choline Magnesium Trisalicylate 3000
- 3. Salsalate 3000
- Treatment of mild to moderate pain and acute or chronic inflammatory conditions. Relatively lower risk of gastropathy compared to aspirin and possibly other NSAIDs. Generally tolerated by patients with asthma. Slower onset and possibly longer duration of action than aspirin or acetaminophen. Do not inhibit platelet function (so coagulation).
- Propionic Acid (3200, 2400 chronic)
- Aka Advil
- Treatment of mild to moderate pain, minor fever and acute or chronic inflammatory conditions. A 200 to 400 mg dose is comparable in analgesic effect to 650 mg acetaminophen or aspirin. Reversibly inhibits platelet function and increases bleeding time. Can alter cardioprotective effect of low dose aspirin. Minimal risk of severe gastropathy with daily dose ≤2400 mg
- -nonselective COX inhibitor, in that it inhibits twoisoforms of cyclooxygenase, COX-1 and COX-2
- - cyclooxygenase(COX), which converts arachidonic acid to prostaglandin H2 (PGH2). PGH2, in turn, is converted by other enzymes to several other prostaglandins (which are mediators of pain, inflammation, and fever) and tothromboxane A2 (which stimulates platelet aggregation, leading to the formation of blood clots).
- Propionic Acid
- aka Aleve
- 1250 acute, 1000 chronic
- -Treatment of mild to moderate pain, minor fever and acute and chronic inflammatory conditions.
- -Reversibly inhibits platelet function and increases bleeding time. Can alter cardioprotective effect of low dose aspirin.
- -Appears to have the greatest relative cardiovascular safety profile among nonselective COX-2 inhibitors.
- -inhibiting both the COX-1 and COX-2enzymes
- Propionic Acid
- Aka as Orudis and Oruvail
- max: 300 mg
- For treatment of mild to moderate pain and acute or chronic inflammation. 25 mg dose comparable to analgesic effect of 400 mg ibuprofen.
- -prescribed for arthritis-related inflammatory pains or severe toothaches that result in the inflammation of the gums
- -inhibiting cyclooxygenase-1 and -2 (COX-1 and COX-2) enzymes reversibly, which decreases production of proinflammatory prostaglandin precursors
- propionic acid
- aka Urbifen, Ansaid,
- 300 mg
- For treatment of mild to moderate pain and acute or chronic inflammation. In some countries it is available as a lozenge for throat pain and as an intravenous injection.
- - in clinical trials for the treatment of metastatic prostate cancer
- Daypro, Dayrun, Duraprox
- propionic acid
- 26 mg/kg up to 1800 mg
For treatment of chronic pain and inflammation, osteo- and rheumatoid arthritis. Once daily dosing may be useful.
- NSAID: Acetic Acid
- 150 mg
- For treatment of mild to moderate pain and acute or chronic inflammation. Also available as a topical patch for pain due to trauma and as a gel for treatment of painful joints.
- NSAID: Acetic Acid
- 1200 mg
- For treatment of mild to moderate pain and acute or chronic inflammation. 200 mg dose has a comparable analgesic effect to 400 mg of ibuprofen.
- NSAID: Acetic Acid
- For treatment of chronic pain and inflammation, osteo- and rheumatoid arthritis.
- Acetic Acid
- 400 mg
- For treatment of acute and chronic pain and inflammatory conditions. More frequently implicated in hepatotoxicity than other NSAIDs. Parent drug and metabolites can accumulate with hepatic insufficiency. Drug and metabolites have been identified in renal calculi (kidney stone).
- NSAID: acetic acid
- An alternate, non first-line option for treatment of mild to moderate pain and acute or chronic inflammatory conditions. GI and central nervous system adverse effects may be more frequent or severe than with other NSAIDs. Intravenous formulation not indicated for pain.
Ketorolac (IV and IM)
- NSAID: acetic acid
- depends on age (150 to 120)
- Short term treatment of moderate acute pain when oral administration of an NSAID is not available and as an adjunct to other analgesics for the treatment of moderate to severe postoperative pain. Not indicated for treatment of chronic cancer pain. Risk of gastropathy is increased when use exceeds five days. An oral preparation of ketorolac is available but offers no advantage over other oral NSAIDs.
- NSAID: oxicams (enolic acid)
- 15 mg
- For treatment of chronic pain and inflammation, osteo- and rheumatoid arthritis. Once daily dosing may be useful. While reported to be selective for COX-2 at lower dose of 7.5 mg, overall adverse effects are similar to other NSAIDs.
- NSAID: oxicam (enolic acid)
- 20 mg
- An alternate, non first-line option for treatment of chronic pain and inflammation poorly responsive to other NSAIDs. Comparatively high incidence of gastropathy in daily dose above 20 mg and in older adults. Concurrent pharmacologic gastroprotection is suggested.
Meclofenamate (meclofenamic acid)
- NSAID: Fenamates (anthranilic acids)
- For treatment of acute or chronic pain and inflammation, osteo- and rheumatoid arthritis, dysmenorrhea.
- 1000 mg
- Fenamates (anthranilic acids)
- For acute pain and dysmenorrhea. Anti-inflammatory efficacy is comparatively low. Not indicated for treatment of chronic cancer pain.
- NSAID: Non-acidic (naphthylalkanone)
- For treatment of chronic pain and inflammation, osteo- and rheumatoid arthritis. While reported to be comparatively selective for COX-2 at the lower dose of 500 mg twice daily, the overall adverse effects when dosed in the usual range are similar to the other NSAIDs. Once daily dosing may be useful.
- Selective COX-2 inhibitors
- 400 mg
- An option for patients requiring chronic NSAID treatment who may be at risk for gastropathy. Demonstrated efficacy and relative reduction in GI toxicity compared to non-selective NSAIDs. No effect on platelet function. Dosage above 200 mg daily associated with increased cardiovascular risk.
- 120 mg
- Selective COX-2 inhibitors
For treatment of acute and chronic pain and inflammation, osteo- and rheumatoid arthritis.
Parecoxib (IV or IM)
- 80 mg
- Selective COX-2 inhibitors
- For short-term treatment of postoperative pain where oral route of administration is not available. Not indicated for treatment of chronic cancer pain.