Opiates/ Drugs of Abuse/ management and titration

dosing/ starting opiates in a patient with chronic pain / case with knee and hip pain -what are the recommendations based on the CDC guidelines - starting -not first line for chronic pain -establish and measure progress to goal -use of urine

*CDC guideline recommendations* 1-*starting opioid therapy for chronic pain * - non pharm therapy and nonopijoid drug therapy are preferred-- due to the lack of clear evidence fro benefit to all patients from long term opioids and risk of harm in some patients, but benefit in others w/ other TX -consider opioid only if benefits for b/ pain and function >risk -combine with non drug and nonopijoid therapy 2-*opioids are not 1st line or routine therapy for chornic pain* -all guidelines agree -use non=drug therapy ie. exercise or CBT to reduce pain and increase function -non-opioid ie/ NSAID APA and anticonvulsant/antidepresant -when opioid is used combine with non-drug therapy for greater benefit -before starting opiate- establish the TX goals and realistic and that therapy will be discontinued if benefit no not outweigh the risks -conintue therapy only if clinically meaningful improvement in pain and function > risk to pt safety 3-*establish and measure progress towards goals* -CDC- pick the scale they recommend -before-determine how TX effectivemness will be evaluated and establish the foals of pain relief and function -access progress with *PEG* assessment- Pain average (0-10), interference with Enjoyment of life (0-10), interference with General cavity (0-10) -before starting and during TX0 discuss the risks and benefits and shared responsibility of pain management -be explicit and realistic about the benefits and pain and canton -discuss- common adverse effects, increase risk of overdose at higher doses, when taken with -OH or other drugs, reassess and monitor and use drug agreements and urine check; risk to family and community if stolen 10-*use of urine drug testing* -CDC states it as applicable to all patients with chronic pain management -use urine testing before starting and consider testing at least annually for prescribes and controlled prescription and illicit drugs -do not test for a substance that would not affect the patient management -before test- explain to the patient that it is for safety, and explain expected results and ask the patient whether there might be unexpected results -unexpected results- discuss with lab abd patient and verify with specific tests -*do not dismiss patients from care based on a urine drug test result*

Hydrocodone -MOA -what are the uses/ combos

*MOA* -semisynthetic MOR Agonise -stronger analgesic then codeine but is less effective than morphine as analgesic -more addictive then codeine *uses/combos* -antisussive -*vicodin*- when packaged with acetominphen -similar to oxycodone in b/ anatolia and side effect -limited evidence that may have themes abuse then oxycodone

heroin MOA -admin

*MOA* -semisynthetic MOR Agonist -not used as a medication -formed from the acetylation via acetic anhydride of b/ hydroxyl groups in morhine--- *increase hydrophobic nature and can cross the BBB* - *faster acting then morphine and wil have more intense and euphoric* -must be delivered IV to maintain desired properties -if given oral will be subject to 1st pass in the liver and *deacylated to morphine and will delay the delivery to the brain*

codeine -what is it from -binding affinity -metabolism - what effect does this have -drug analog- what allows for safer side effect profile?

*source* -semisynthetic MOR agonist -methyl ether of morphine -small amounts in opium and produced from morphine -less effective analgesic, but fewer side effects then morphine -least addictive Binding -*weak opiate*- low affinity for Mu receptor Metabolism -15% is O-demethylated to morphine in the liver by CYP2D6--*leads to the analgesic effects* *drug analog* -*tramadol*-weak MOR agonist and influences *5HT and NE* uptake into neurons *leading to safer side effects and unique MOA*- can cause *serotonin syndrome* if given with certain anti-depressants -more effective analgesic then codeine

palliative care population and opiates -what makes them special -goals -what is the dual effect?

*special* - well studies and are *different with overall low risk of addiction and abuse of opiates and other medications*- improved length and quality of life when effective pain control is given -focus is to *ease suffering and understands that the illness causing the pain will progress over time* *goals* -clarified with the patient and the family and are more likely to acknowledge the limitations on function will occur due to the illness and comfort is considered the 1st proiority -if still in pain after prescribed dose -- assess the pain and then pain meds including opiates should be titrated to balance pain and sedation -*as the pain from the illness becomes more intense with disease progression, the dose will be increased*---then may decide fully conscious and in pain vs sedation w/out pain -- must use shared decision making -*dual effect*- increased sedation and quickening of death (respiratory depression from need for high dose) if adequate pain control is the priority -*pain control can almost always be achieved if the side effects of sedation and respiratory depression are accepted in order to ease the suffering*

what is the difference in effect b/t a full and partial MOR receptor agonist

- *ceiling effect*- partial- produce less of an effect ie. buprenorphine and will have *lower risk of abuse potential* at increase doses - full agonist- hydrocodone, codeine, oxycodone heroine continue to increase

GPCR -what are the opioid specific ones

- 800 in the human genome and 3classes of opiate receptors are a subset of the them -all members are similar at the 2 and 3 structure that will span the membrane 7 times -primary structure- opioids are more similar to one another then to other GPCR family -M, K, D -4th receptor with sequence similar to the 3 opiod receptor and is *opioid-like receptor 1* -40% clinically approved drugs will target GPCR including opioids -coupled with trimeric G protein that will turn on a signal path to express the receptor

general rules for starting and titrating dosing opiates -what is the general rule -what do you start with - what is the progression with increase dosing -what are the doing schedules -what do you do once you gain initial control -potency and bioavailability consideration -what about codeine

- apply to meds that are dosed to produce a physiologic effect and does not have a dose limitation/ ceiling other than toxicity of the drug and does not cure or modify the disease -- similar with insulin -monitor the pt response to the drug to gauge and modify -b/ opiates and insulin- start with best guess dose and monitor the response and titrate the drug to achieve the desired level of control ---use math for daily dose, 1/2 life and how it can overlap with drugs and short vs long acting forms --- if wrong can kill the patient quickly with math or prescribing error 1-start with guideline based starting doses 2-start on short acting medication -helps to avoid long acting toxicity or overdose if we overshoot the initial dose 3-plan for frequent reassessment and dose adjustment 4- prn or as needed basis or scheduled -scheduled are given *at time interval that is about the same as the 1/2 life* -PRN- can be given more frequently- *based on the time to onset of peak effect* 5-pt in active pain will progress as successive doses of opioids increase *Severe pain --> decreased pain--> sedation --> respiratory depression --> coma --> death.* -*sedation will always proceed respiratory depression* unless the doing guidelines are exceeded -if a patient is alert and complaining of pain it is sage to give more -w/ sedation- stop increasing the dose and wait for the patient to be alert before the next dose 6- once you have control we will know the total daily dose of short acting meds -consider long acting and recalculate to convert for more consistent control 7-dose conversion will use *morphine milligram equivalent* MME that will convert with *equianalgesic table* for drugs of different potency 8-*potency*- inversely related to drug needed for pain control - mg or mcg with more potent 9-*bioavailability of oral opioids = % drug abs into the circulation and the affect the oral dose needed to achieve the same IV effect* -ie. the oral dose of morphine is 3X that of IV to have the same effect 10- all pt on opioids require *bowel regimen*- laxative TX to precent opioid induced constipation 11- some have higher rates of side effects ie. nausea, rash, and are less preferred initial choice- ie. morphine 12-*codeine is dangerous due to the variable metabolism* and death are common in children -can also lead to lack of pain control in adults -highest risk of side effect like rash and nausea -*avoid codeine as pain relief and always use another opiod*

concept of total pain -what is its importance -what role can opiates play

- for both chronic pain adults and palliative care this accounts for *all of the contributors that modulate pain - psychosocial, spiritual, cultural and other physical factors* -like hangry when mad and hungry- -increase physiologic arousal and sympathetic stimulation happens w/ pain and *pain is amplified with depression , anxiety, social stressors, isolation, lack of physical activity, loss of job, cultural inhibition against expression personal needs, alienation from family, existential fears about dying, sinning, or other spiritual grief, poor nutrition, and other things that humans experience.* *opiates* -one manage physical pain -- other disciplines are needed ie. social workers, psychologist and CBT, chaplains, psychiatrists for depression and anxiety, and community for TX of the entire diease

adult patient population with chronic pain -what is the challenge and opiate concern -escalation of doses -what is a better approach to TX -what are the new CDC guidelines

- pain >3 months or past the time of usual recovery *challenge* -frustrated -tratemnet with opioids <12 weeks will provide short term relief but *there is not sufficient evidence that longterm opioid use will improve quality of life or achieve pain control* -*long term opiate use results is increased risk of drug abuse, addiction, overdose and death especially as doses are increased to control pain* *dose escalation* - must access the risk vs benefit -in the absence of worsening of the chronic pain, increase dose request is likely due to *physiologic tolerance, physical dependence, inefficacy of opiate treatment for that type of pain, abuse, or diversion-- rather then increase physiologic pain from disorder* *better approach* -*multimodal Tx of the chronic pain*- PY, meditation, regular physical activity, treatment of depression or anxiety, adaptive devices, non-opioid medication, and referral to specialists *new CDC guidelines* -though opiates can help pain the CDC limits their role in TX of chronic pain -new warnings are the result of the drug addiction, overdose and death after more liberal prescribing --*now the focus is on function and reducing harm* -if opiates are used it is much more strict and *once guidelines fro PCP are exceeded it is time to refer to pain specialist*

starting an opiate in a patient with a palliative care approach / mets breast cancer case -access the pain - what would be a reasonable opiate to start and what should be avoided -dosing strategy

- pain interferes with daily life, is daily, constant and worsens with activity -pain not neuropathic or other that would benefit from non-opiate -pain from known cause and additional medical workup is not needed at this time -non-opioid pain controls been initiated and is limited by NSAIDS toxicity -concerns for other pain aspects- spiritual, depression/anxiety, financial, lack of cavity, impaired nutrition, need additional referral and potential for opiates -she is inpatient, predictable pain and made worse with movement *start/avoid* -*start*- on short acting and watch due to renal impariemtn decreased elimination --if pain is severe you can use a higher dose starting and PRN -*avoid*- codeine *interval*- short acting every 3-4 hours *strategy* -caution with renal impairment -scheduled-start on morphine 2mg IV every 4 hours -hold dose if sedation occurs "Morphine 2 mg IV q 4 hours, hold for sedation" -scheduled- 2 mg x 6 doses in 24 hours = 12 mg of morphine total in 24 hours if every scheduled dose is given. -PRN- 5-15% of the total daily dose 0.05 X 16 mg TDD = 0.8 mg as the low end of the dose range, and .15 x 16 mg TDD= 2.4 mg at the high end of the prn dosing range.---2mg and time based on the *peak effect time* up to every 12 minutes "Morphine 2 mg IV q 12 minutes prn uncontrolled pain"

switching IV to oral opioids in palliative care -what are the only long acting -what would you do for PRN

- the only long action opioids are PO long acting oxycodone, PO long acting Morphine, long acting hydromorphone, and transdermal fentanyl decrease the total daily dose we calculated by 25-50% due to incomplete cross-tolerance due to switching opioids! 53 mg x 25% = about 13 mg so total dose at 40mg a day -and divide in1/2 every 12 hours "Extended-release oxycodone, 20 mg, take PO every 12 hours. Dispense 14, no refills" *PRN* - needs to be short acting -use the same opiod to limit the side effects -5-15% of the total daily dose 40 mg x 0.05 = 2 mg and 40 mg x 0.15 = 6 mg. "Oxycodone immediate release 5 mg PO every 2 hours prn pain, dispense 24, no refills" - since this is palliative there is less abuse potential at the 60MME dosing, but there is still increase respiratory depression-- consider nalaxone for emergency and instructions on how to use -nalaxone- comes in nasal spray or injection "Naloxone nasal spray 4 mg, prescribe 2-pack, administer as directed for suspected overdose"

Opiates-intro -how are they produced? -MOA

- used for pain for thousands of years -diverse - are natural from plants, synthesized endogenously by humans or produced via manufacturing *MOA* -mediated through receptors on surface of cells *at GPCR* -recepots will be involved in signaling w/in cells and will have b/ CNS and PNS impact

what is the receptor interaction for opiates -what is the goal ligand?

- will bind GPCR -ligands can have full, partial, biased and negative agonism or antagonism (neutral antagonist- bind and cause no effect) *goal ligand -efforts to ake structural analog of morphine or synthetic ligand for opiod receptor that have similar or better analgesia with fewer side effects and less abuse and addiction -*all synthetic structures are closely related to morphine and are derived from morphine* -heroin is a morphine derivative that was actually worse

what are yellow and red light doses of MME

-"Yellow Light" dose > or = to 50 MME/day: evaluate carefully, consider offering naloxone -"Red Light" dose: > or = to 90 MME/day. Consider what else needs to be done or refer patients to pain specialist who appear to need this much a day to treat pain.

You are caring for a patient who is a 64 yo with lung cancer. She has been on opioids for months for pain and dyspnea control. Her current oral regimen is OxyContin 60mg PO Q12H routinely, and oxycodone 10mg PO Q1H PRN pain or dyspnea. Her symptom relief on this dose is good, but stops a few hours before the next scheduled dose, requiring 3 breakthrough doses each time what do you do?

-You change OxyContin to 60mg PO Q8H routinely. Her total daily dose has increased 50% and is now 180mg. -You adjust her breakthrough dose to oxycodone 15mg PO Q1H PRN pain or dyspnea. Her breakthrough dose remains 8% of her total daily dose. -You check that she has enough Senna S and that she has a bowel movement t least every 2-3 days

Morphine

-derived from poppy plant papaver somniferum -drug with which derivatives to bind opiate receptors are modeled from

equianalgesic calculations- how to switch to another opiod -what are the conversions rates accuracy -what about switching breast cancer pt case

-ie. if a patient has well controlled non but now there are side effects ie. N/V due to morphine or codeine that have the highest rate of SE -doses of different opioids that produce the same degree of pain relief are equianalgesic -non opioids are not included in the calculation ie in combo percocet -Fentanyl 25mcg/hr patch = morphine 50 mg PO/day -Fentanyl 100 mcg IV = morphine 10mg IV (or 30mg PO) -Hydrocodone < Oral Morphine < Oxycodone (but calculate ratio 1 : 1.5 : 1 ) *accuracy?* - they are not that exact and are based on a few small studies -this is why conversion factors are only a rough guide to approximate the correct dose *case* -hydromorphone- unlike morphine can be given oral and is 4-5X more potent 1.5 mg IV Hydromorphone to 10 mg IV Morphine 1.5/10=.15 she is on 24mg morphine so the dose is 24mgX.15=3.6 mgIV hydromorhpone and action at 3-4 hours new prn hydromorphone order that is about 5-15% of total daily dose of hydromorphone. 0.05 x 3.6 mg = 0.18 mg and 0.15 x 3.6 mg = 0.54 mg. Split the difference and give a 0.3 mg IV dose RX -Discontinue all IV Morphine -Start 0.6 mg Hydromorphone IV q 4 hours -Start 0.3 mg Hydromorphone IV q 12 minutes prn uncontrolled pain

opiate pharmacokinetics -what are the influence of other drugs and an example

-may interact with other drugs through pharm mechanisms -influenced by other drugs that inhibit or induce opiate metabolism at CYP450 or other drug metabolizing enzymes.---to make opiates more or less effective ie. alternative substrates and inhibitor for CYP3A4-fluconazole clathromycin or cimetidine --- increase opiate actions and induce respiratory depression -rifampin- induce many CYP and CYP3A4 and can reduce the effectiveness of opiates metabolized

pharmacodynamics of opiates

-opiates can interact with other drugs with dynamics -opiod efficacy and toxicity are *potentiated through mechanisms that converge on common targets ie. synergy of drug effects when opiates are combine with -OH or other drugs like benzos* - co-abuse of opiate and -OH and Benzo is major problem and part of the synergy is in relation to kinetics as diazepam can inhibit p450s -facor with co-abuse is though to be dynamic and the ability for the bento to enhance the rewarding and re-enfoce opiate effect complication of co-abuse - lethal overdose with respiratory depression

euphoria/ addiction -what is the receptor -what is the mechanism

-opiates will influence please centers via action at *GABA-inhibitory neurons of the ventral segmental area VTA and inhibit them* 1-agonist of MOR reduce the amount of GANA release from inhibitory neuron of DP release of nucleus accumbens 2-increase DP release stimulating the pleasure center - substances that trigger dependence are associated with increase in Dp release from nucleus accumbens *from figure* -Actions of opiates, nicotine, alcohol, and phencycline (PCP) in reward circuits. Ventral tegmental area (VTA) dopamine neurons (bottom left) project to the nucleus accumbens (NAc) (bottom right). Different interneurons, interact with VTA neurons and NAc neurons. -*The rewarding properties of opiates are mediated by μ opiate receptors found in two locations in brain reward circuits*. VTA dopamine neurons are tonically inhibited by GABAergic interneurons that express μ opiate receptors. Opiates acutely inhibit these interneurons thus disinhibiting the dopamine projection neurons, which then release dopamine in the NAc and other terminal fields. In addition, there are* μ opiate receptors expressed by NAc and dorsal striatal neurons. Opiates can stimulate these receptors directly and produce reward in a dopamine-independent manner*. Nicotine, acting on nicotinic acetylcholine receptors (NAChRs) in the VTA, cause dopamine release. Ethyl alcohol, acting on GABAA receptors in the VTA, can also cause dopamine release. Phencyclidine (PCP), which blocks the NMDA glutamate receptor channel and cannabinoids acting via CB1 cannabinoid receptors in the VTA (not shown), also produce dopamine release. Cannabinoids, alcohol, and PCP can also act directly on the NAc. PCP, phencyclidine ("angel dust").

Nociception -what is the pathway -what is the molecular level of action ---what is the main way opiates mediate their effect? -where are opiate receptors found

-pathway involved in pain sensation -perception of pain resulting from neural processing of pain stimuli *path* 1-nociceptor primary afferent bound by noxious substance in PNS -when opiate receptor is bound it 2-transmit to the spinal cord via dorsal horn cells 3-onto the brain somatosensory cortex via thalamus- location and intensity -cingulate and insular cortex from connection in brainstem and amygdala- affective component of pain -rostral ventral medulla adn midbrain periaqueductal gray to engage descending feedback that will regulate output from the spinal cord -neural processing of pain will have AP transit along the fiber and communicate with NT at synapse *molecular* -when bound by agonist opiate receptor w/in many of the different neurons will *disrupt the transmission of nociceptive info with Gai- decrease AC- decrease CAMP and GIRK* -CAMP- contribute to the tempering of the nerve transmission through IC signaling -*opiate receptor agonist temper nociceptive signal via activation of BY- with GIRK to hyper polarize * -*activation of BY- also inhibit CA channel controlling Ca dependent NT release at the synapse * *opiate receptors* - found in PNS and CNS and thus influence b/

incomplete cross tolerance -what does this mean for long term pain management and switching opiates

-patients will develop tolerance to an opioid they have been taking -applies to longterm use of a drug (not the acute onset) ie. days or more have potential for this phenomenon -if a new opioid is started--- the difference in structure will change the interaction in the opioid receptor in the liver and the drug will not be metabolized as quickly and will lead to *greater degree of pain relief from an euqianalgensic dose of a new drug* ie. if a patient is used to old med and switch drugs *start the dose at 50-75% of the equianalgesic dose of the new drug* -titrate as you normally would and this is advantageous if switching due to side effects -lower dose of new drug may provide relief with fewer side effect ie. if pain not well controlled on the old drug then yuse an equianalgesic dose of the new drug or potentially higher dose

endogenous opiates -what are they produced from - what is common -difference

-peptides produced from larger protein by proteolytic processing -larger proteins pre-prro-opiomelanocortin, pre-pro-enkephalin, and pre-pro-endorphin give rise to endorphins, enkephalins, and dynorphins, respectively. -secreted by neurons throughout the body and differ in affinity for the different opiod receptor commonality -AA terminal sequence TYR-GLY-GLY-PHE (met or leu) differ -C terminal sequence white size range from 5-31

Opiate receptors -what are the 3 classes - systemic and peripheral actions with the effect, agonist and antagonist of each -which one involved pain management

-receptors that will be engaged by endogenous compouds- endorphins, enkephalins and dynorphins in order to regulate processes including behavior 1-*Mu u*-MOR Mu opiate receptor "MORphine" *systemic-* analgesia, euphoria, constipation, and respiratory depression -agonist-endorphine>enkephalins and dynorphins. Morphine, fentanyl and burprenorphine -antagonist-nalaxone *peripheral*- analgesia and constipation -agonist- loperamide -antagoinst- naloxegol -*main receptor involved in pain management* 2-*delta d* *systemic*- analgesia, convulsion, anxiolytics and constipation -agoinst- enkephalines> endorphins and dynorphins -antagoinst- naloxone and burprenorphine *peripheral*- analgesia and constipation 3-*Kappa k* *systemic*- analgesia, diuresis and dysphoria -agonist-dynorphins>>endorphins and enkephalins -antagonist- naloxone and burprenorphine *peripheral*- analgesia

Buprenorphine -binding? -what is abs -what is it used for? -what is if often used with AND GOAL -new concern

-semisynthetic MOR partial agonist -antagonist at d and k -full occupancy of MOR receptor w/ partial agonist activity and lower risk of abuse potential and dependence and is *used to wean addicts from opiates while minimizing the w/drawal when discontinued* -ceiling effect with plateau at increase dose -less analgesia, side effects and with drawal -absorbed via GI (nalaxone is not)- prevents IV injection used with -nalaxone -MOR antagonist - together as zubslov, suboxone, bunavai -goal-limit abuse b/c naloxone will induce w/drawal symptoms when taken IV -appproach w/ physicians and does *not need an addiction center* increase concern - anecdotal data - pregnant women in rehab may be at risk for birth defects of GI with this drug-- no clear mechanism

Mu opioid receptor MOR -how do they act?

-similar in mechanism to M2 on cardiac cells Para - Ach- M2- Gai- decrease CAMP *action* -transmembrane protein that will have domains exposed to the env/ and will form binding site for ligant- agonist or antagonist -binding of agonist- conf change - change in cytoplasmic domain with trimeric G (a, b, y subunit and a binds guanine nucleotide) protein interaction- GDP off to GTP on state -interacts with Gai-inhibit AC-decrease CAMP -B and Y when agonist bind- with bind BIRKS (g protein inward rectifier potassium channel) to *hyper polarize the membrane of nerves involved in pain sensation*

tramadol

-weak MOR agonist and influences *5HT and NE* uptake into neurons *leading to safer side effects and unique MOA*- can cause *serotonin syndrome* if given with certain anti-depressants -more effective analgesic then codeine

opiate side effects -what mediates these and receptor

1- constipation -MOR peripheral activation at ENS decrease peristalsis 2-respiratory depression -life threatening and high mortality with overdose -optiate receptor of the respiratory control center of the brainstem and mechanoreceptor that transmit peripheral info to the brain 3- pruritus -common in neuroaxial admin -b/ MOR and serotonin 5-hydroxytryptamine say-type 3 5HT3 are present in teh spinal trigeminal nucleus -"Itch center" and opiates at 5HT3 cause effect -5HT3 antagonist have mixed TX results 4- miosis -constriction of the pupil through high [ ] MOR in the dinger westphalia nucleus -*pupil constriction is a sign of opiate overdose* 5- sedation / antitussive -MOR on hypocretin neurons 6- nausea and emesis -MOR in area prostrema vomiting center outside of BBB 7- euphoria 8- addiction

dosing in chronic pain - knee OA pain case

1- discuss the risks and benefits and CDC guidelines -pain improvement but not pain free -close followup and monitoring -risk of addiction is real and will be discussed at every visit -if pain is not controlled as usual dose she will be referred to specialist -*pain management contract*- sign and violation will lead to termination of all controlled medication -random drug screens and look to see if prescriptions from other providers -lost prediction are not replaced -tapered off ASAP -side effects- *sedation* and dangerous with -OH or other meds and cannot take benzos or drink -*pain diary*- activity and pain level and PEG goal -return in 2 weeks and repeat pain scoring, assess mobility 2-dosing -if already taking acetominophen, you avoid combination products that include APAP and prescribe morphine, 5 mg PO, every 4 hours prn pain. - for 1st time only give enough pils for 14 doses if she takes 6 a day and warm about constipation -*start senna-S if she is taking more than 1-2 doses a day* -start at night- to see how she feels and *warn not to drive* until she knows the medication effect

what factors help to determine which opiate to use -liver, renal, age, lung

1- liver issues - can be hard to predict the response -*chronic alcoholics are relatively opioid tolerant*- due to -OH induced increase in mets. enzymes -*liver failure may have increased risk for sedation and respiratory depression esp with long acting meds*- increase met intermediates--*only use short acting* 2-*renal impairment will accumulate active metabolites of codeine and morphine*- lower the dose and monitor close 3-*long acting may accumulate in elderly with less organ function* 4-*patient with active lung disease*- higher risk for injury if respiratory depression occurs but still need pain control--- titrate and monitor more often 5- *long acting in general cannot be crushed and put in feeding tube etc* for those that cannot take pills 6-combo products with acetominophen can be *dangeous and cause overdose if the patient is not warned to avoid other APAP containing products*

initial dosing of opiates -what do you do for route of admin -dosing intervals -PRN dosing - what is dosing and what are given?

1- pick the correct one for your patient 2-initial dose will differ on route and potency and action duration 3- start on short acting route of admin - oral, SC or IV -*never give IM*- very painful ---give SC at see dose and interval if IV access is lost *intervals* -determine with medication *duration effect via 1/2 life* -short acting- every 3-4 hours -long acting- Q24H or Q12H *PRN dosing* -determined with *peak effect time* -IV-given as often as every 10 minutes -*b/t 5-15% of the estimated daily dose* -only *short acting meds are given PRN,* if the pt is on long acting you need another PRN -to avoid polypharmancy- give the same drug for PRN -*long acting are never given PRN they are only used as scheduled meds* -*w/ PRN pick a time and dose and use it*- 1-2 pills or 4-6 hours is not current and can lead to accidental overdose

palliate care - adjustment in pain regimen after initial dosing--- breast cancer case -adjustment if controlled but using PRN -adjustment if uncontrolled

1-*adjustment of regimen* -if the pain is stable on schedule pain meds and i using additional doses of meds w/out sedation or symptoms of excess dosing-- safe to adjust the scheduled dose to include the amount of PRN meds -1-calcualte how much opioid the pt has had in the past 24 hours MME of MEDD (daily dose) -2-MME/dosing interval= new dose ie. 6 scheduled 2 mg morphine doses = 12 mg and 6 additional doses = 12 more mg. Her MME is 24 mg of morphine. If we divide this the dosing interval we used, we get a new dose of Morphine 4 mg IV q 4 hours two options - leave current PRN 2 mg IVq 12 minutes -increase the dose the same 2-*adjustment if uncontrolled* -increase the total daily dose by a % depending on the severity of patient pain by 25-50% if mild pain by 50-75% if moderate pain by 50-100% if severe pain

what are additional CDC recommendations for outpatient management of chronic pain with opiates -what type of opiate delivery should be used and metabolism -start low and go slow -with acute pain -reevaluation and monitoring

4-*starting therapy use immediate release opioids* -CSC specific and is better b/c long acting will take longer to titrate and thus effectiveness can take longer to evaluate -when starting use immediate release instead of extended release/ long acting ER/LA opioids -choose predictable pharmacokinetics and dynamics to decrease chance of overdose -avoid use of immediate and ER?LA in combo -*methadone should not be 1st choice for ER/LA- b/c of unpredictable metabolism should only be prescribed by specialist * -only provider with methadone experience and prepared to educate patient and closely monitor should PX -only transderminal fentanyl if familiar with dosing and abs/ and can educate Pt--- can only be titrated every few days and *poor choice for patients wo are undergoing dose titration or pain the changes rapidly*- used for stable patient w/ contraindication to oral long acting pain med ie. pt on feeding tube and cannot swallow 5-*start low go slow* -start with lowest effective dose -balance the pain relief with risk of harm and caution prescribing at any dose and individual benefits and *risks when increasing dosage to ≥50 morphine milligram equivalents (MME)/day, and should avoid increasing dosage to ≥90 MME/day or carefully* -If total opioid dosage > 50MME/day ---reassess pain, function, and treatment ---increase frequency of follow-up; and ---consider offering naloxone.-avoid increase >90 MME/day -if increase need for dose- discuss other therapies, and work to taper down or offf opiates and consult pain specialist --not all physicians agree with the yellow and red light 50, 90 MME suggestion of the CDC and think that it may lead to worse pain control outcomes 6-*when PX for actue pain start low and prescribe a limited amount* -target the number of days -*long term use often begins with TX of acute pain*- use the smallest dose and immediate release -*3 days or less is often sufficient*- rarely >7 days - do not give just in case -reevaluate severe acute pain that is longer then expected duration and confirm/revise the DX and adjust managemtn -*do not PX ER/LA for acute Pain* 7-*reevaluation and monitoring* - all guidelines agree that risk and benefits must be weighed and PX stopped if the benefit is not sufficient -attempt to taper at each visit or discontinue -w/in 1-4 weeks of staring long term therapy reevaluate and at least every 3 months -determine if the opioids are meeting TX goals, common or serious *advere events* or early warning signs, benefits of opioids outweigh risk and reduce the dose -work with the patient if there is no sustained improvement in main and dose >50 MME/day and no benefit and concurrent Benzo ---try to reduce or discontinue -taper slowly enough to minimize w/drawal *decrease 10% per week* -access if appropriate to taper during pregnancy - optimize non opiod pain management and psychosocial support

what are additional CDC recommendations for outpatient management of chronic pain with opiates -manage risk of harm from opioids -use state monitoring programs and intervene when necessary -benzos -opioid use disorder

8-*manage his of harm from opioids* -consider naloxone and ID high risk populations -provide naloxone at a opioid daily dose in addition to patient fragility factor -use *additional caution with renal or hepatic insufficiency and >65YO* -optimize TX of depression -naloxone- if history of overdose, substance abuse disorder, taking CNS depressants, >5oMME/day 9-*state monitoring programs and intervene when necessary* -prescirption monitoring database each time you start a new PX and discuss concerns PDMP -do prior to starting and every 3 months afterward -if from multiple providers, high dose, or dangerous combo- talk about safety, include increased risk for overdose, consider taper or nalaxone -consider opioid abuse disorder -consider urine test to see if selling or sharing to determine discontinuation w/out withdrawal -*do not dismiss patient from care- use the opportunity to give lifesaving information and interventions* 11-*avoid prescribing benzos* -increased risk of overdose and death 12-*offer EB treatment for opioid use disorder* -recogniztion of abuse/addiction and effective TX -consider referral for TX with medication assistance- buprenorphine or methadone and other therapy

semisynthetic MOR partial agonist/ antagonist

Buprenorphine naloxone nalbuphine

semisynthetic MOR agonist

Codeine, Hydrocodone, and oxycodone

naloxone- Narcan -what is the different effect with admin

MOR neutral antagonist - no effect - used to TX opiate overdose -*not absorbed efficiently through GI tract* b/c 90% 1st pass -given with oral buprenorphine and will not expert effect - when injected- will induce with drawal effect - not good for rehab b/c it would be like quitting cold turkey vs. buprenorphine

tolerance -what is the mechanism

a decrease in response to a drug upon repeated administration and as a consequence increases in dosage are necessary to produce a consistent effect. Mechanism -GPCR desensitization -repeat admin of agonist will lead to P by GPCR kinases --binding of arrestin that will interfere with interaction of receptor with G protein -arrestin interaction will lead to internalization and degradation -more agonist is required to obtain the desired effect with desensitization -not all receptors responding to an agonist are desensitized in the same manner so there is *difference in timing and magnitude of tolerance that will occur*

loperamide

agonist at MOR -activley piped out of the CNS by P glycoprotein so will not have CNS impact -used to treat diarrhea to suppress the nerves of GI motility -minimal risk of dependence

cross tolerance

can occur with multiple agonists targeting a single receptor subject to desensitization -also can involve changes in common pathway mediating effects downstream of one or more different types of opiate receptor

Nalbuphine -receptors -what is the difference fro morphine

opiate analgesic of agonist/antagonist -related to naloxone *receptors* -agoinst for K- most analgesia -antagonist for mu-less abuse potential *difference from morphine and potent mu agonist* -less respiratory depression due to its agoinst-antagagonist ceiling effect -only drug of class that is not controlled by the controlled substance act

constipation from opiates -main receptor - what is the problem that result -what is the solution to the receptor problem -what is a drug to help - why are normal TX ineffective

receptor -MOR expressed on cells of enteric NS -problemiatic b/c it is the same receptor that produces the most analgesia -hard to use MOR antagonist as there would be counteraction of opieate analgesia solution to receptor -different location of MOR in peripheral and central - goal-opiate antagonist ideally will nt cross the BBB and interfere with PNS w/out influencing the anti-nocucptive effect of opioid in the CNS -*naloxegol*-MOR peripheral antagonist that will decrease constipation but not impact dental analgesia ---treat opioid induced constipation --- binding the MOR antagonist from naloxone bound polyethylene glycol to prevent crossing the BBB ---wil escape 1st pass so is given orally counteract? -laxative, stool softener, and osmotic agents are *ineffective * -b/c the same mechanism that opiates temper nociception will temper the ENS and gut motility and will decrease peristalsis with relaxation of myenteric motor neurons

oxycodone

semisynthetic MOR agonist -analgesic effects but also *eurphoirc similar to heroin and will have more abuse potential and addiction * percocet- when w/ acetaminophen

methadone -what is the action -use -what is metabolism- what does this mean for its use

synthetic MOR agonist -similar analgesia to morphine but less euphoria and less addictive potential (contrast with buprenorphine that will be less then morphine) use - given in structured treatment program to wean individuals from opiates b/c of its higher addictive potential -last longer in the system so the adverse effects last longer and are more difficult to treat -*tolerance can develop and with higher doses there is risk of overdose and death* -dependnece can occur as a result of rehabilitation therapy metabolism -*longer lasting 24 hours vs morphine 4-6 hours* in the system -if you overlap the doses there will be higher [] and increase risk for over dose so needs *controlled setting*

fentanyl -what gives it its quality -what is the dosing and drug often combined with

synthetic MOR agonist -derived from pethidine and is 50-100X *more potent then morphine as analgesic and anesthetic * -left shift relative to morphine qualities from - *hydrophobicity that increase crossing of BBB* dosing/combo -often with morphine at a lower dose based on the relative [ ] of the 2 drugs for analgesia -failure to reduce the dose has lead to the overdose in street drugs

carfentanil -production

synthetic MOR agonist -elephant tranquilizer not intended for human use more potent then fentanyl production -more potent than fentanyl- both of which are synthetic and easy to make form non-PX drugs and enter in the US via China -1g-1000g of heroin so easier to smuggle -mixed with many types of drugs of abuse or replace fentanyl -lack of regulation- users do not know how much fentanyl or this they are getting and if no adjustment is made to account for the more potent drugs then there is *increase risk for overdose *