28. Pain Management for the Cancer Patient - opioids, adjuvent tx and steroids

What is Pain? Pain Classification in cancer by etiology and legth of pain, Type of pain? Distinguish between nociceptive & neuropathic pain symptoms and assessment of pain. (ref set term for pain pathway, slide 11,10 set 17 GERD, slide 6,7, 10 set 18 constipation, slide 16 of this set). PAD guideline ie guidelines- pain, agitation (not anxiety), delirium, for ICU ventilator patients. use non-verbal pain scales ref under terms. ref PNS nociceptive sensory receptor act through C- fiber (glutamate) for pain-temperature afferent pathway. neuropathic pain is associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli (allodynia). tx of pain can be with opioids or non opioids.

"an independent and emotional experience associated with actual or potential *tissue damage* or described in terms of such damage". pain is a normal phenomena when opioids block pain, pain receptors are upregulated and tolerance develop to pain medications. Etiology- Tumor related (presses on soft tissues and nerves) or Treatment related 1. *Nociceptive* (adaptive pain) a. Somatic - *sharp, localized,* throbbing, pressure-like if its *superficial* -skin. difficult to locate like in visreal if its *deep* somatic tissues- *muscle* or bone/connective tissue pain b. Visceral - *diffuse,* irritating, cramping, *difficult to locate* (ex organs or viscera pain. organs respond to stretch or lack of oxygen) 2. *Neuropathic*- burning, tingling, "electrical", *pins and needles, sharp or shooting pain, Numbess* (allodynia). Ex. Hitting the "funny bone" in your arm due to *somatosensory nerve* damage. (crude touch goes through pain pathway not through dorsal pathway, based on PNS sensory receptor/fiber involved). these are pathological pain not adaptive. Pain may be *muscul*oskeletal pain, bone and *neuro*pathic pain *Chronic (>3 months)* vs. Acute pain (a week) NCCN Adult Cancer Pain panel guidelines- Formal pain assessment. Pain intensity is quantified numerically by *Verbal pain assessment scale* of 1-10. Reassessment at appropriate intervals. Pain Symptoms Analysis *(PQRRSTLA)* P - Precipitating factors. What causes or increases pain (movement?) and paliative Q - Quality. Somatic, Visceral,Neuropathic R - Relief. What has been tried, what has worked? (both Rx/nonRx) R - Radiate (transmitted along a nerve) S - Severity. *Mild = 1-3, Moderate = 4-6, Severe = 7-10* T - Temporal. Onset, duration, course L -* Location *(THIS IS THE 1st Question ASKED) A - Associated sxs, alleviating factors, aggravating/ppt factors

Discuss an appropriate strategy for *treating new-onset acute pain* in the opioid naïve and opioid tolerant adult cancer patient. Or *Acute Cancer Pain Mgmt plan in Opioid Naïve pt* (Pain table 2,3,4)? And Steps to Solving a acute Pain with IV or PO rx or *initiation of proper daily dose (IR) *? {in Acute pain find proper TDD of IR starting dose PO morphine IR - 5-15mg starting dose IV morphine IV - 2-5mg in opioid non naive pts calculate TDD (CR+ IR), and find *TDD/hr, then administer 10-20%/hr* po or IV morpine IV 10 mg = 30mg PO}

* Mild Pain (1 - 3)*- consider acetaminophen or *NSAID* (non opioid) or *short acting opiates,* Along with all level of pain tx. NSAIDs are good but has risk of renal toxicity, GI bleed, cardiac toxicity, thrombocytopenia. If 2 NSAID are tried without efficacy, use another approach to analgesia. *Moderate Pain (4 - 6)- titration* of short-acting opiate (Begin bowel regimen), Along with all level of pain tx. *Severe Pain (7 - 10)- Rapid titration* of short-acting opiate (Begin bowel regimen). * For all level of pain,* Provide psychosocial support and non pharmacologic intervention, pt and family education, Consider adjuvant meds (antidepresants, anticonvulsant, Local anesthetic, steroids, NSAIDs (opioid sparing effect). May schedule IR opiods instead of giving PRN. Steps to Solving a acute Pain with IV or PO rx Determine if patient is opioid naïve or tolerant and initiate proper dose (think in terms of full/partial/no *response or relief or remission*) a. *Initiating short acting opioids in opioid naïve* (pain 3 table) *usual starting dose* of morphine is 5 - 15mg po (peak effect in 60 min) or 2 - 5mg IV (peak effect in 15 min). JS' pain is then *reassessed in 1hr if PO* (don't wait for 4 hrs in severe pain) or *15 min if IV*. * If no relief or increased pain* → *double dose & reassess* in 1hr if PO. *After 2-3 cycle consider IV* or if already on IV consider subsequent management plan (pain 5 table). *If <50% relief (moderate -severe pain >4)* → *repeat initial dose* & reassess in 1 hr if PO. After 2-3 cycle consider IV or if already on IV consider subsequent management plan (pain 5 table). * If > 50% relief (mild pain 1- 4)* then *repeat initial effective dose PRN* & reassess in 2 - 3 hr if PO for *continue for 24 hrs.* consider subsequent management plan (pain 5 table). b. *Initiating short acting opioids in opioid non naïve pt* (pain 4 table) *calculate TDD and administer 10-20% po* (peak effect in 60 min. Make sure to add CR and *average daily dose of IR* to calculate TDD). calculate TDD of Po, *convert PO to IV equivalent and administer 10-20% as IV* (peak effect in 15 min). remember *morpine IV 10 mg = 30mg PO.* JS' pain is then reassessed in 1hr if PO *(don't wait for 4 hrs in severe pain)* or 15 min if IV. If no relief or increased pain →double dose & reassess in 1hr if PO. After 2-3 cycle consider IV or if already on IV consider subsequent management plan or pain 5 table. If <50% relief (>4) → repeat initial dose & reassess in 1 hr if PO. After 2-3 cycle consider IV or if already on IV consider subsequent management plan or pain 5 table. If > 50% relief (1- 4), then repeat effective dose PRN & reassess in 2 - 3 hr if PO for continue for 24 hrs. consider subsequent management plan (pain 5 table).

*Adjuvant for Neuropathic pain *-TCA -classification of agents, efficiency or adv, disadvantages, dose, ADR, DI, precaution Non-tricyclic *Antideppressants* (SSRIs, Mixed NA/SSRI, Noradrenergic) - class, agents , efficiency or adv, disadvantages, dose, ADR, DI, precaution ref slide 7,13,17 set 24 depression. clomipraine *high dose for OCD, IBS (low doses* than antidepressant doses). in the natural analgesic pathway, SE, NE and endorphine are involved. TCA has *high noradrenaergic action in synapsesis* due to NET block so good for pain (they also block alpha receptors). TCA are antidepresent with CNS depression action like opioid, so used in pain (action in 1 week when used for pain) tx at low dose but suicidal issue. but SSRI is not good due no action on NE (good for anxiety at higher dose. its a CNS stimulant/antidpresent). remember presynaptic alpha 2 *agonist (adrenergic which decrease NE*) is also used for pain. low BP is due to block of *post sympatic NE, and block of down stream effect.* opioids reduce NE presynaptically. rx that cause serotonin syndrome- cyclobenzaprine has TCA str. zyvox MAOI str. cocain and amphetamine block dopamine reuptake and MAOI increase synaptic dopamine and NE. opioids (meperidine/demerol, *tramadol*, fentanyl (short half life so not much of a probem), NMDA blocker (dextromethorphan, ketamine), diphenoxylate has meperidine str. Wellbutrin has amphetamine str.

*Tertiary amines (high anticholinergic* action ie, *high HR*)- amitriptyline, imipramine, doxepin, clomipramine Secondary amines (preferred in elderly)- desipramine, nortriptylipain class-Drugs that block both SERT and NET). *pain effect (due NET block). * Dosage for adjuvant pain syndromes: starting dose *low and go slow* to *reach target dose.* Dose escalate q 3-5 days (up to 14 days). usual effective *dose is lower than antidepresent* dose 50 - 150 mg HS. Efficiency Or adv.- *very effective* and cheap for nuropathic pain. Unlike antidepressant effect (not used much due to ADR, overdose problem in these suicidal pts) which take *6 weeks to full effect, effective analgesia within 1 week* of therapeutic dose. If no benefit change therapy ADR or disadv- *anticholinergic- high HR (also due to high NE from NET block)*, anticholinergic crisis. CVS: postural *hypotension (alpha receptor-block),* *life-threatening ventricular arrhythmias and QT prolongation (direct cardiac depression like class 1a antiarrhythmics),* CNS: confusion, sedation (due to H1 block. taken at night), weight gain, sexual dysfunction (less than SSRI due to NE effect). Remember SE receptors in CNS, GIT and platelet for adr. Precautions: elderly, narrow angle glaucoma, cardiac hx Potential DI: QT-prolonging drugs (antiarrhythmics), anticholinergics, *MAOIs, SSRIs (block SERT cause Serotonin syndrome). *TCA + any 2D6 inhibitor (including fluoxetine) → ↑ plasma TCA levels. Very commom combination. Serotonin syndrome If MAOIs (10% of monoamine inactivation) combined with drugs (opioids (meperidine/demerol, *tramadol*, cycobenazaprine, zyvox), that block SERT (Majority of synaptic monoamine neurotransmitter are removed by transporters 90%. ex. SSRIs, SNRIs,TCAs) → marked increase of 5-HT levels in the synaptic space → *overstimulation of postsynaptic 5-HT receptors* esp. in the central gray nuclei and the medulla → potentially *life-threatening serotonin syndrome with HTN (anticholinergic are red, mad and dry, high BP) and triad of symptoms (shaky, hot and wet).* TCAs *potentiate CNS depression* (euphoria synergism) if combined with other CNS depressants such as: alcohol, *opiate,* BNZ and ant seizure rx. SNRI (Mixed NA/SSRI, no receptor block)- *effective* for for neuropathic pain (venlafaxine, duloxetine, milnacipran (Savella).* pain effect (due NET block).* class-Drugs that block both SERT and NET *Target dose is less (or half) than antidepressant* dose. Starting/Effective dose= 37.5mg /37.5-112.5 mg/day *(venlafaxin) no FDA approved indication for nuropathic pain but are used.* Starting/Effective dose = 30 mg / 60 mg q day (duloxetine. dual action on NET and SERT) 12.5 mg daily titrated over 7 days to 50 mg bid (milna) ADR- sexual dysfunction, Nausea, Somonolence DI- TCA, MAOIs, SSRIs due to Serotonin syndrome SSRIs (paroxetine, citalopram)- *not very efficient *for neuropathic pain. * pain effect (due NET block).* class- Selective serotonin reuptake inhibitors effective dose = 20-40 mg/day ADR- *sexual dysfunction due to high serotonin, *Nausea, insomnia *(sleep and GIT issues due to serotonin)*, headache DI - TCA, MAOIs, SSRIs due to Serotonin syndrome. Noradrenergic (bupropion or wellbutrin)- *not very efficient* for neuropathic pain. pain effect (due NET block). Added *benefit of improving fatigue /sedation.* Effective dose = 75-150mg bid. *class- norepinephrine-dopamine reuptake inhibitor (NDRI)*. related to *amphetamines* in structure. give positive *urine drug screen test.* ADR- *Insomnia,* headache, *anorexia* (due to dopamine or SE) agitation, tremors, seizures. *No sexual dysfunciton (due NE effect and no serotonin effect)*. DI - TCA, MAOIs, SSRIs due to Serotonin syndrome

4 (classic and nonclassic) Opioid receptors types? *Endogenous opioid* peptides and synthetic opioid pepetides- functions, and preferred receptor types? ref slide 13, 19, 20 of this set. MOA of gabapentine: Even though they are structurally resemble GABA, neither drug acts directly on GABA receptors. Instead, gabapentin and pregabalin bind to presynaptic VG Ca2+ channels → ↓ Ca2+ entry → ↓ release of glutamate Orphan receptors are called ORL-1 (opioid Like subtype 1 receptor) or *Nocieptin receptor* (NOP) orphanine FQ receptors (OFQ). (nociceptive pain and neuropathic pain) opioid act on the presynaptic receptor (Gi protein coupled receptors) and inhibit release of NT glutamate (no pain transmission). substance P (NK receptor agonist, NK antagonist for N/V tx), Ach, NE, SE. It increases GABA (inhibitory NT) and dopamine (Euphoria). No more normal pain, body upregulate receptors (action in any CNS depressant rx unlike stimulants) for pain. then we need more opioid to control pain

1. Mu (μ) receptors μ1, μ2, μ3. *Major Opioid receptors.* 2. Delta receptors 1and 2 3. Kappa receptors1, 2, and 3 - *analgesic without respitory depression* 4. Orphan (N/OFQ) receptor (NOP-R) *Endogenous/natural opioid* peptides includes *enkephalins, Endorphins,* Neoendorphin and Dynorphins and others. *affect pain perception and are opioid receptor agonist* Dynorphins & Neoendorphin they are potent agonists at mu, delta,and kappa receptors. most active at *kappa 1* receptors. *Enkephalins *- located in brain and spinal cord areas for pain perception. also in *adrenal gland* (morphine reduce catecholamine in MI) and in GI tract. potent agonists at Mu and *Delta* opioid receptors beta- Endorphin - processed from prepro-opiomelanocortin (POMC). POMC *precursor of endorphine yields ACTH,* MSH, beta Endorphin. found in brain regions involved in pain perception. main endogenous *ligand for the Mu receptor (like major morphine* receptor) Endomorphins - are highly selective & potent Mu receptor agonists. widely distributed in brain, spinal cord Orphanin/*Nociceptin* (N/OFQ) - which acts at the unique N/OFQ or so called "orphan" receptor. *nociceptor release* glutamate and cause pain. *(Gabapentin has str of GABA but block glutamate*). Synthetic Opioid Peptides or injectable *enkephalin analogs* DAMGO enkephalin (a specific μ agonist), DPDPE enkephalin ( a specific delta agonist), DADL encephalin and Many others...

Given a patient case, provide appropriate *recommendations for long-acting opiates* and short-acting opiates (breakthrough pain* BTP*) ? *subsequent Pain Mgmt plan after initiation of opioids in chronic pain* (Pain 5 table) {in chronic pain divide proper TDD of IR between IR (PCA/po for BTP) and CR (IV/po for basal pain control). a. Conversion to oral CR formulations from IR proper TDD of IR = TDD of CR *well controled* TDD of CR = TDD of CR, cut back 25-50%, if *converting to another opioid.* b. calculate breakthrouh pain dose basal (mg/hourly) rate of the TDD= TDD/24 hrs to get hourly TDD IR, BTP dose = 10-20% of basal rate ( hourly TDD), every 1 hr PO or 1/4 of the hourly BTP dose, q 15min in a PCA ( hourly BPT dose is the lockout dose).}

6 Steps to Solving a *chronic Pain* 1. Determine if patient is opioid naïve or tolerant and initiate proper dose 2. Convert to a *long acting opioid based on how much short acting opioid was effective* on the past 24-48 hrs in opoioid naïve pt. this help not to have peak and low pain cycle in chronic situations. *It is ok to have a scheduled short acting rx for acute pain instead of adding a longacting. * if TDD is given as a *basal* (mg/hourly) rate, divide TDD by 24 hrs to get TDD/hr. if a well controlled Pain pt is *converting to another opioid *due to ADR, *TDD dose has to be decreased 25-50% due to incomplete cross tolerance.* If pts pain is poorly controlled, don't decrease TDD. 3. Calculate breakthrough pain *(BTP) dose 10-20% TDD every 1 hr* ok in severe cancer pains. If using *PCA ¼ of hourly rate given every 15 mins* or just calculate for q 10min. Remember BPT answer is a range. remember to calculate a *lockout dose* (hourly limit to prevent overdose due to pt control of PCA. Lockout dose should be mentioned in the prescription along with hourly TDD and BTP doses). if using IV basal and PCA for BTP, by adding hourly PCA dose and hourly TDD (hourly basal rate). 4. *Convert to another opiod using equianalgesic dosing* table *(TDD of oral opioid to TDD of oral morphine then to IV morphine then find breakthrough dose)*, if pt cant tolerate it. Make sure to add CR and average daily dose of IR to calculate TDD or total daily dose. 5. Provide supportive care of ADR: constipation, N/V, sedation. ref slide 8 of this set. 6. Identify monitoring parameters & frequency and reassess pain before next dose is taken Moderate to Severe Pain (4 - 10)- *continue titration* of dose or reevaluate titration, Along with all level of pain tx. Pain speciality consultation. Mild Pain (1 - 3)- reassess and modify regimen to *minimize ADR*, Along with all level of pain tx. * For all level of pain,* Consider adjuvant meds titration, Provide psychosocial support and non pharmacologic intervention, pt and family education.

Morphine effects on CVS, eye, angalgesia (CNS), respiratory, GIT, bladder and other effects {If you have a *opiate receptor on the GABA an inhibitory interneuron, opiate block GABA release and no more inhibitory response thus turn on excitation pathway like dopa and serotonin.*} (sleep and GIT issues due to serotonin) ref slide 3, 17,19 of this set. ref slide 19 set 24 depression. ref afferent pathways by Dr Najeeb youtube, term 2 set. to decreases dose needed we could add opioid sparing agent NSAID or NMDA antagonist α2 = Gi central vascular relaxation by inhibition of release of NE in CNS and Ach in PNS, inhibit release of insulin from the pancreas. has some cholinergic effect due to *histamine release*, like *N/V high GI motility*, pin point eye, but some adr are *Atropin like* constipation (due to *low GI motility, so for spasms)*, low urine, high bp, no effect on HR, flushing . NK receptor agonism cause N/V (substance P is agonist), antagonist help with tx N/V.

Analgesic Effects: Brain *perception of pain is reduced (reduce substance P). Continuous dull pain* (through reticular pathway of the venterolateral afferent pathway) reduced better than sharp acute pain (goes use dorsal afferent pathway). these are *agonist, Acts primarily at presynaptic μ 1 receptors in the brain (PAG area) and at the μ2 receptors in the spinal cord.* morphine given at *both spinal cord & brain *decreases dose needed so less ADR (In MI pain increase catecholamine and further aggravate ischemia. Can be treated with morphine which *blocks sympathetic efferent (NE) from CNS* and thus *decrease vasoconstriction* (also through *Histamine release* which also cause* itching)*, decrease oxygen demand and symptomatic improvement in MI. action similar to clonidine. *reduce BP, but no effect on HR * (but *methadone prolonged QT)* since affecting CNS. monitor -Pain, respiration, *BP* ref slide 9,19 set IHD 8, slide 1, 10, 13 of this set) Other non-analgesic effects : Drowsiness w/o loss of consciousness, *Euphoria* (through high dopa, addiction), *Cough suppression* *Respiratory depression (CNS depresent. *can use ephedrine and *amphetamines to counter* this effect, *increase NE and Dopa release* acting presynapitcally, decrease reuptake by MAO inhibition) *Convulsions can be triggered, Nausea & vomiting (Histamine release)* are common Neuroendocrine effects : ↓GnRH and CRF from *hypothalamus,* leads to : ↓ LH, FSH, & ACTH (also high prolactin) Constriction of the pupil (via stimulation of *parasympathetic NS to eye).* *GI tract effects shut down (↓ gastric motility,* ↓ intestinal, biliary, & pancreatic secretions Skin (causes *flushing* of the face & neck via *release of histamine).* Urticaria is common at the injection site *Urinary bladder shut down* (↓ urinary voiding reflex & high tone of external sphincter).

*Descending (efferent) Pain Control* Pathway (natural analgesic pathway of body), explain Cortical and subcortical response and Inhibitory synapses response to pain stimuli (ref slide 2 set 24 depression, ref slide 8,9, 12,17,19, 20 of this set. ref adjuvent tx for GABA, glutamate effect on pain. *dopamin* NTs. Opioid receptor : a GPCR member (not nuclear receptors like steroids/hormones or tyrosin kinase receptors). The opioid receptors are ~40% identical to somatostatin receptors. Opioids (peptide inhibitory neurotransmitter) act as a ligand or mimic the NT, not an agonisy. Peptides neurotransmitters (based on the str) ex: somatostatin, substance P, cocaine and amphetamine regulated transcript, opioid peptides. substance P (It is a neuropeptide, acting as a NT and as a neuromodulator). know gate theory of massage for analgesia and reflex arc.

By *sending responses* back to the periphery, the *CNS can induce the release of neurotransmitters* (mainly inhibitory NT endorphins) which reduce the transmission of pain signals (feedback loop). *central modulation (one target of analgesic rx)* - Neuronal centres of the *cortex* and subcortical areas of the brain respond to incoming (ascended) pain signals and can modulate pain signals by *activating inhibitory descending pathways.* the periaquaeductal grey *(PAG) in brain stem/midbrain* (has high affinity *binding sites for opiate drugs),* receives pain signal and initiates inhibitory nerve impulses which descend the CNS in two different tract systems. a• The *medial tract* is triggered by the so-called *Raphé nuclei* and is mainly influenced by the neurotransmitter *serotonin* which can execute pain inhibitory as well as pain facilitating activity. b• The *lateral tract* starts in the *Locus coeruleus.* In this pathway, the neurotransmitter *noradrenaline* plays a central role. (help with pain) *corticospinal (dorsolateral tract)* Inhibitory impulses descend to the *dorsal horn of the spinal cord* segment (one target of analgesic rx) where respective painful stimuli are transmitted to the second order neuron. Activated *inhibitory interneurons* release inhibitory NTs such as *endorphins, GABA, noradrenaline and serotonin* (dopamine agonist help to tx respiratory depression, dopa antagonist help with nausea. *glutamate increase pain, endorphin/ opioid agonist reduse pain*)

*Adjuvant for Neuropathic pain*- Anticonvulsants- class, agents , efficiency or adv, disadvantages, dose, ADR. ref slide 5,20 of 24 depression. NMDA receptor blockers is ketamin. used for pain.

Classic agents of *seizure* -Phenytoin (Dilantin), Carbamazepine (Tegretol), Oxcarbazepine (Trileptal - better tolerated than carbamazepine), Phenobarbital *(GABA receptors receptor agonist)* Newer agents for seizure- Gabapentin (Neurontin) well tolerated; few side-effects. not used for seizure much. Pregabalin (Lyrica) same MOA as gabapentin but *quicker onset of action.* Lamotrigene (Lamictal), Levetiracetam (Keppra) Topiramate (Topamax), Tiagabine (Gabitril) , Zonisamide (Zonegran). (mainly Na channel blocker thus reduce glutamate. Gabapentin and Pregabalin -*Structural relative of GABA but don't work on GABA receptors.* Both are *effeicint* in neuropathic pain. MOA: bind to *presynaptic VG Ca2+ *channels at the postsynaptic dorsal horns→ ↓ Ca2+ entry →* ↓ release of glutamate* Adverse effects: *well tolerated*. somnolence, *dizziness (so start low and go slow in titration)*. *Pedal edema,* fatigue, ataxia, weight gain Gabapentin and Pregabalin- GABA analogues are not metabolized and excreted unchaged in urine. Renal Dosing based on creatine clearence. Gabapentine 125 - 325 mg/day suppl post HD Gabapentin max dose - 300mg TID *(max 3600mg/day). Absorption is dose-dependent reduced with doses > 1200mg/day, no more lenear absorption.* Gabapentin was *designed to be a centrally active GABA agonist, with its high lipid solubility *aimed at facilitating its transfer across the BBB. typical titration *to avoid diziness* is day 1-2, 300mg qhs, Day 3-4, 300 BID, day 5-7, 600 Bid, day 8, 600 tid. Titration should be more slower in elderly. Onset of therapeutic *effect within 1-2 weeks (pregabline quicker onset).* No effect stop rx. Pregabalin Dosing: *Diabetic *Peripheral Neuropathy- 50 mg po tid, Increase up to 300 mg per day within 1 week. 600 mg dose studied but no extra benefit Post Herpetic Neuralgia (PHN)- 75 mg bid -or- 50 mg tid. May increase to 300 mg per day within 1 week, based on efficacy & tolerability. If no improvement after 2-4 wks then may increase to 300 mg bid or 200 mg tid. *Fibromyalgia* Side effects: * mild euphoria (Schedule V *controlled substance), *Pedal edema,* anaphylaxis, decrease platelets, weight gain, blurred vision, somnolence, CK elevation. Use with glitazones increases risk of edema and heart failure. Caution in Class III or IV heart failure

Codeine pharmacology and polymorphism, Fentanyl, Methadone,* Demerol* (not tramadol), Mechanism for tolerance (ref slide 10 set 18constipation, slide 19 set 14cirrhosis. ref slide 7, 11 of this set, also substance abuse)

Codeine is 60% as effective orally as parenterally. It has *greater oral efficacy than morphine* due to *first-pass metabolism* in the liver (liq good for cough). Codeine *binds poorly* (affinity) to opioid receptors. Its analgesic effect due to its demethylation to *morphine (only occurs in 10% *of administered drug. week analgesic). *Conversion to morphine requires CYP2D6 in liver.* Chinese produce less morphine from codeine than Caucasians 10% and are less sensitive to morphine's effects due to Genetic *polymorphisms in CYP2D6* Other polymorphisms enhance the formation of morphine from codeine. Fentanyl (SUBLIMAZE)- 100x *more potent than morphine.* Synthetic opioids,* potent µ agonists.* Rapid onset. (duragesic *patch takes 12 hrs to start action.* used in opiod tolerent pts only. used for ATC protection/ long acting effect) Meperidine (DEMEROL) is predominately act µ receptor agonist. Due to its *metabolites (Normeperidine) is no longer* used for treatment of chronic pain. Should *not be used for longer than 48 hours* in doses > 600 mg/day due to normeperidine effect on *lowering seizure potential* (like tramadol). good for *pain due to biliary spasm* (low GI motility). *diphenoxelate* (opioid agonist used for tx of diarrhea, especially during heroin withdrawal period loperamide is used) has *merperidin str*. opioids (meperidine/demerol, *tramadol*, fentanyl (short half life so not much of a probem), dextromethorphan (NMDA blocker) can cause *serotonin syndrome*. Methadone-* A long-acting (formulations are IR) µ-receptor agonist* with pharmacological properties similar to morphine. Its extended duration makes it *useful in suppressing withdrawal symptoms/ craving in heroin addicts.* ADR- Heart arrhythmia including *prolonged QT.* Development of* Tolerance Occurs* at different rates for different actions. develops rapidly for *analgesia (do opiod rotation*. no natural pain,* pain receptor upregulation)*, respiratory depression, and euphoric actions. tolerence develops* hardly at all for GI*(constipation. also eye) effects. Mechanism for tolerance :* opioid receptor down-regulation* via phosphorylation, uncoupling of the receptor to G - proteins, increased adenylate cyclase activity

*Monitoring of Opioid ADR* and Mgmt. in acute/ chronic pain in the hospital setting? Discuss an appropriate strategy for *preventing and treating* opioid-induced* constipation and Opioid-Induced Nausea/Vomiting* - mechanism, prevention goal and agents, constipation treatment agents? ref slide 11,10 set 17 GERD, slide 6,7, 10 set 18 constipation, slide 14, 17 of this set Naltrexone (ReVia & Vivitrol) opioid antagonist. Indication: craving. Decrease heavy drinking but do not cause abstinence Naloxone (Narcan)- opiod antagonist used to reverse opioid overdose prokinetic agents (ex cholenomemetic agent, Dopamie antagonist, 5-HT4 receptors* agonist*) are used for tx of GERD and opioid induced constipation. (sleep and GIT issues due to serotonin) ref slide 3, 17 of this set Treatment Antiemetics- Promethazine (phenergan is a H1 antagonist), Prochlorperazine (phenothiazine antipsychotic, d2 antagonist), Metoclopramide (d2 antagonist, dopamine agonist for resp. depression of opioids), 5HT3 *serotonin antagonist* (ex. ondansetron, structurally similar to SE but antagonist). naloxone (opioid antagonist for resp. depreesion and over dose, addiction of alcohol and heroin) opioid antagonist for constipation, dronabinol (cannabis dt for pain, anorexia and N/V) NK1 antagonist (substance P antagonist) is for N/V tx. dexamethasone for N/V and cancer pain. ketamine is opioid sparing agent NMDA antagonist.

Constipation - assess *every 24hrs* or pts normal habit. *No tolerance developed.* Nausea/vomiting - assess *every 1hr* or before each dose Sedation - assess every 1hr or before each dose Respiratory depression - assess every 1hr or before each dose. adjuvent tx with *wellbutrin help (dopamine agonist with amphitamine metabolite).* Note: for inpatient treatment, monitor adverse effects before each dose also pain assessment. consider *addiction and dependance and tolerence* mechanism of constipation- Opioid therapy decreases intestinal motility and causes constipation. *Prevention* Goal = one non-forced BM every 1-2 days Stool softener (normally for prevension not for tx) *+ Stimulant laxative* (no push no mush). docusate + senna, 2 po daily →max 4 po bid. *Increase dose of laxative with increasing dose of opioid* Increase fluids, fiber & exercise *Treatment of constipation-Add another agent PRN* if not bowl movement for *48 hrs.* ex. MgOH, Bisacodyl tabs or suppos., Lactulose, Sorbitol, Magnesium citrate, PEG, Enemas Increase dose of stimulant laxative *Opioid reduction or rotation* Peripheral Opiod *antagonist* help with constipation with out affecting analgesia. Opiod antagonist has limited use due to *risk of opoid withdrawl effect. *Methylnaltrexone (Relistor®) Metoclopramide - D2 receptor *antagonists* for Nausea. Rule out other causes- Obstruction, impaction, *hypercalcemia* Prevention - have antiemetic Rx on hand or* prn* Treatment Antiemetics- Prochlorperazine, Promethazine, Metoclopramide, 5HT3 *serotonin antagonist* (ex. ondansetron) Administer antiemetics *ATC before each opioid dose* (like in chemo induced N/V) If persistent* n/v > 1 wk* → reassess cause, change opioid Add nonopioids or reduce opioid dose if possible Rule out other causes. *Tolerance develop to Opioid induced nausea*.

*Adjuvant analgesics and coanalgesic* definition and *agents for each type of pain,* bowl obstruction and aduvants drugs for cancer pts? *Adjuvant analgesics* In chronic Cancer Pain Management for *musculoskeletal pain, *bone and neuropathic pain and opioid sparing drugs? ref slide 5 of 24 depression, slide 20 of this set. bowl obstruction can be caused by constipation and no GI movement as well . so give cholinergic agents/rx treating paralytic illus, opioid antagonist. prokinetic 5HT4 agonist- cisapride, regalan, 5HT3 antagonist - alosetron. secretiory laxative in IBS lubiprostone (amitiza). linaclotide (linzess) Class- guanylase cyclase C agonist. indirectly increase chloride NSAID and steroids act on Ecosanoid pathway (inflammatory pathway) for acute pain

Definition: a drug that has a *primary indication other than pain,* but is also analgesic for some painful conditions. Ex. Antidepressants, Anticonvulsants, *Neuroleptics, Alpha2 adrenergics,* Corticosteroids, Local anesthetics, *NMDA receptor blockers (opioid sparing effect, anesthetic*, hallucinogen class like opioid). *'coanalgesic*' or First-line certain chronic non-malignant pain syndromes as *monotherapy* (post-herpetic neuralgia, diabetic neuropathy). ex. NSAID (has opioid spairing effect). Choice of adjuvant based on Pain assessment and type of pain Nociceptive vs neuropathic or Bone pain or musculoskeletal pain (different afferent pathways for each pain). also based on Comorbidities/ disease states like Depression, Seizures, Anorexia Pain associated with *inflammation-NSAID or glucocorticoids. (opioids are for chronic pain*, C fiber, A-delta fiber pain) *Musculoskeletal pain- muscle relaxants * (include *centrally acting* muscle relaxant (but exclude peripheral agents or NMJ blockers) and rx for *acute muscle spasms*): cyclobenzaprine, carisoprodol, orphenadrine, metaxolone, methocarbamol, *tizanidine*, baclofen, *benzodiazepines*. *Bone pain*- NSAIDs or *Corticosteroid *plus/minus (added if you have bone involvement) *Bisphosphonate, Calcitonin,* Radiopharmaceutical (Strontium, Sumarium) *Effective Neuropathic pain* agents- antideprasant (TCA, SNRI. SSRI not effective. *analgesia in 1 week*) and/or anticonvulsant (quick analgesia in *1-2 week with lyrica*), and/ or local anesthetic (lidocaine patch, *long time for analgesia*) or other interventions. Bowel obstruction- bowel *rest* or suction, Anticholinergics (hyoscine, scopolamine, glycopyrolate (Robinul, to reduce saliva) are *antispasmodic* (reduce GI motility like opium, no Nitric oxide and vasoconstriction *ADR is constipation*) and used for *urinary incotinence *to relax muscles), octreotide (good for chemotherapy induced diarrhea, vasoconstrictor of *splanchnic (sympathetic- alpha 1 agonist)* system used to improve perfusion to organ, stop bleeding, dont raise BP like midodrine), corticosteroids

Why change from *one opioid to another*? Who should dose *Methadone*? Given a patient case, recommend an appropriate starting dose for fentanyl transdermal *patches* , indications and CI for starting fentanyl pathes? {DO you use IR and CR opiods with methodone? ref slide 15 of this set} {in *Acute pain* find proper TDD of IR starting dose PO morphine IR - 5-15mg starting dose IV morphine IV - 2-5mg in opioid non naive pts calculate TDD (CR+ IR), find *TDD/hr then administer 10-20% /hr *po or IV morpine IV 10 mg = 30mg PO. in *chronic pain* divide proper TDD of IR between IR (PCA/po for BTP) and CR (IV/po/patch for basal pain control). a. Conversion to oral CR formulations from IR proper TDD of IR = TDD of CR, given qd or bid 1/2 TDD of * PO morphine* = TDD of fentanyl patch (mcg/hr) give q 72 hrs well controled TDD of CR = TDD of another opiod, cut back 25-50%, if converting to another CR. b. calculate breakthrouh pain dose basal (mg/hourly) rate of the TDD= TDD/24 hrs to get *hourly TDD basal* IR, BTP dose = 10-20% of basal rate (hourly TDD), every 1 hr PO or 1/4 of the hourly BTP dose, q 15min in a PCA *(hourly BPT dose, hourly TDD (basal) and hourly lockout dose should be mentioned in the rx*). pump measure in ml/hr, bag dose is in mg/ml. dose for the pt is mg or mcg/kg/ml or hr. lock out dose of PCA dont include CR TDD in critical care since pt is just getting IR. If a patient requires more than 2 to 4 breakthrough doses in a 24-hour period on a routine basis, consider increasing the dose of the extended-release preparation. Conversion to oral formulations from IV. find TDD and then convert IV dose to equvalent oral dose. then follow step a and step b. Convert to another opiod using equianalgesic dosing table. Refer to Equianalgesic Opioid Dosing and relative potency Table from NCCE guidelnes. ref slide 5, 6} alcohol withdrawal symptoms cause DT and seizure. tx with BDZ due to its cross tolerance. to help with the craving and abstinence use CIWA protocolwith disulfuram (aldehyde dehydrogenase blocker) or Acamprosate (Campral, GABA modulator, glutamate inhibitor), Naltrexone (ReVia & Vivitrol) heroin addiction Opioid substitution methadone (full agonist) buprenorphine (partial agonist), naltrexone (opioid antagonist) for detoxification. for suppress withdrawal symptoms clonidine, to avoid withdrawal symptom methodone dose 40-120 mg (higher than pain dose). taper 5-10mg/day over 7-21 days. Maximum time allowed in OTP is 180 days. But some people stay on it cant get off. methadone (when used for withdrawal tx) peak = 72 hr. Duration = 2 weeks. T1/2 = 24-36 hrs. DOA: pain is 4-6 hr; withdrawal prevention: 24-36 hr

Done if pt* cannt tolerate it due to ADR.* Or *lower analgesic effect* due to *incomplete tolerance.* *opioid rotation* help to recover analgesia due to difference binding capacity to each receptor, but there is *cross tolerance.* But *no dose ceiling* for opoids. When changing from one opioid to another, allow for incomplete cross-tolerance so *cut back 50% when changing to new (if pain is well controlled)*. Convert to Methadone dose always consult a pain specialist. It is an IR formulation, Its extended duration makes it *useful in suppressing withdrawal symptoms and help with craving in heroin addicts, but need a high dose than pain dose.* (ref addiction) Fentanyl patch dosing Rule of thumb: mcg/*hr patch* dose approximates *1/2 the daily oral morphine* equivalents (mg/hr to hr conversion) give q 72 hrs. Refer to manufacture specific conversion tables for fentanyl. When Converting to *long acting Fentanyl* Transdermal *(for IV fentanyl use regular equianagesic table. IV is short acting, can be used in opioid naiive pt), *Calculate total daily dosing (TDD). Then *Convert to oral morphine equivalents* (use equianagesic chart. If you are converting from an IV non morphine opioid, first convert to IV morphine then convert to PO morphine) before Useing table to determine fentanyl patch dose (this fentanyl table is not used when converting FROM fentanyl patch). Ex. 150 mg of TDD of morphine fall in the *a range of * 135 - 224 mg/day oral morphine in fentanyl chart = 50 µg/*h* patch, replace q 72h. If you use the rule of thumb for 150 mg of TDD of morphine, use 75 µg/*h patch replace q 72h.* DURAGESIC® is indicated for management of persistent, *moderate to severe chronic pain* that: requires continuous, *around-the-clock opioid* administration for an extended period of time, and cannot be managed by other means such as non-steroidal analgesics, opioid combination products, or immediate-release opioids it should *ONLY be used in patients* who are already receiving opioid therapy, who have demonstrated *opioid tolerance,* and who require a total daily dose at *least equivalent to DURAGESIC 25 mcg/h*. Patients who are considered opioid-tolerant are those who have been taking, for* a week or longer, at least 60 mg of morphine daily* or an equianalgesic dose of another opioid. Because serious or life-threatening hypoventilation could occur, DURAGESIC® *(fentanyl transdermal system) is contraindicated:* in patients who are *opioid-naïve* in the management of* acute pain* or in patients who require opioid analgesia for a short period of time or in the management of post-operative pain * (but IV fentanly good in acute pain)*, including use after out-patient or day surgeries (e.g., tonsillectomies) or in the management of mild pain or in the management of intermittent pain [e.g., use on an as needed basis (prn)]

*Adjuvant for Neuropathic pain* - Local anesthetics- agents, efficiency and ADR? Alpha 2 Adrenergic* agoNists*- agents, effiecieny and ADR. ref slide 3, 12,13, 14, 20 of this set. ref slide 18, 19, set 24 depression. in the natural analgesic pathway, SE, NE and endorphine are involved. TCA has *high noradrenaergic action in synapsesis* due to NET block so good for pain (they also block alpha receptors). TCA are antidepresent with CNS depression action like opioid, so used in pain (action in 1 week when used for pain) tx at low dose but suicidal issue. but SSRI is not good due no action on NE (good for anxiety at higher dose. its a CNS stimulant/antidpresent). remember presynaptic alpha 2 *agonist (adrenergic which decrease NE*) is also used for pain. low BP is due to block of *post sympatic NE, and block of down stream effect.* opioids reduce NE presynaptically. substance P is peptide like opium but cause pain not analgesia. act on NK1 receptors (apripipant (emend) antiemetic NK1 antagonist)

Lidocaine 5% patch (Lidoderm) -*FDA approved for PHN, effective for neuropathic pain* Efficacy may take *several weeks*. Dose -Up to 3 patches applied x 12 hours then *off 12 hours (otherwise too much in blood and cause cardiac side effects)* ADR: local skin reactions Capsaicin 0.025% & 0.075% cream (Zostrix), takes *long time to show effects.* Apply 3-*4 x day* Depolarizes terminal C-fiber nociceptors & *depletes Substance P, *leading to decreased pain perception. ADR- *burning *sensation Clonidine (Catapres) also intraspinal Tizanidine (Zanaflex, centrally acting muscle relaxant with MOA like clonidine)- po, topical, *Not first-line* but can be used in - Myofacial pain syndromes, Prophylaxis of daily headache, Opioid refractory cancer pain (intraspinal) ADR: *hypotension, lower HR,* somnolence

3 major/classic Opioid receptors types classification and functions of receptors? mechanism of opioid receptors? signal transduction pathways of opiod receptors ? types of *peptide neurotransmitter * affecting opiod receptors? Opioid receptor subtype coupling and signal transduction? 2 types of NT * receptors * or classification and 2 signal transduction pathways involving the GPCR? slide 12,14, 19 of this set. Pancreatic delta cells produce somatostatin (GH). butorphanol Nasal spray is management of migraine, IV for pain, general anesthesia, pain during labor (selctive Kappa agonist activity with no respiratory depression). opioid act on the presynaptic receptor (Gi protein coupled receptors) and inhibit release of NT glutamate (no pain transmission). substance P (NK receptor agonist), Ach, NE, SE. It increases GABA (inhibitory NT) and dopamine (Euphoria). No more normal pain, body upregulate receptors (action in any CNS depressant rx unlike stimulants) for pain. then we need more opioid to control pain *insulins, glucagon, somatostatins are peptide hormones*. ref insulin release cellular events and GPCR classification in term 2

Mu receptors- *majority of CNS analgesia is mu1. beta - endorphin and morphine bind* to this receptor with high affinity. *mu 2* receptors mediate analgesia in *spinal cord.* also mediate *respiratory depression and depressed GI motility* (also N/V) Delta receptors -Involved in *both spinal and supraspinal analgesia. enkephalins* are endogenous agonists at these receptors. Morphine does not bind to these receptors Kappa receptors- *analgesic without respiratory depression*. kappa1 receptors are located in the spinal cord. kappa 2 are in the brain. *Dynorphins* A & B stimulate kappa receptors. Morphine interacts poorly with these receptors. the morphine derivative *butorphanol (STADOL NS for migraine tx) binds selectively to kappa 1 *receptors in the spinal cord Salvia divinorum "Sage of Seers" or Divine sage has Salvinorin A. Potent and selective kappa- opioid receptor agonist, have potential as a novel analgesic agent. Opioid receptor : a * Presynaptic GiPCR member* ( like NT- dopamine or noradrenalin, milirinone but has *inhibitory actions on glutamate/pain transmission* not nuclear receptors like steroids/hormones or tyrosin kinase (enzyme linked) receptors or ionotropic receptors). The opioid receptors are ~40% *identical to somatostatin* receptors. Opioids (peptide inhibitory neurotransmitter) act as a ligand. *Peptides neurotransmitters (based on the str) ex:* *somatostatin, substance P, opioid peptides.* cocaine and *amphetamine regulated transcript.* Opioid receptor subtypes and its coupling Mu & Delta receptors are coupled to *Gi* and the inhibition of adenylate cyclase & *decreased cAMP and Ca channel is closed presyanptically (decrease substance P)* They are also coupled to Go and a *K+ efflux* (pump/dump out of cell or open to go out of the nerve at muscle end plate reduce Ach) channel which leads to nerve cell *hyperpolarization (decrease excitability. muscle relaxation)* Kappa receptors are coupled to a Go that closes Ca 2+ channels If you have a *opiate receptor on the GABA an inhibitory interneuron, opiate block GABA release and no more inhibitory response thus turn on excitation pathway like dopa and serotonin.* You can also classify NT receptor based on the type of neurotransmitter attached to it. or based on the mode of action: ligand-gated receptors or *ionotropic receptors* and G protein-coupled receptors or metabotropic receptors. Ligand-gated receptors can be * quickly excited or inhibited by glutamate or GABA* NTs in interneurons. Conversely, *GPCR are neither excitatory nor inhibitory. Rather, they modulate the actions of excitatory and inhibitory NTs, slow action.* There are two principal *signal* transduction pathways involving the *GPCR*: adenylate cyclase and *cAMP signal pathway* (with high or low Ca based on inhibition or exicitation) with effector PKA or *Gαs/Gαi *and *PLC and the IP3* phosphatidylinositol signal pathway with effector PKC or *Gq coupled receptor*. When a ligand binds to the GPCR it causes a conformational change in the GPCR and activate an associated G-protein by exchanging its bound GDP for a GTP. The G-protein's α subunit, together with the bound GTP, can then dissociate from the β and γ subunits to further affect intracellular signaling proteins or target functional proteins directly depending on the α subunit type.

*Adjuvant for Neuropathic pain* - NMDA receptor blockers -mechanism, agents, dose and efficiency Corticosteroids as adjuvants- uses, ADR, dose ? (ref Asthma and COPD and end of this lecture) ref slide 19, 20 set 24 depression. Phenobarbital binds to GABA receptors. gabapentin block glutamate. ketamine is a hallucinogen like opioid, so called special K (kappa receptor) and like opioid CNS depression by blocking glutamate (NMDA) receptor, *antidepressant* by *increasing AMPA* and synaptogenesis. *used for tx of pain like opioids and anesthetic agent. *hallucinogens generally act on SE. ketamine cause serotonin syndrome like meperidine and TCA. felbamate is a glutamate *(AMPA) antagonist*. used in tx of seizure. Antitussive agent *dextromethorphan* (NMDA blocker) *dexmetomidine *(alpha 2 agonist like clonidine) but a anesthetic and anti agitation drug. add steroids- steroid pharmacology

Neurophysiology of NMDA receptor: inflammation causes nociceptor sensitization with spontaneous discharge & *ongoing pain. Glutamate is released by C-fiber nociceptors,* which binds with NMDA receptors in the spinal cord. This leads to central sensitization. NMDA-receptor *blockers *can suppress this central sensitization. NMDA-receptor activation also leads to decreased *opioid sensitivity*. Agents-* Dextromethorphan, Ketamine (Ketalar), Amantadine (Symmetrel), Memantine (Nemenda), d-Methadone* Dextromethorphan: positive study in post-surgical patients with bone malignancy; other results mixed. Usual dose = 45 - 60 mg/day, up to 1000 mg/day Ketamine (Ketalar, *special K)*: it is an *anesthetic* agent. several reports in treating cancer *pain (in combo with opoid).* Usual doses 0.1 - 0.15 mg/kg bolus iv/sc and/or continuous iv/sc infusion of 0.1 - 0.15 mg/kg/hr. *(Rapid antidepressant effects (~2 hours) → effects last a couple of weeks (once a month IV dose fine)* Corticosteroids are used in cancer pain syndromes for *Bone pain, Neuropathic pain* due to tumor infiltration or tumor compression *(antiinflamatory effect help),* Headache due to increased intracranial pressure, *Visceral pain, Anti-Nausea* Sxs of spinal cord compression (need higher dose) Typical doses: 2 - 4 mg to *100 mg/day dexamethasone* ADR- GI prophylaxis; esp. in combo with NSAID. *(IV hydrocortisone* is used in sepsis infection as an anti-inflammatory drug).

*monitoring, *prevention and tx of Opiate-Induced *Respiratory Depression?* MOA, PK, dose and use, monitoring of naloxone? signs and symptoms of opoiod withdral? what is the *Oncologic Emergencies* in a well controlled cancer pain and how dou you treat it? Bowel obstruction tx and adjuvent tx for cancer pts? ref slide 17 set addiction, slide 8, 20 of this set *hyaluronidase* increases the absorption rate of parenteral fluids given by hypodermoclysis or sq infusion and reduce swelling. these should be given slowly 1 mg/ml. and max 3 L in 24 hrs in 2 different sites. . NMDA receptor antagonists (ketamine, dextromethorphan), NMDA blocker is nemenda. (parasympathetic- ex vagus nerve also a cranial nerve) or *(sympatheic - ex.splanchnic nerves)* origins. • Splanchnic circulation from aeorta to gut* (except gut) *include hepatic artery, celiac artery (and artery to stomach, spleen, pancreas) and mesenteric artery *(intestinal* and pancrease Artery, ENS, meynthric plexus). celicac and mesentic vein join to form portal vein. portal vein and hepatic artery (thus the whole gut or splanchnic circulation) join to go back to venecava.

Opiate-Induced Respiratory Depression *not big problem unless rapid tritration.* (may need to reduce dose if excessive sedation) Slow, gradual titration, esp. if opioid naïve, since its *dose corresponds to resp. depression. But pain itself is a respitory stimulant,* so don't have to worry about sedation or respitory problem until pain is under control. *It help with breathing by relaxing respitory muslces* (it is a *vasodilator and reduce NE* so good in tx of angina, vasodilation, hypoxia is also by *release histamine, it cause itching and low BP, *bronchospasm in anaphylactic shock). opioids are *CNS depresants.* Rule out other causes, esp. if persists over 1 week.- Hypercalcemia, CNS meds, other meds, sepsis, dehydration, *hypoxia* *Use adjuvants/ NMDA antagonist/NSAIDs to reduce opioid use due to opioid sparing effect* *respitory stimulants* is rarely used. Caffeine, Methylphenidate, Dextroamphetamine, Modafanil, bupropion (dopamine agonist with amphitamine metabolite). Naloxone MOA: pure mu, kappa & sigma opioid receptor *antagonist* PK (after *IV* administration, oral BA is very low, in suboxone it help with IV abuse of buprenorphine): onset = 2min (quick); *duration - short, *20 - 60 min; t ½ = 60min. so may need multiple dosing, since it don't match with opioid peak (unlike naltrexone in heroin addiction tx) . Dosage *Acute overdosage* in adults: 0.4mg - 2mg IV, based on respiratory status & *risk for precipitating withdrawal (problem in opioid non naïve pt. so use partial reversal with Naltrexone* (ReVia & Vivitrol, alcohol and heroin addiction tx) . methadone is used to mask withdrawal effects/ craving and maintence in heroin addicts. some opioid antagonist are used for tx of constipation and some agonist like loperamide for tx of diarrhea) and *pain returns*. *Partial reversal for respiratory depression:* 0.1mg to 0.2mg IV, repeated q 2-3 minutes until desired response achieved. monitor for respiration and withdrawal at least 2 hrs after last dose of naloxone. s/s of withdrawal = *agitation, n/v (also in opioid use), diarrhea, diaphoresis, tachycardia, htn*, (no more low NE due to opiod antagonism) tremors, shivering, yawning, *seizures*, pain retuns. Oncologic Emergencies in a well controlled cancer pain with ibuprofen and MS-IR when reports *sudden onset of new pain* which is severe (10/10) best recommendation after increasing dose or adding adjuvents is to consult oncologist and *Add dexamethasone* to take care of the inflammation (IV hydrocortisone is used in sepsis). Bowel obstruction- bowel rest (if too much motility) or suction (if No motility is the cause), Anticholinergics (hyoscine, scopolamine)- for excessive salivation(N/V), glycopyrolate (Robinul IV anticholinergic to reduce saliva (sialorrhea) treat hyperhidrosis), octreotide (good for chemotherapy induced diarrhea, vasoconstrictor of splanchnic system used to improve perfusion to organ, stop bleeding, dont raise BP), corticosteroids

Terminology- Opium, Opiates, Opioids, Narcotics, cannabinoids, Cocacaine, heroin, crack, marijuana and its CNS effects and street names A hallucinogen is a psychoactive agent which can cause hallucinations, *perceptual* anomalies (alter the perception of reality), and other substantial subjective changes in thoughts, emotion, and consciousness. criteria for establishing that a drug is hallucinogenic are as follows: in proportion to other effects, changes in thought, perception, and mood should *predominate;* addictive craving should be *absent.* intellectual or memory impairment should be minimal; stupor, narcosis, or excessive stimulation should not be an integral effect; autonomic nervous system side effects should be minimal; cause effects by initially disrupting the interaction of nerve cells and the neurotransmitter *serotonin, (perceptual changes),* glutamate. Pharmacological classes of hallucinogens Psychedelics (drug with perception-altering effects ). ex. 5-HT2A receptor agonist (Tryptamine), *LSD* *Cannabinoids* (CB-1 receptor agonists with inhibitory action on NTs like opioids. dronabinol (marinol) can be used for tx of pain and N/V) Dissociatives (produce analgesia, amnesia and catalepsy at anesthetic doses). ex. NMDA receptor antagonists (has opioid sparing effect. *ketamine,* dextromethorphan), *κ-Opioid* receptor agonists Deliriants (cause extreme confusion and an inability to control one's actions like in agitation) ex. Anticholinergics (atropine, belladonna)

Opium is made from the latex of the opium poppy's (Papaver somniferum) unripe seed pods or capsule. Its active ingredients are a collection of plant alkaloids, mostly *morphine.* It's a *painkiller, sedative (not anxiolytic like BDZ* but both are addictive and CNS/respiratory depressant), and *respiratory depressant (morphine, also relax respiratory muscles so help with breath by pumping K out at nerve on muscle end plate to reduce Ach), CNS depresent*. used for relief of pain, insomnia, and *cough* (codine). Heroin is obtained by acetylation of Morphine and are called *Dope,* Brown Sugar. It is a *CNS and GIT depressant & slows down* (but cause N/V) the body functions. Opiates - drugs derived from morphine and thebain Opioids -natural and synthetic *agonists & antagonists of morphine & endogenous* opioid *peptides receptor *(don't mimic NT) Narcotics - now a *legal term for many abused drugs* (use Vs abuse) for its *psychoactive properties (change in perception)*. Hallucinogens are Narcotic without addiction and dependence. Narcotics from natural plants* opium, cocca (not codeine) and cannabis* are completely different since comes from different plants and contain different drugs with different effects. Natural cannabinoids are obtained from inflorescences of the plant Cannabis sativa (hemp) used to produce *marijuana (weed),* hashish/hash, charas & ganja. Its active ingredient is *tetrahydrocannabinol* (THC), which has a variety of effects, some stimulant, some *CNS depressant,* and some *hallucinogenic/change in perception. * Dronabinol (Marinol) is a CB agonist with inhibitory NT (like oipiods) . help with N/V, pain, anorexia Cocacaine or *crack* is an Alkaloid obtained from the coca plant. It interferes with the transport of the neuro-transmitter *dopamine.* (dope is Heroin from opium). It has a potent *CNS stimulant*, producing a sense of *Euphoria,* excitement & increase in energy. Excessive dosage of cocaine can cause *hallucinations.* used as a local anesthetic.

Opium alkaloids ex, Pharmacologic classification- chemical and agonist action

Opium poppy juice Contains at least 20 distinct alkaloids but major is *Morphine (10%) addictive with analgesic effects.* Later on *Codeine (0.5%)* (cough supressant), a methylated morphine is isolated from opium (analgesic). It has to be demthylated at liver to be active and release morphine. Other alkaloids are *Thebaine *(0.2%), Has little analgesic effect itself but is an important precursor of many opiate drugs. *Papaverine (1.0%) a smooth muscle relaxant through GABA (help with breath, watch for respiratory depression. also reduce catecholamines like clonidine).* Later on Heroin (acetylated morphine) are isolated from opium (*highly addictive/euphoric by increase dopamine)*. *Strong agonist* Phenanthrenes- *Morphine* (low potency ie need high dose), Hydromorphone, Oxymorphone Phenylheptylamines- *Methadone* (used in addiction in withdrawal and maintenance phase) Phenylpiperidines- *Fentanyl* (very potent),* Meperidine* *Mild to moderate agonist* Phenanthrenes- *Codeine, Oxycodone,* Hydrocodone Phenylheptylamines- Propoxyphene Phenylpiperidines- *Diphenoxylate (lomotil* in combi with atropine. meperidine str), *Loperamide (Imodium OTC, antidiarrheal*, low NE action, especially during heroin withdrawal period) Opioids with *Mixed agonist/antagonist* Actions Phenanthrenes- Nalbuphine, *Buprenophrine* (used in addiction in acute withdrawal phase) Morphinans- *Butorphanol (Stadolol NS for migraine*) Benzomorphans- Pentazocine opioid antagonist *Naloxone (Narcan*. pure antagonist. tx *overdose*), *Naltrexone (Vivitrol, revia. Partial antagonist.* used in *alcohol/opioid addiction* or post acute withdrawal phase as a *final step* after pt is weaned off of methadone or buprenophrine), Apomorphine, Nalmefene Peripheral Opioid receptor antagonists - *methylnatrexone (Relistor), alvimopan (Entereg) for tx of opioid-induced constipation* • Natural opiates (least potent): morphine, codeine, and thebaine, but not papaverine • Semi-synthetic opioids: hydromorphone, hydrocodone, oxycodone, oxymorphone, ethylmorphine and buprenorphine; • Fully *synthetic opioids (highly potent)*: fentanyl, pethidine, levorphanol, methadone, • *tramadol* (demerol is meperidine) and tapentadol are chemically* not of the opioid class, but do have agonist actions at the μ-opioid receptor.*

Determine the most appropriate opiate *dosage form to use* for a given patient case. or What alternative routes of administration are available for opioid delivery & what are the benefits & drawbacks of each? Why change from one dosage form to another? How do we Choosing the *Appropriate Route of Administration*? [these should be given slowly 1 ml/min. Rates from 40ml/hr if continuous infusion, (up to 125 mL/hour), 500ml/ hour if given bolus at a single site. and max 3 litters in 24 hrs in 2 different sites (at least 2 inch apart)].

Oral - preferred whenever possible Nasogastric/*PEG tube* - liquid dosage forms or* IR tab grind up ex, methadone* when used for maintenance tx. Parenteral- IV* (bolus or infusion)*, IM, *SC (hypodermoclysis*- for continuous hypodermal inj at home rather than IV. Site need to be *changed every 72 hrs.)* ref insulin delivery in set terms and values Transdermal - fentanyl (highly potetent and long acting. So it takes *12 hrs to start action.* There is still *depo rx in the skin*, even if you peal off. Fever and occlusion increase rate of absorption. *No subQ fat may not work well)* Rectal - ex. morphine (PO can be placed rectally for good absorption, but not convenient), hydromorphone *Buccal/sublingual - concentrated solutions*

Adjuvants for* bone pain*- IV bisphosphonates, calcitonin-agents, use, dose and ADR? hyperparathyroidism increase Ca in the blood ie, squeeze Ca out form the bone, thyroid hormone (calcitonin), decrease Ca in the blood by depositing into bone. CALCITROL - active vitamin D produced in kindney to increase Ca when its level are low. *Procalcitonin* may be used to guide LOT in sepsis infections- a biomarker that increases in response to endotoxins and inflammatory cytokines released during systemic bacterial infections. Butorphanol (Stadol) NS is used for migraine tx. in bone cancer, cancer cells sent some signals to the ocsteoclast to accelerate chewing of bone/resorb and thus imbalance with osteoblast action. and cancer cells attach them self to the space of the bone and proliferate. then increase osteolytis or osteoblast formation.

Pamidronate (Aredia) - *Analgesic *effects in metastatic breast cancer & multiple myeloma and *prevent bone fracture, by increasing mineralization, inhibit osteoclast (chew bones)*. rx binds to the mineralized portion of the bone, during osteoporosis when osteoclast eat rx, it die/apoptosis of osteoclast despite the increase in osteoclast no. by cancer. in normal patients rx will increase mineral density for 3-5 years. when osteoblast painting/building of the dirty surface of bone certain part of the *bone can break *due the inherent structure weakness or imbalance in osteoclast. so need to take a *drug holiday.* Usual dose 60-90 mg iv q 3-4 weeks Zoledronic acid (Zometa)- Analgesic effects & reduction of skeletal events shown in several tumor types, including breast, prostate, myeloma, lung Usual dose 4 mg iv over at least 15 minutes *q 3-4 weeks* Pamidronate, Zoledronic acid ADR: *hypocalcemia in blood (deposite in bone), inj site reactions, osteonecrosis, renal toxicity* calcitonin- Palliation of *bone pain* from skeletal metastases. calcitonin is a *thyroid hormone* regulating calcium level Nasal: 1 spray (200 IU) in nostril q day; *alternate nostrils daily* ADR- minimal; nausea, *hypocalcemia*-

2 different pain pathways and structures are involved in the pain pathway? define modulation, transduction, transformation and transmission of pain signals? explain *ascending (afferent) pain pathway* or pain *perception * process or 4 elements of The pain process? {The brainstem is the region of the brain that connects the cerebrum with the spinal cord. It consists of the midbrain, medulla oblongata, and the pons.} ref slide 12,13,19 of this set. pain pathway, chemical stimuli in set terms, pain and temperature pathway is ventero (anterio) lateral pathway. AP is transmitted via electrochemical method. chemical (NT) for pain signal transmission is glutamate.) gray matter of the spinal spinal cord has a dorsal horn or a posterior horn, ventral horn or anterior horn, and lateral horn. all sensory stimuli that goes to CNS, enter in to the dorsal route of the spinal cord and all motor stimuli that goes out to the effect tissue exit through ventral route. *Tract* is a bundle of axon/white matter connecting *brain and spinal cord* going up or down. can be *ascending or descending tracts*. *ascending tracts*- start from the sensory receptor up to CNS. a. antrerio lateral pathway (lateral *spinothalmaic tract for pain and temp, *antero spinothalmaic tract for crude touch and spinotechtal tract for visusal sensation in the midbrain). b. dorsal column pathway (for fine touch, locomotor stimuli) c. spinocerebellar tract pathway 3minor ascending tracts are spinotectal tract (visual stimuli), spino olive tract to the cerebellum from the medulla (for touch and pressure), *spino reticular tract (dull pain)* *analgesia* can be caused by a. desending inhibitory pathway for pain is called *cortico spinal pathway* or dorsolateral pain pathway b. massage on the periphery and gate theory Gate theory says that, pain pathway can be modified by other overstimulation pathways like a massage on the skin. glutamate is released at the pain path ways. other neuronal pathways when stimulated can produce collateral *connector neurons (interneurons)* whcih can sent a *inhibitory NTs* to the 2nd order neurons in the spinal cord of the pain pathway and can modulate the pain or reduce pain. *cortico spinal pathway or dorsolateral painpathway efferent* pain pathway has some analgesia pathway from cortex to the brain stem to the dorsolateral spinal cord (cell body of the 2nd neurons) releasing *endorphins* to relieve pain. these pathway start from peri-venticular gray mater or PAG (mid brain) or raphe nucleus of the medulla. serotonin (TCA), NE (TCA) and GABA (use gabapentin) are also affected in this pathway. dronabinol (cannabis dt for pain, anorexia and N/V) NK1 antagonist (substance P antagonist) is for N/V tx. dexamethasone for N/V and cancer pain. ketamine is opioid sparing agent NMDA antagonist. NSAID also opiod sparing agent. addiction start in *VTA* releasing dopamine.

The *ascending pain pathway* transmits sensory pain signals from the periphery to the *spinal cord, *brain stem, *thalamus, cerebral cortex* and other regions of the brain The *descending pain pathway* conveys pain *modulating* signals to the periphery/*effectors*. Modulation: neural activity controls transmission of pain signal/AP by *either inhibiting or enhancing* • Peripheral *nociceptors* are activated by painful *stimuli*. Signal transduction: A basic process in molecular cell biology involving the conversion of a signal from outside the cell to a functional change within the cell. • Signal/AP is transmitted to *dorsal horn of spinal cord* (all sensory signals of afferent pathway ie, ventero (anterio) lateral pathway and dorsal pathway) via 1st order neuron, A-delta and C fiber. • Then interpretation/perception of pain in CNS pain centers in *brain stem (reticular fibers, PAG) and cerebral cortex.* 1. Transduction: *Pain receptors* (nociceptors, *one target of analgesic rx ex. local anesthetics*. 1st order neurons originate here) is a sensory nerve ending in peripheral tissues and are simple mechanoreceptors usually with high thresholds. And it recognize stimuli of tissue damage or pain and modify membrane potential. *Conversion of membrane potentials to action potentials is called transformation* (at the nociceptors). Inflamatory autocoids such as* 5HT, histamine, bradykinin,* etc from the chemical (dull pain) stimuli can sensitize nociceptors to pain stimuli. *PGs, substance P* (released as a response to pain) are pain modulators to reduce AP threshold (modulate pain by enhance pain). 2. Transmission: pain stimulus is transmitted via two types of *1st order* sensory neurons, sensory *nerve fibres: A-δ* nerve fibres* (fast *pain, surrounded by thin layer of myelin) and *C nerve fibres (slower pain*, non-myelinated, for *chronic pain).* The first order neuron enters the dorsal horn of the spinal cord where it transmits the pain signal to a second order neuron utilizing the NT, substance P (It is a neuropeptide, acting as a NT and as a neuromodulator) and glutamate. These *second order *neurons *cross* the midline of the *spinal cord* or goes through *spinothalamic tract (lateral)* and synapses with a *third order neuron in the thalamus* which then carries the pain signal to higher brain areas. Cells of the *dorsal horn of the spinal cord or nucleus of the 2nd order neuron are first processing* level for pain stimuli *(one target of analgesic rx).* Here, direct activation of *motor neurons* can result in restrictive and thus protective movement (reflex). 3. Modulation: neural activity controls transmission of pain signal/AP by *either inhibiting or enhancing it. Peripheral modulation* of pain occurs at the nociceptor level. *Central modulation* can either facilitate or inhibit pain as well. 4. Pain perception: perception of the pain stimulus is processed in the Specific areas within the brain stem (the periaqueductal gray *(PAG) region of midbrain- lots of opioid receptors to desensitize the pain)* and interpret the pain. somatosensory region of the *cerebral cortex*, is also involves in the interpretation activity. *The thalamus (with nucleus of 3rd order neuron) acts as a relay station:* dissemination of the signals to the cerebral cortex.* limbic cortex* is a regulation centre of the pain threshold and of *emotional reaction.* Some ascending fibres reach the *hypothalamus where endocrine response* is triggered (e.g.,* endorphin* release from the pituitary gland for pain desensitization).