Pain Pathways
pain is the most common symptom of disease and the request for its relief probably the most common demand placed on the doctor
Pain Transmission
Cells: primary sensory neurons with free nerve endings and whose cell bodies are located in the dorsal root and trigeminal ganglia
Noxious Stimuli: intense thermal, mechanical or chemical stimuli activate the free nerve endings
- chemical mediators that are released after tissue damage or inflammation can either activate or sensitize the nociceptors
- Activators of primary afferent fibers:
- Potassium – from Damaged Cells
- Serotonin – from Platelets
- Bradykinin – from Plasma Kininogen
- Histamine – from Mast Cells
- Sensitizers of primary afferent fibers:
- Prostaglandins – from Arachidonic acid
- Leukotrienes – from Arachidonic acid
- Substance P – Primary afferent
- non-steroidal anti-inflammatory drugs (NSAIDs) prevent pain by inhibiting the metabolism of arachidonic acid to prostaglandins by cyclo-oxygenase; NSAIDs do not effect lipoxygense which is involved in leukotriene production
Nociceptive Afferent Fibers:
- (1) small-diameter unmyelinated C fibers (80%), very slow conduction (3 m/sec)
- (2) small-diameter, thinly myelinated Ad fibers, slow conduction (5-30 m/sec)
- most unmyelinated afferents can be activated by noxious stimuli
- large-diameter myelinated sensory neurons respond maximally to innocuous stimuli
Spinal Cord: nociceptors enter gray matter of the superficial dorsal horn, ascend or descend for a few segments in the tract of Lissauer and terminate primarily in the superficial dorsal horn (marginal zone and substantia gelatinosa)
- nociceptive afferents form direct or indirect connections with three classes of neurons:
- (1) projection neurons relaying incoming sensory information to higher center in the brain
- (2) excitatory interneurons
- (3) inhibitory interneurons
- interneurons modulate the relay of info to the projection neurons and demonstrates pain modulation within the spinal cord
- large diameter, myelinated neurons activate inhibitory interneurons that control pain transmission and can reduce pain transmission; therefore an intense stimulus that activates both small diameter (pain neurons) and large diameter neurons will produce less of a pain sensation than if the small diameter neurons were activated alone
- polypeptides contained within the primary afferent nociceptors (substance P, somatostatin, vasoactive intestinal polypeptide and cholecystokinin) are all present in different populations of small diameter unmyelinated primary afferents which terminate in the superficial dorsal horn
- Substance P
– excites pain transmission neurons in dorsal horn
- Capsaicin
(hot pepper extract) – destroys substance P and reduces pain response
Peripheral Response of Substance P: released from peripheral terminals of nociceptors; causes cutaneous wheal and flare
- found in nerve fibers on large and medium sized cranial blood vessels Þ antagonists of substance P could provide a new approach to control of inflammation and pain; capsaicin cream is now used to treat pain associated with Herpes zoster
Pain Pathways
(1) Spinothalamic tract Þ VPL of thalamus Þ cortex
(2) Trigeminothalamic tractÞ VMP of thalamus Þ cortex
both tracts send branches to the brainstem reticular formation, periaqueductal gray
Pain Modulation System
Endogenous opioid substances: endorphins, enkephalins(met-Enk and leu-Enk), dynorphins; synthesized by nerve cell
- b
endorphin: anterior and intermediate pituitary lobes; hypothalamus
- Enkephalin
: periaqueductal gray matter; rostral medulla (raphe nucleus); dorsal gray horn of spinal cord
- Dynorphin
: hippocampus; deep layers of cerebral cortex; caudate; putamen; globus pallidus
bind opiate receptors and action is blocked by the opioid receptor antagonist naloxone
endogenous opioids are coded by separate genes and present in different cell populations of the brain, pituitary, adrenal gland, gut and sympathetic nervous system
endorphin-mediated analgesia system (EMAS) demonstrates how narcotic analgesics relieve pain
drugs like morphine, demerol and percodan mimic actions of endorphins at synapses in pain-modulating networks
Serotonin and norepinephrine: also important neurotransmitters involved in modulating the pain response
- particular importance because they can be manipulated by a variety of pharmacological agents
Descending Pain Modulation Pathways: pain modulating neurons from the cortex, hypothalamus, midbrain periaqueductal gray and rostral medulla alter pain response in the dorsal horn of the spinal cord Þ much of the pain modulation is carried out by the endogenous opioids
- electrical stimulation of rat brains produced a phenomenon called stimulation produced analgesia (SPA) which is a function of endogenous opioid release
- endogenous opioids caused selective reduction in pain with few side effects (warmth and/or sleepiness)
Management of Pain
Three Treatments:
(1) Transcutaneous Electrical Nerve Stimulation (TENS) – commonly used to treat pain
- Action
: because large diameter myelinated axons have a lower electrical threshold than smaller diameter axons and do not produce pain when activated, it is possible to stimulate them selectively without producing discomfort Þ stimulation of large diameter fibers causes inhibition of small diameter pain fibers and modulation of pain response
- Uses
: routinely used for postoperative pain, but it is not as promising for the treatment of chronic pain with nerve damage – TENS is most effective when stimulation is applied to the injured nerve proximal to the site of injury; also used for spinal cord injury
(2) Psychotropic Drugs
Action: ex. imipramine, amitriptyline and doxepin; ß depression and therefore ß pain associated with depression; also produce analgesia by acting directly upon pain modulation systems
Tricyclic Antidepressants: most useful group of psychotropic drugs used for pain management
- block serotonin (5-hydroxytryptamine, 5HT) and norepinephrine (NE) reuptake, increasing the levels of 5-HT and NE, which are part of the endorphin-mediated analgesia system (EMAS) (discussed above)
- tricyclics can produce analgesia directly or by enhancing the action of opiates
Phenothaizines: usually used as adjuncts to narcotic analgesics
- little analgesic action alone or in combination with opiates, but may be useful when combined with tricyclic drugs in the management of neuropathic pain
(3) Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) – ex. aspirin and acetaminophen
- most commonly used analgesics
- new NSAIDs have altered dosing regimens and toxicity but lack greater efficacy
- considered more effective because of their better patient compliance due to the better dosing regimens and because they contain a higher effective dose
- parenteral administration of NSAIDs may allow them to be used for treatment of pain syndromes for which they were not considered applicable due to GI toxicity or because of the severity of the pain; ex. renal and biliary colic
- demonstrates that NSAIDs may be effective in the treatment of severe pain syndromes
- recently used to prevent post-operative pain Þ prophylactic administration before surgery decreases inflammation via prostaglandin synthesis and prevents sensitization of the peripheral terminals of nociceptive afferents
Other Specific Treatments and General Treatment Strategies
- NSAIDs and narcotics
: alter the pain pathway in different ways, so combining the two classes of drugs to enhance analgesia makes sense
- Surgical Lesions
– disruption of the spinothalamic tract
- Sympathetic Blocks and TENS
: use independent modulatory mechanisms and can be used together to enhance analgesia
- sympathetic block reduces abnormal excitatory influences on peripheral nociceptors; sympathetic therapy may be enhanced using catecholamine depleting agents such as reserpine or guanethidinne Þ only proven to work when given by regional perfusion in high concentrations
- TENS inhibits nociceptive transmission and perhaps sympathetic preganglionic fibers in the spinal cord
- Enhancement of Non-opioid analgesia
- Opiate, Tricyclic Combinations: Tricyclic antidepressants enhance opiate analgesics by potentiating biogenic amine links in the endorphin circuit
- Opiate, tricyclic NSAIDs- may be effective for pain with an inflammatory component
Behavior or Psychologically Oriented Pain treatments
hypnosis, biofeedback, guided imagery and psychotherapy are used in pain management
many patients unwilling to take this approach, or unable to pay for it
since chronic pain produces anxiety, depression and other emotional problems, it is useful to evaluate these patients psychiatrically; psychiatric factors are difficult to quantify and it is difficult to determine efficacy of psychiatric therapy