Pain

opiates: derivatives of poppy plants (heroin, morphine) opioids: any drug that occupies opioid receptors (fentanyl, methadone)

Beta-endorphin comes from beta-lipotropin, which comes from POMC

Mu receptors -spread throughout CNS and gut and WBC

involved at inhibiting GABA (decrease) and thus disinhibiting dopamine (increase) -receptors in descending pain circuit (amygdala, mesencephalic reticular formation, PAG, rostral ventral medulla)

primary afferent neurons, peripheral sensory nerve fibers, dorsal root ganglia -inhibition of substance P and other tachykinin release

2 systems in place: central and peripheral • peripheral: mediated by stress and ACTH co-release • -corticotrophs in anterior pituitary synthesize ACTH and beta-endorphin in equimolar amounts • central: innervation of hypothalamus, midbrain, and rostral medulla • -cell bodies of opioidergic neurons in median eminence of hypothalamus

ACTH during stress reactions from anterior pituitary • RM: 5-HETE, LTA4, LTB4, and other lipoxygenase products; angiotensin II, 5-HT • -evidence of beta-endorphins in T and B lymphocytes, monocytes, and MP during inflammatory reactions • process involves activation of cAMP by beta-adrenoreceptor activation

Rx for more than 1 month should trigger more complex thinking • full physical; is pain unusual • high dose opiates generally not helpful • hyperalgesia is reduced when off opiates, risk of misuse, death, sharing, selling • ongoing risk assessments

PGEs protect the stomach lining from acid -COX-2 specific inhibitors like celecoxib and low dose meloxicam cause less gastric irritation than other COX inhibitors

prostaglandin E2; signals hypothalamus to increase body’s thermal set point

reversible decrease in renal blood flow

aspirin -prevents coronary artery occlusion and colorectal cancer

• neuropathic pain should be addressed via neural function: anticonvulsants, tricyclics • NSAIDs address cause of inflammatory pain, such as post-tramatic, post-surgical • opioids make patient less concerned about the pain

lowering a neuron’s ability to fire by hyperpolarization and disallowing depolarization

• bipolar disorder • anxiety disorder • substance withdrawal • migraines • fibromyalgia • diabetic neuropathy these all involve neuronal excessive firing rates as their final pathway

A-beta-fiber: non-noxious mechanical stimuli A-delta-fiber: noxious mechanical stimuli C-fiber: noxious heat and chemical stimuli activated by injury and AP occur via Na+ and/or Ca++ channel activation, influx, and depolarization

• spinal reflex • thalamus/limbic semiconscious • cortex conscious

when inflammatory pain goes awry • subthreshold pain response (no pain, only annoying) shows small Ca++ influx • full pain response (acute) shows significant Ca++ and Na+ influx • system goes awry, gets stuck, and circuits get glued together (central sensitization and excessive/chronic pain response that is segmental or supra-segmental) - neuropathic pain from Na+, Ca++ influx, and now glutamate release

long-term potentiation of pain

central sensitization • Ca++ channel blocker (gabapentin) • Na+ channel blocker (carbamazepine) • glutamate blocker (lamotrigine, actually Na CB)

generally cause sedation, psychomotor/cognitive impairment, ataxia, tremor

for trigeminal neuralgia -ASE: aplastic anemia (requires blood levels), p450 3A4 inducer causing drug interactions

no FDA approvals for pain, but used off-label as AED to block glutamate -causes Stevens-Johnson syndrome rash

for diabetic neuropathy -ASE: weight gain, sedation