LO 18 Pain Pathways and Pharma Mgt OA

8/6/2019 LO 18 Pain Pathways and Pharma Mgt OA

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LO 18 Review Pain pathways and pharmacology of pain management in osteoarthritis (Halima)

³Pain is not a sense, like touch, sight, or hearing. Pain is an emotion ´

Pain pathways

Both A (localised shooting, stabbing pain) and C (chemical, thermal,mech - dull diffuse), fibres enter the spinal cord at the dorsal horn. The

dorsal roots are made of layers, known as laminae, into which the sensorynerve fi bres enter. Synapses are made with the transmission neuronsthat direct the impulse across the spinal cord to motor neurons and canelicit a refl ex arc from the offending source of the noxious stimuli.Alternatively, the impulse may ascend the spinal cord to the brain.

Second-order neurons send their sensory inputs to the thalamus via twoascending pathways: the dorsal column medial-lemniscal system and theanterolateral system (includes the spinothalamic, spinoreticular, andspinotectal fibers) . The axons of 2nd order neurons synapse on 3rd orderneurons in the thalamus. The Thalamus is the crucial relay for thereception and processing of nociceptive information in route to thecortex. Axons terminating in the lateral thalamus mediate discrimativeaspects of pain . Axons terminating in the medial thalamus mediate themotivational-affective aspects of pain ( emotional aspects of pain;attention to and memory of pain). These 3rd order neurons in thethalamus in turn send their axons to the cerebral cortex. Note: neurons inthe lateral thalamus (for discrimination ) project to the somatosensory cortex. Neurons in the medial thalamus (for affective aspects of pain

project to other areas of cortex (prefrontal, insular and cingulate gyrus).

As important as the ascending pathways, are descending pathways thatmodulate the incoming signal . T hese are predominantly noradrenergicand serotonergic, and can be modulated by stimulation of opiatereceptors. Descending tracts leave the reticular formation within the

brain, travel along the spinal cord and synapse with the transmission and interneurons within the substantiagelatinosa. The descending tracts function in order to modulate incoming messages from peripheral nerves. Thus,they act as a filter and partial inhibitor of the messages ascending the spinal cord from the nociceptors. This limitstransmission of the impulses from the sensory A and C fibres along the transmission fibres. The descending nervefibres arise at the periaqueductal grey within the reticular formation and flow into the medulla. From the nucleusraphe magnus in the medulla , impulses then pass down the dorsolateral tracts in the spinal cord to connect withthe transmission neurons and interneurons in the substantia gelatinosa of the spinal cord. The major



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e © esce nding tra cts is ser otonin whi ch stimulat es int ern euron s within th e sub stantiagelatino sa to r e lease peptid es noradr enalin e and endog enou s opioid s such a s endorphin s enkephalin s anddynorphin es All of th e ar eas associat ed with pain pro cess ing ar e rich in opiat e rece ptor s whi ch could e plain th e action s of our analg es ic pr eparation s

Almo st 1 in 5 pati ent s see n in g eneral pra ctice ha s som e form of chroni c pain, with symptomati c osteoarthriti s and

ba ck complaint s th e mo st common condition s Chroni c OApain would b e classified s d ee p so ti or

m us ulosk e le t l p in and chroni c pain i s defined a s

y being that whi ch la sts for long er than 3 month s (as

per lec tur e not es - though som e te

ts say 6 month s? ,y associat ed with fun ctional, p sychologi cal and social

probl ems that can n egati vely impa ct a p erson s lif e andy oft en r eport ed a s Tortur e and Suff ering.

The tr eatm ent how eve r should not b e delayed for thatlength of tim e and should b e multidim ensional for OA

pati ent s as shown in th e diagram at l eft. Th e main goal s of pharma cologi cal int ervention s for OA ar e re liev in ! p " in and re du # in ! infl amma tion . Treatm ent aim s to impro ve fun ctioning and qualit y of lif e while minimi sing th e risk of side eff ec ts

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a in Mec h anis m s in OA ( qui ck rev iew of se nsitis a tion and h%

pera l!

e sia this hop e full%

he lps und er st andin!

of ph armac ol choi ce s &

Inflammation in th e joint cau ses per iph era l se nsitis a tion (increase of se nsitivity of no cicepti ve primar y aff erentneuron s ' and ce nt ra l sensitis a tion (hypere ( citabilit y of no cicepti ve neuron s in th e central n ervou s system). Th e proce sse s of se nsitis a tion are thou ! ht to be th e ba sis of ar th riti c pa in that app ear s as spont ane ous pa in ( joint s atres t) a nd h % pera l! e sia (augm ent ed pain r es pon se on noxiou s stimulation and pain on normall y nonpainfulstimulation). Sensitisation al so fa cilitat es eff erent n euronal pro cesses through whi ch th e nervou s system influ ences th e inflammator y pro cess . Periph eral se nsitisation i s produ ce d b y th e action of inflammator y mediator s such a s brad ykinin, pro staglandin s, neurop eptid es , and cytokin es whi ch a ctivat e corr es ponding r ece ptor s in proportion s of nerve fibers. In addition, th e e xp re ssion of rece pto rs, for exampl e, brad ykinin and n eurokinin 1 rece ptor s, is





iii An ant ip ) r 0 t ic e1 1

e ct : this is pa rt owi t o a dec rea se i th e med iat or prost agland in (whi ch is gene rat ed in respon se t o th e inflamma t or pyrogen int er leu in-1) th at is respon si le fo r eleva tingth e hypo thalam ic set -po int for t empe ratur e con tr ol, thus causing feve r

A d 2 e r 3 e4

1 1

e cts: Unwan t ed effec ts , owing la rgely t o inhi iti on of cycloo xygena se-1, a re common, pa rti cular lyin the elde r ly, and include:

y D yspep sia, na usea and vom iting; al so ga stri c damage in chr on ic users , with ris of haemo rrh age,resu lting f rom ab roga tion of th e prot ective effec t of prost agland in (P ) on ga stri c mucosa.

y Sk in reac tions.y Reve rsi ble renal insu ff iciency ( in ind ividuals wh o have no rad rene rgic - or ang iot ensin-med iat ed

vasocon stri ction) thr ough lack of compen sat ory P E -med iat ed va sod ilat ation.y 'A nalge sic-associat ed nep hr opa thy' ; this can occ ur follo wing long-con tinued high do ses of NSA ID s (e.g.

pa race t amol) and is of t en irr eve rsi ble.y Less commonly, l iver disorde rs , bone ma rr ow dep ressi on.y B ronc hospasm in 'aspirin- sen siti ve ' asth ma tics.

AVO5

D in people with heart failur e, ris k s of HF ,hype rt en sion, renal fa ilur e, diabe t es and a spirin - inducedasth ma and G I ris k s

Comb ining an N SA ID with pa race t amol allo ws lower NSA ID doses t o be used. Int ermitt en t use (fo r example,befo re ac tivit y or duri ng a fla re in pa in) has a lower ris k of adve rs e effec ts th an con tinuous use.

Pa r a cetamo l: mode of ac tion no t f ully de t ermined b ut similar t o NSA IDs. Analge sic affec t due t o th e inhibitionof prost agland in synth esis. Antipyretic effec t due t o th e reduced p roducti on of p rost agland ins in th ehypo th alam us .

O pi o id s

Noc isen sors can be inhibit ed by op ioids (de sen sitis ation) and sti mulat ed by p rost agland in E or brady k inin,whi ch is relea sed in respon se t o inflamma tion ( sen sitis ation). Endogeno us op ioids (e.g. dyno rphin, en k ephalin,endo rphin) and e xogeno us op ioids (e.g., mo rphine) a s well a s inhibit ors of p rost agland in synthesis ar eth erefore able t o allev iat e pa in (analge sic action). A weak op ioid may be con side red an al t erna tive t o an N SAID wh en pa race t amol alone is inadeq uat e, pa rti cularly for people a t high ris k of NSAID -induced adve rse effec ts .Guidel ine s also suggest th at a weak op ioid be added if a pa tien t s pa in doe s no t respond adeq uat ely t o an N SAID (with or with out pa race t amol). Co d e ine is the weak o pi o id o

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cho ice .Str ong op ioids can be used wh en o th er analge sics do no t provide su ff icient pa in relief or are unsuit able beca useof adve rs e effec ts . Morphine is usu ally con side red the str ong op ioid of f irst choice beca use of fam iliarit y, co st and the range of fo r mulations ava ilable. O xycodone and hydromo rphone a re al t erna tives for people whocanno t t ole rat e mo rphine.

Regular rath er th an a s-needed do ses should be p rescribed fo r around- the-cloc k pa in con tr ol (if needed).

R elevance to the case

Diclofenac is an NSAID that inhibits cyclooxygenase thereby reducing prostaglandin synthesis. It tends to concentratein synovial fluid. Paracetamol is an analgesic. These were initially prescribed by the GP who got the boot Hesimply prescribed Diclofenac (NSAID)50mg twice daily and Paracetamol (non-opioid analgesic)1g twice daily andtold her she would get better in a few weeks. This has made little difference to her pain and stiffness . She has RAthus needs the DMARD therapy.

R efs

Lecture notes L@G; Porth - Chapter 39; National Prescribing Service Limited. NPS News 47: Analgesic options for pain relief. 01/ 08/2 006 .

R oyal Australian College of General Practitioners. Guideline for the Non-Surgical Management of Hip and K nee Osteoarthritis. July 2 009 .

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LO 18 Pain Pathways and Pharma Mgt OA