Opioids Flashcards
Opiate
drug derived from opium, mixture of compounds from poppy, Papaver somniferum
Opioid
drug not derived from opium but interactions with opioid R
o Prototypical analgesics, antitussives, antidiarrheal drug class
Opioid R system/opiod R effects identified in:
ascarids, scallops, fish, reptiles, birds, mammals
Variants of MOR
o Alternative splicing may produce differences in structure, function of R despite R produced from same gene
o Single nucleotide polymorphism identified in dogs may also increase diversity in R structure, function –> altered drug effects
SNP identified with high prevalence in dogs experienced dysphoria with opioid admin
Different sensitivities to opioids may be due in part to individual differences in types of MOR subtypes
Nociception/ orphanin FQ receptor
Often called N/OFQ [NOP] receptor
Significant homology to other ORs
Naloxone hydrochloride does not have significant antagonistic action at R
* N/OFQ[NOP] R investigated, but details of interactions of endogenous ligand with R not well described
Antagonists of N/OFQ [NOP] produce analgesia
* May be target for future development of analgesics, analgesic adjuncts
MOR endogenous ligand
Beta-Endorphin
DOR endogenous ligand
Dynorphin A
KOR Endogenous Ligands
leucine, methionine-enkephalin
Full Agonist
dose-dependent increase in effect until maximal stimulation of R achieved
Y axis of dose response curve
Partial Agonist
dose-dependent increase in effect, plateaus at maximum effect less than maximum effect of full agonist
Can act as antagonist by partially reversing effects of full agonist
May be preferred over full antagonist if some analgesia needed
Antagonist
binds to R with high affinity, produces no effect, inhibits binding of agonists (both endogenous, exogenous) DT greater R affinity of antagonist
Also displaces previously bound agonists
Most opioid R antagonists considered competitive
* Lack of intrinsic activity, ability of agonists to overcome effect to produce maximal effect
* Shifts dose-response curve right
Potency
How much drug required for 50% Emax? (x axis on dose response curve)
Response = analgesia measured as change in latency of withdrawal or increased threshold to noxious stimulus
Fentanyl > morphine: dose of fentanyl (0.01mg/kg) needed to produce equivalent analgesia response to morphine (1mg/kg) is lower
Location of OR in Higher Centers
o Brain, brainstem: neurons, microglia, astrocytes
Periaqueductal grey
Locus coeruleus
Rostral ventral medulla
CRTZ/vomiting center
Location of OR in SC
o SC: lamina II of DH (substania gelatinosa); Adelta, C fibers synapse with projection neurons
Neurons, microglia
Conflicting evidence about astrocytes
Other Sites of ORs
o GIT
o Synovium
o UT
o Leukocytes
Immune cells can actually synthesize opioid peptides
o Uterus
o Periphery: neuronal, non-neuronal cells immune cells, periphery sensory neurons (A and C fibers)
o Others
Opioid R MOA
GPCR via Gi/o
Inhibition of AC
Decreased formation of cAMP
Inhibition of Ca2+ channels in presynaptic neurons resulting in decreased release of excitatory neurotransmitters (glutamate and substance P)
Enhanced outflow of K from postsynaptic neurons - increased activation thresholds, hyper polarization of nociceptive neurons/nociceptors
Functions Mediated by MOR
-Analgesia (+KOR, DOR)
-Antidiuresis
-Decreased biliary secretions, GI motility (+KOR), GI secretions (+KOR)
-Decreased urine voiding reflex
-Emesis/antiemesis (drug specific)
-Euphoria
-Immunomodulation (+DOR)
-Increased appetite (+KOR, DOR)
-Decreased uterine contraction
-Miosis/mydriasis (species specific) (+KOR)
-Resp Depresson
-Sedation (+KOR)
Functions Mediated by KOR
–Analgesia (+MOR, DOR)
–Decreased GI motility, GI secretions (+MOR)
–Diuresis via inhibition of ADH release
–Increased appetite (+DOR, MOR)
–Miosis, mydriasis (species specific) (+MOR)
–Sedation (+MOR)
Functions Mediated by DOR
–Analgesia (+MOR, KOR)
–Immunomodulation (+MOR)
–Increased appetite (MOR, KOR)
Absorption of Opioids
Lipophilic Compounds - typically well absorbed SC, IM; rapid absorption
Unless SR formulas used, prolonged effect vs IV not typically expected from IM or SC admin
Oral Absorption
PO: usually substantial first-pass metabolism so low PO bioavailability, may be ineffective when admin PO at standard doses
Exception: drugs that can produce active metabolites, eg codeine in humans
First Pass Metabolism
Drugs absorbed from GIT, usually following PO admin
Drugs pass through mucosa –> intestinal metabolizing enzymes (both Phase I metabolic reactions, Phase II conjugation reactions) biotransformation drug before enters intestinal capillary system
If enters intestinal capillaries intact, enters portal vein/liver site of metabolism
Any drug that makes it through the liver intact can enter systemic circulation, be distributed to elicit effect
* Despite large fraction of opioid absorbed, relatively small amt enters systemic circulation in active form where interactions with R elicit effect
Benefit of Transdermal Administration
–Bypasses first-pass metabolism
–Stratum corneum presents substantial barrier to drug absorption for some drugs
–Ex: Zobrium for cats, fentanyl patches/transdermal solution dogs
Transmucosal Opioids
bypasses first-pass metabolism
Mucosa: thinner, more vascular than stratum corneum –> less of a barrier
Buprenorphine = lipophilic, only effective if not swallowed
* Viable route of admin in cats but still somewhat variable due to conditions (eg pH) that can alter chemical properties
Absorption of TM buprenorphine in dogs small: may not be practical route of delivery DT volume, cost limitations
Distribution of Opioids
- Lipophilic compounds –> diffuse throughout body, easily cross blood-brain barrier
-Large Vd
-Primary effect site = CNS for analgesia, antitussive effects, sedation
-Drug must penetrate CNS (ie cross BBB) for effects
Role of P-glycoprotein efflux pump
-Active transporter
-Efflux absorbed drug from CNS back to vasculature, causes limitation of central effects
Loperamide
Absorbed, rapidly in the brain, but pumped back out as a result of P-glycoprotein efflux pumps, most effects non central now (Anti-diarrheal)
MDR1
- Deficient in functional P-glycoprotein efflux pump
- Significant central effects following loperamide administration including heavy sedation –> reversible by naloxone
- In people, rodents: morph, methad, fenta, bup, oxycod have substrate for P-glycoprotein
- When using known MDR1 substrates in heterozygote/homozygote MDR1 gene mutation carriers, increased duration/intensity of effect may be recognized
Regional Blood Flow of Tissues, Organs and Opioid Uptake
- Tissues receive greatest blood flow per tissue mass, equilibrium, btw plasma concentrations and tissue concentrations occurs most rapidly
o Assuming drug = lipophilic, rapidly crosses tissue barriers
IV bolus admin results in highest plasma concentrations at end of bolus dose –> plasma concentrations decrease over time DT drug metabolism, excretion, movement of drug from plasma into tissues (redistribution into SkM, adipose tissue)
Why is redistribution important?
Loss of effect DT drug movement out of CNS more rapidly than that predicted by elimination half life
May play greater role than metabolism in termination of CNS effect for some anesthetic vs analgesia drugs
Lipophilicity: morphine vs fentanyl
–Morphine: less lipid soluble vs fentanyl
–Slow distribution into, out of CNS –> beneficial for epidural admin where have longer duration at spinal OR
Metabolism
extensive metabolism in mammalian species
o Phase I +/- Phase II metabolism depending on specific drugs, species
Most species metabolize morphine by Phase II glucuronide conjugation to morphine-3-glucoronide
* Hepatic 60%, renal 40%
* Approx 10% metabolized to morphine-6-glucoronide, which is more potent than morphine
Opioid Metabolism in Cats
relatively deficient in glucuronide action, eliminate via sulfate conjugation
Remifentanil metabolism
hydrolyzed by plasma esterases, independent of hepatic metabolism
Virtually no context sensitive half life
Morphine Metabolism
-Most species: hepatic metabolism - phase II glucuronide conjugation to morphine-3-glucoronide (M3G)
-Hepatic 60%, renal 40%
-10% metabolized to M6G - more potent than morphine
Cats and Morphine Metabolism
relatively deficient in glucuronide action, eliminate via sulfate conjugation
Opioid Metabolites
generally less potent or complete loss of activity vs parent drug
Morphine glucuronide listed as active metabolite but must be given intracerebroventricular to elicit effect
Not lipophilic so cannot penetrate CNS on own
Chloramphenicol..?
significantly decrease metabolism of methadone in dogs
Elimination of Opioids
o Typically metabolized prior to elimination in mammals
o +/- excretion of parent drug in urine, feces
o Opioid metabolites usually more water soluble, often eliminated in urine –> can be eliminated in feces by biliary secretion as well
Tolerance
loss of in vivo potency over time, shift of dose-response curve right
Higher doses of opioids may be needed IOT achieve similar effect
Not as well recognized in vet med vs human med
Know that tolerance, withdrawal observed in animals
Drug Dependence in Dogs
dogs administered MOR agonists for >7d could display signs of opioid withdrawal if given drug can reverse MO effects eg partial MOR agonist, MOR antagonist/KOR agonist, MOR antagonist
Effect of Pain on Opioid Response
o Presence of pain may blunt some of undesired effects
Ex: vomiting, dysphoria less common in painful dogs following morphine admin
Ex: sedation/euphoria observed in painful cats following morphine, dysphoria rarely observed
General MOA
decrease release of excitatory NT, hypopolarize nociceptors –> decreased transmission within SC
Supraspinal Analgesia
–Mediated by PAG
–Binding of opioid agonists to R within PAG results in inhibition of GABA interneurons leading to activation of medullary pathways that selectively inhibit dorsal horn nociceptive neurons
Spinal Analgesia
mediated by inhibition of presynaptic NT release, postsynaptic hyperpolarization of neuronal membranes –> decreased excitability
Bulbospinal Pathways
Results in release of NE, serotonin in DH of SC
Peripheral Analgesia (eg IA admin)
localized peripheral opioid R
o Reversible by naloxone
o Peripheral opioid R activated, upregulated by trauma/inflammation
o Can be targeted by local admin of opioids to produce analgesic effect
o IA opioids reduce nerve terminal excitability of primary afferents with enhanced spontaneous activity
Analgesic Effects of Systemic Opioids
more effective at decreasing pain transmitted by C-fibers than A-delta fibers
o Reason why analgesic doses of opioids alone may not produce effective analgesia for surgical stimulation
Higher IV doses, epidural administration (saturate spinal opioid R at site of administration) result in effects on both C fiber and A-delta fiber nociceptors
Epidural Opioids
will not prevent transmission of all tactile and nociceptive input (this can be done with local) blunted, not blocked
Sedation, Excitation Assoc with Opioids
–Cat, horse: more likely to experience excitation than other species
–Breed can also influence response eg Huskies, vocalizing
–Rapid IV administration produces high concentrations initially, even at clinically appropriate doses –> can produce transient excitement in any species
Cats vs Dogs
Smaller volume of distribution of opioids
Opioid Induced Neuroexcitation in horses
o 0.6-0.66mg/kg IV (2.5x recommended dose) = excitement
o Increased locomotor activity = another manifestation of opioid-induced neuroexcitation in horses
Pacing, weaving patterns in horses admin opioids
Agonists-antagonists also produce increased locomotor activity, often accompanied by ataxia
Possible MOA of Increased Locomotor Activity
increased dopamine activity
* Drugs that decrease dopamine release show some efficacy at reducing step counts
* Admin of specific DA1, DA2 R antag not successful in reducing activity
Opioid Induced Resp Depression
increased PaCO2, primarily mediated by MOR
Impt to distinguish btw drop in resp rate (bpm) vs true respiratory depression (decreased alveolar minute ventilation)
RR can be depressed but not result in depression if VT increases to maintain alveolar minute ventilation
Less of risk vs humans
Wooden Chest Syndrome
Increased chest wall rigidity reported in human pediatric and adult patients admin large doses of mu agonists
Not common in veterinary medicine, anecdotally reported in dogs
MOA Wooden Chest Syndrome
Experimentally, supratherapeutic doses of fentanyl (20-60mcg/kg IV) decrease inspiratory and increase/prolong expiratory neuron activity (tonic discharges) –> increased excitatory drive to IC neurons and abdominal motor neurons that control chest wall compliance
* Increase in IC, abdominal m tension –>increase in chest wall rigidity, decreased chest wall compliance
* Similar effects produced on pharyngeal constrictor, motor neurons –> tonic vocal fold closure, pharyngeal obstruction of airflow –> increases airflow resistance, resting abdominal wall tension
Placental/Fetal Effects
–Readily cross placenta
–Can depress fetus
Antitussive Effects
–Direct effect at cough center in medulla oblongata by actions at both MOR, KOR
–Independent of resp effects
–VAA paper: dose of fentanyl just as efficacious as suppressing cough for ETT as IV lidocaine
CV Effects
–Bradycardia in dogs: centrally mediated enhanced PSNS activity in neurons innervating heart
–CO usually maintained by increases stroke volume, typically results in beneficial or protective effect on heart DT less work and oxygen consumption
–Awake horses, cats: no change or HR increases IRT to opioids
–Under GA: decreased in cats, no change in horses
Histamine Release with Morphine
Circulating histamine levels can increase 800-fold following 3mg/kg morphine IV
Mast cell degranulation, histamine release with associated hemodynamic and anaphylactic responses (hypotension, tachycardia, bronchospasm) dependent on opioid administered, dose, ROA
* Rapid IV injection being most provocative method for triggering histamine release
Clinically relevant doses of morphine (<0.5mg/kg IV) in healthy dogs usually produce no detrimental effect on MAP IV SLOWLY
Caution or avoid in dogs with MCT
Emetic Effects
o Produce emetic or antiemetic effects depending on opioid, dose, ROA
o Emetic effects
Stimulation of dopamine R in CRTZ
Mediated by DOR effects –> MOR, KOR appear to be anti-emetic
Maropitant and vomiting
o Maropitant (NK1 R antagonist) admin 1h prior to opioid admin can reduce incidence of emesis, retching, CS of nausea in dogs by preventing binding of substance P to NK1 R in emetic center of brain
ACP and vomiting
Prior admin ACP significantly reduces likelihood of opioid-induced emesis in dogs
More Lipid Soluble Opioids and Vomiting
Fentanyl, butorphanol, methadone: tend to produce more prominent antiemetic effect DT faster penetration into CNS and inhibition of emetic center
IV: inhibitory effects first
IM: stimulatory effects first, then inhibitory
Low vs High Doses Morphine and Vomiting
o Low doses of morphine tend to produce emetic effect through stimulation of dopamine R in CRTZ
Higher doses: antiemetic effect (subsequent antiemetic effect = stronger)
Pupil Constriction MOA
increased outflow in parasympathetic neurons leaving Edinger-Westphal nucleus
Parasympathetic neurons innervate sphincter pupillae (constrictor) m, leading to ctx of iris
Species that Experience Pupil Constriction
o Dogs, rabbits, rats
Species that experience pupil dilation
Cats, horses, ruminants
MOA Pupil Dilation
Mechanism incompletely understood
Peripheral component: sympathetically mediated response generated by release of catecholamines from adrenal glands acting on pupil
Central component: possibly at Edinger-Westphal nucleus
Normal Control of GI Motility
myenteric plexus, dependent upon NT released from enteric neurons
o Major NTs: ACh, serotonin (5-HT), vasoactive intestinal peptide, nitric oxide (NO)
ACh activates cholinergic excitatory motor neurons
NO, VIP control non-cholinergic inhibitory motor neurons
Balance btw ACh and NO plus VIP release coordinates contractile, propulsive gut motility
Role of Opioids with GI Motility
inhibit release of motility-modifying NTs –> impair coordination of motility, inhibition of colonic motility (morphine), jejunal motility (butorphanol)
o Peripheral effect DT MOR, central DT MOR, KOR
o Primary effects on GIT, thought to be mediated by release of ACh, substance P
Decreased propulsive ctx
Increased non-propulsive ctx (enhancing fluid absorption)
Decreased GI fluid secretions
Net effect = constipating or antidiarrheal effect depending on condition of GIT
Effect of Opioids on Stomach Antrum, Duodenum Tone
Increases tone - can be more difficult to pass endoscope
MOR Effect on Bile Duct
dose dependent
Increased bile duct tone, increased bile duct sphincter tone observed with low doses and decreased tone at high doses
Sphincter of Oddi spasm, increased GB pressure documented SE of MOR agonists
Morphine GI Effects in Horses
Correlation of reduced GIT motility, lower fecal production, increased incidence of colic leads to conservative use of opioids in horses
* Other studies failed to identify increased risk for colic following opioid admin –> differences in opioid admin duration, concurrent medications play contributing role
GI inhibitory effects more profound when opioids combined with a2s
SE: ileus, constipation, obstruction
Effect of methylnaltrexone administered to horses
partially prevented adverse GI effects while preserving central analgesic effects
Urinary Effects via spinal, epidural route
May cause urinary retention to varying degree DT spinal OR-mediated decrease in detrusor m contraction, increased tone of urinary sphincters, inhibition of micturition
Morphine: longer duration of urine retention DT longer residence time in the epidural or SAS allowing for continued spinal inhibition of micturition
Incidence of urine retention following epidural admin of opioids in dogs: 0-44% for epidural, 5-8% intrathecal; cats 9% in epidural bup+morp
Reversible with naloxone
Urine Production
KOR agonists enhance urine production: diuretic response DT decreased release AVP
Exact MOA of MOR decrease in urine production unknown
Thermoregulation
directly interact with neurons in preoptic anterior hypothalamus to alter thermoregulatory set point, compensatory responses
Resets - pants bc think hotter than are
Generally temps in dogs decrease - hypothermia assoc with prolonged recovery
Hyperthermia
Cats: up to 41.6C/107F hydro, morph, buprenorphine, torb for up to 5h after extubation
Ax with sx may increase magnitude of hyperthermic response
Ideally monitor body temp in cats for at least 5h following end of ax
Other Species that Become Hyperthermic with Opioids
cats, horses, swine, goats, cattle
Hyperthermia in zoo, wildlife species
–Potent Opioids
– Partially DT effect on preoptic anterior hypothalamus to change thermoregulatory set point as in domestic species
Predominantly DT stress response generated by capture
Much higher doses of opioids used –> possible dose-dependent effect
Immunomodulatory Effects: Morphine
natural killer cell activity, IFM cytokines, mitogen-induced lymphocyte proliferation through supraspinal mechanisms
Immunomodulatory Effects of fent, Remi, tramadol:
protective effects on natural killer cell function, can increase function at some doses
Pain and Immune System Function
o Pain produces immunosuppressant effects, withholding opioids worsens immune system function in painful p
o Opioids assoc w both immunostimulatory, immunosuppressive effects
–Cats: admin of morphine delayed effects of experimentally induced FIB
–Humans: immunosuppressive effects observed, unclear whether applies to vet med
MAC Sparing Effect - dogs
Full MOR agonists dose-dependent MAC reduction in dogs, ceiling effect observed
o Ax-sparing effects generally accomplished with single IV doses of longer acting opioids or CRIs of short-acting opioids
Non-IV routes (epidural) also produce ax-sparing effects
MAC Sparing Effects - Cats
Minimal with opioids
comparatively less inhalant ax-sparing effects compared to dog
One study: no ax-sparing effect in cats admin remifent infusions up to 75x analgesic effective dose concentration (EC50)
Horses and MAC Sparing Effects of Opioids
Morphine INCREASES MAC at higher doses
MAC Sparing Effects - other LA (goats, cows, sheep, pigs)
more MAC-sparing effects than horses, cats; less than dogs
MAC Sparing Effects in Rodents
dose-dependent inhalant-sparing effects in rodents
Partial agonists: equal sparing to full agonists
Birds
Forebrain opioid R distribution in avian species likely differs most from mammals
Full MOR, mixed ag-antag: similar MAC reduction in multiple avian species - effect of KOR???
Inhalant-sparing effects of tramadol appear to be result of action at opioid R vs effects on serotonin, NE reuptake inhibition or alpha-adrenergic R
Morphine
MOR agonist with KOR effects at higher doses
Mild to severe pain, increasing doses producing increasing analgesic effects
Widely used DT safety, efficacy, tolerability, cost-effectiveness
o Less lipophilic
Octanal/water partition coefficient of 1.2
Ideal opioid analgesic for epidural injection - provides sustained analgesia for 24hrs
Morphine Administration
-Slow onset (5-15’), max effect at 30-45’ with HL 1hr
-PO, rectal poorly absorbed
-Near complete absorption via IM, SC ROA
-Also IA
Metabolism of Morphine in Dogs
Primarily metabolized to morphine-3-glucuronide in dogs not active metabolite
* Very low concentrations of active metabolite morphine-6-glucuronide formed
* No accumulation after 7d of infusion
50% hepatic metabolism, 50% extrahepatic vs near complete hepatic metabolism of other opioids –> acceptable in p with hepatic dysfunction, dose adjustments needed
Morphine - Patient Populations
-Avoid with head trauma: increased ICP with vomiting
-MCT - histamine release
-Can be admin to neonates as young as 2d old with minimal resp depression (more sensitive than adults
Cats and Morphine
Effective analgesic, well-tolerated
CNS excitation at high doses: 5-20mg/kg
Clinically useful doses: 0.1-0.25mg/kg, though 2-3mg/kg well-tolerated
Unwanted behaviors similar to those in dogs
* Also: purring, kneading, rubbing, euphoria, mydriasis, marked affection
Cats, Metabolism of Morphine
Metabolism: rapid sulfate conjugation
Terminal half-life ~1hr (similar to dogs)
Volume of distribution smaller for cats, why clinically recommended doses lower for cats than dogs
Morphine in Horses
IA morphine: analgesia, anti-inflammatory effects in experimentally induced LPS synovitis models for up to 24hrs – 0.05mg/kg
Well tolerated
Higher doses: excitation, other effects
Oxymorphone
o Synthetic opioid, full MOR agonist
o 10-15x more potent than morphine
o Effects similar to morphine, less nausea/vomiting when admin at equianalgesic doses, does not commonly produce histamine release when admin IV
o Duration of effect ~morphine
Absorption, Metabolism, Excretion of Oxymorphone
o Routes: IM, CRI, SQ, IV
o PO bioavailability poor
Metabolism: conjugate formation
Dogs: small amount excreted as other metabolites, intact drug
Similar effects to morphine in horses
Expensive, not currently available
Hydromorphone
–Full MOR agonist: effects very similar to morphine at equianalgesic doses
o 8x potent than morphine, duration similar to morphine
o Minimal histamine release IV in dogs
o May be more likely to cause postoperative hyperthermia in cats vs other opioids
Hyperthermia also noted following morph, bup, butor
o Cats: SQ = slow absorption, long lag time
IM, IV > SQ
o Routes: IV, IM, SC, CRI
Not effective orally DT poor bioavailability
Fentanyl
o Full MOR agonist
o 100x more potent than morphine
o Short DOA IV, IM, SC
–30min to2hr depending on ROA
o Less nausea, vomiting –> predominantly antiemetic effect
If admin results in ileus, nausea/vomiting may occur
o PK IV, SC reported: can admin as IV bolus, IV infusion, SC, IM
Poor bioavail PO: not effective
o Mild pain on SC admin, if mixed with 8.4% sodium bicarbonate (1mL Nabicarb:20mL fentanyl) eliminates pain on inject
o Use by routes other than IV usually limited by lrg volume of inj needed for all but smallest p
Fentanyl and context sensitive half life
Dramatically increases after 2-3 hours
Transdermal Fentanyl Solution
–Approved for Use in Dogs Only
–Effective if applied 4h prior to sx with DOE of at least 4d after admin in postop orthopedic p
–Significant variability in absorption, DOE –> monitor for analgesia, SE
–Effects reversed by naloxone, single admin can improve p responsiveness
–Dose: 2.7mg/kg once
Risk Minimization/Action Plan (RiskMAP) for TFS
developed for TFS
* Educational training for vets, staff, clients required prior to use
* Safety precautions for admin: gloves, protective glasses, lab coat to minimize exposure
* Restrain dogs for 2min after application, warm patch with gloved hands over p, site should not be disturbed for 5min
* Advise clients: no contact with site for 72h, isolate from children for 72h
* Absorption not the same in cats, product not approved for use in cats
* Dose in dogs: 2.7mg/kg once
Transdermal Fentanyl Patch
Used in: horses, sheep, dogs, cats
Dogs: up to 24h may be required until effective drug concentrations reached –> longer than 4h lag time for TFS
DOE: 24-72h after patch application, approx 48h efficacy
Lag time to reach effective plasma concentrations shorter in cats, approx 12hr
* DOE 100h (~4d) after application
Horses: effects with 6hr, 48hr duration
Variability in absorption, effect of TFP substantial: some animals may have pain poorly controlled with patch, adverse effects
Dosing of TFP
1-5mcg/kg/hr
Placement Locations for TFP
Dogs: Thorax, inguinal area, metatarsal/carpal areas, base of tail, dorsal or lateral cervical area (no leashes)
Cats: Lateral thorax, inguinal area, metatarsal/carpal areas, base of tail, Avoid cervical area because patch tends to fall off
Horses: Neck, antebrachium
Pigs, Rabbits: Lateral thorax
Sheep, goats :Abdomen, cervical area
Application of Transdermal Fentanyl Patch
- Direct contact with heating pads will significantly increase fent absorption, risk toxicity
- WEAR GLOVES
- Clip area, no scrub – alcohol, sx scrubs may “de fat” skin, alter drug absorption
- Hold patch in place on skin for 2-3’ – heat of hand allows adhesive to bind to skin, failure to perform will cause patch to fall off
- Cover with light bandage, clear adhesive, label with dose/date
Side Effects of Fent Patch
bradycardia, resp depression, urinary retention, constipation
Methadone
–Full MOR - similar effects, potency (1.5x) morphine
–NMDA antag effects, more effective analgesic for chronic and refractory pain than morph
*Decreases development of tolerance
*Two optical isomers: D/L forms both bind to, antag NMDA R
PK of Methadone
Similar to morphine: IV bolus, SC, IM
Repeated IM or SC admin may result in tissue damage, irritation
Low bioavail in most vet species (not case in humans): not effective when admin PO
Metabolism of Methadone
o Metabolized by metabolic pathways inhibited by chloramphenicol (possibly other hepatic enzyme inhibitors) in dogs (potentially other species)
Markedly prolonged effects can occur in animals tx concurrently with both drugs
o Exhibits synergistic effects when admin with some other MOR agonists eg morphine
Levomethadone
Dose would be half racemic methadone
DOA Methadone
dogs, cats 3-4hr; horses 4-8hr
OTM in horses, cats: well-tolerated
Meperidine
–MOR, less potent than morphine (0.16x)
–Risk of serotonin syndrome: meperidine, normeperidine (metabolite) = serotonergic effects
Do not admin with other serotonin drugs, MOA inhibitors
Normeperidine: minor metabolite in dogs
Meperidine ROA
o Used alone for IV regional anesthesia
o Routes: IV (bolus 2-3’, slower than other opioids), SC, IM
PO bioavailability poor
o Short duration of action: 2-4hrs in dogs, cats
Horses and Meperidine
hyperesthesia, m fasciculations, sweating adverse CV effects
Hydrocodone
o Poor PO bioavailability in dogs, variably metabolized to hydromorphone which may produce opioid effects
o Long used as effective antitussive in dogs
o 0.2-0.5mg/kg PO Q8-12hrs anticipated to produce plasma drug concentrations consistent with analgesia
Analgesic efficacy studies not reported
No studies in cats
o Most formulations combination products with NSAIDS, acetaminophen/paracetamol or hamtropine
No Tylenol in cats!!!
Codeine
-MOR agonist
-Routes: IV, CRI, SC, IM
-Dogs: 4% PO bioavailability, negligible amount of morphine as a metabolite in dogs and cats
* Efficacy of codeine PO in dogs low at best
Lrg amts codeine-6-glucuronide formed in dogs –> some opioid effect?
Norcodeine (active metabolite) produced in cats
Oxycodone
MOR
o Oral dosage forms, not commonly used in vet med DT low PO bioavailability in dogs, rapidly eliminated
o No data/evidence for use in cats
Remifentanil
o Remi: fent derivative, metabolized by extrahepatic metabolism by nonspecific plasma and tissue esterases
Very short elimination half-life, approx 6min
Animals with impaired hepatic function still should have consistent and predictable elimination of the drug
Must have CRI DT short HL –> clinical analgesic effects subside quickly after d/c, need additional opioids with more sustained DOA for pain control
As efficacious as fentanyl, similar doss used for producing MAC reduction in dogs, cats –> ceiling effect in both species
Sufentanil, alfentanil
Potency: alfent < fent < sufentan
Buprenorphine
o MOR partial agonist, approximately 25x more potent than morph
o ROA: IV bolus, IV infusion, SC, IM, OTM (CATS ONLY), transdermal (CATS ONLY)
SC, OTM less effective than IM or IV in perioperative setting
o Effects: similar to morphine, lower maximal efficacy
Possibly more effective than morphine for chronic pain
Poor PO bioavailability
Safety Profile of Buprenorphine
o Safety profile very large
Even supratherapeutic doses produce minor adverse effects on CV, resp systems
Produces less nausea, vomiting than morph
May produce fewer adverse effects in cats vs morph
Buprenorphine as an MOR Antagonism
antagonize effects of full MOR agonist, but degree of antagonism may not be complete
Prior administration of bup believed to render subsequent admin of full MOR less effective/ineffective DT much greater affinity for opioid R
Degree of interference affected by relative doses, timing btw doses, species, type of nociceptive environment
R interference persists for duration of bup’s effect
Duration of Effect of Buprenorphine
4-8h, up to 12h depending on dose, route, species, pain intensity, individual response to drug
Buprenorphine OTM in Cats
Oral pH in cats (8.0-9.0) closely approximates buprenorphine’s pKa (8.4) –> allows for good absorption of OTM buprenorphine
Acidifying formulation may limit absorption, clinical efficacy
OTM Buprenorphine in Dogs
Reasonable uptake, produces antinociceptive effects
Large volumes: cost prohibitive
OTM Buprenorphine in Horses
not effective ROA
Transdermal Buprenorphine Patches
Dogs: available in some countries, slow absorption (Tmax range 48-60h), mean plasma levels low for first 36h with total duration of 72h
Cats: better absorbed than dogs, 12-24h lag to target concentrations persisted until ~96h even when patch removed at 72h
Simbadol
Once daily SC admin for up to 3d to control postop pain in cats
Safety (up to 5x label dose), efficacy (OVH, castration, onychectomy) studies completed for drug approval processes
Dosing: 0.24mg/kg SC once daily for up to 3d
Simbadol - Hansford et al 2021 (VAA)
0.12mg/kg Simbadol (1.8mg/mL) = three compartment model with slow first order input, slow first order elimination
* SQ admin: high volume of distribution, rapid absorption followed by slower, delayed reabsorption
* Further study indicated to determine if obtained buprenorphine plasma concentrates correlate with clinical antinociception
* Bioavail >100% - possible experimental error
Zobrium
transdermal solution for cats
Effective for mild to moderate pain in cats, 10-30mcg/kg
0.4mL for cats 1.3-3kg
1mL for cats >3-7.5kg
Contents: solvent, permeation enhancer, buprenorphine
Application of Zobrium
Application
* Transdermal onto cervical area, allow to dry for 30’
* Cage sign
* Wear PPE
* Recommended onset time 1-2hr prior to surgery, duration up to 4d
Common AEs of Zobrium
during first 96hr
* During ax: increased hypoxemia, bradycardia, hypotension
* Postoperatively: increased hyperthermia (days 1-4), sedation (day 1)
* Dysphoria <3hr
* Mydriasis 10-12hr
Avoid Zobrium In:
- Debilitated, renal, hepatic, cardiac or respiratory disease
- Pregnant/lactating, <4mo of age, outside weight ranges
- Opioid hypersensitivity, intolerance to vehicle
- Abnormal skin at application site
Buprenorphine SR
Compounded, unapproved formulation that is delivered in biodegradable matrix allowing for controlled release over 72h
SC admin
Demonstrated to provide analgesic effects up to 72h in post-surgical models (cats, rats) and thermal threshold models (mice, rats)
No available data for use of compounded drug in dogs
Dosing, 3mg/mL; cats 0.12mg/kg, dogs 0.12-0.27mg/kg SC
Unclear if SR compounded formula results in dose-dependent release when surface area changes with volume injected
Buprenorphine Extended Release
(1mg/mL) marketed as indexed, unapproved drug in USA for use in rats
* Dosing for rats: 1.0-1.5mg/kg SC
* Dosing for mice: 0.5-1.0mg/kg SC
* Provides pain control for 72h
Antagonism of Buprenorphine
DT high affinity of bup at MOR, complete antagonism with opioid antag may be difficult
Butorphanol
o MOR antag to partial MOR agonist, KOR agonist approved for use in dog (PO only), cat, horse
o ROA: IV bolus, CRI, SC, IM
o PO bioavail low, not reliably produce effective analgesia in dogs, cats despite ability to produce antitussive and some sedative effects PO
Butorphanol Ceiling Effect
o Effect plateau (ceiling effect) occurs with torb: increasing doses do not produce increased analgesic effects
Efficacy of torb = dose dependent, higher doses producing more clinically relevant analgesia but effect less than that with morphine
Dose-response studies: duration of effect also dose-dependent with higher doses, up to peak effective dose, producing more prolonged effect in dogs, horses
* Not seen in cats
Torb Use
o Can be used clinically to control mild to moderate pain if appropriate doses administered and relatively short DOA considered
Not effective/adequate for severe pain
o More efficacious antitussive than morphine or codeine
Torbutrol Tablets
FDA approved antitussive in dogs
Other Uses of Torb
o Also used as antiemetic - used to prevent chemotherapy-induced emesis in dogs
AEs Butorphanol
o AE similar to morphine, but occur with less severity
Less dysphoria at clinical doses, +/- less CNS excitement vs full MOR in horses, cats
Large doses, as with other opioids, likely to induce ataxia, excitement, dysphoria
Butorphanol in Horses
o Admin of 0.1mg/kg to nonpainful horses produced increased locomotor activity, reduction in GI motility
Total dose administered, presence/absence of pain likely contributes to development of adverse effects in horses
Horses in particular: adverse CNS effects likely DT large peak plasma concentrations as CRIs assoc with fewer CNS effects
May decrease GI motility ileus, colic, GI effects also depended on portion of GIT studied
Effective analgesic in both visceral pain models and for colic surgery, particularly when combined with an a2 R agonist
Butorphanol, P-glycoprotein and MDR1
speculated to cause more profound, prolonged sedation in dogs with MDR1 gene mutation
No well-designed studies performed
Conservatively recommended that dogs heterozygous for MDR1 mutation should be given reduced dose (25% or less), homozygous dogs administered doses (30-50%) than that recommended for normal dogs
Nalbuphine
o MOR antagonist, KOR agonist (similar to torb)
o Not currently a DEA scheduled drug, occasionally used in veterinary species
o Potency, PK, duration of effect of nalbuphine similar to morphine
Analgesic effects expected to be less
o Efficacy likely to be sufficient for mild, +/- moderate pain
Lacks extensive analgesic studies
AE Nalbuphine
generally mild; panting, nausea, vomiting, CNS stimulation if admin rapidly IV or in higher doses to horses
Dosing Nalbuphine
dogs, cats: 0.25-1mg/kg IM, SC, IV
Pentazocine
o MOR antag, KOR ag rarely used in veterinary species
o Mild to moderate pain
o DOE 1-3h
One study: analgesic effects as long as those reported for morphine (4h)
Following ortho sx in dogs, morph, bup, and pentazocine all assessed as providing adequate analgesia
Tramadol
- Centrally acting analgesic that elicits effects through several different mechanisms
o Humans: primary analgesic effect DT metabolism of tramadol to O-desmthyltramadol (M1) –> acts as full MOR agonist
Additional effects can occur DT activity of both tramadol and M1 as serotonin and NE reuptake inhibitors
Studies in humans: without formation of O-desmthyltramadol (M1), tramadol has little effect
Metabolism of Tramadol in Horses, Dogs
do not make substantial amounts of O-desmthyltramadol (M1) –> analgesic effects weak at best
* Plasma concentrations following 7d continuous PO admin reduced to only 33% of those reached on day 1, further suggesting poor analgesic choice in dogs for chronic administration without p monitoring and dose adjustments
* 5-10mg/kg PO q8: provide tramadol concentrations within ranges achieved in humans
Metabolism of Tramadol in Cats
Produce substantial amt of O-desmthyltramadol (M1)
* Likely an effective analgesic
* Bitter taste: routine PO admin difficult
* 1-2mg/kg PO q8-12h expected to produce O-desmthyltramadol (M1) plasma concentrations clinically effective in humans but control clinical trials not yet published
Injectable Form of Tramadol
Bioavailability higher, recommended dosing range 2-4mg/kg
Tramadol and Serotonin Syndrome
RISK!
Do not combine with: meperidine, tricyclic antidepressants (amitriptyline, clomipramine), or selective serotonin reuptake inhibitors (SSRIs; fluoxetine, paroxetine) DT risk of serotonin syndrome
When severe, serotonin syndrome can present as fever, seizures, muscle tremors/fasciculations, hyperthermia, salivation, rarely death
Toxicity of Tramadol in Dogs
restlessness, unsteady gait, reduced spontaneous activity, mydriasis, salivation, vomiting, tremors, convulsions, cyanosis, dyspnea
Opioid Antagonists
- Primary indication for admin: reversal of severe opioid-related adverse effects or reversing sedation after non-painful procedure
- Safety margin of opioids = very large, life-threatening adverse effects, even with substantial overdoses = rare if supportive measures instituted
- DOE of antagonists < agonists –> multiple doses may need to be admin
- Admin to painful animal may result in adverse CV sequelae, presumably DT unmitigated pain from reversal of both exogenous and endogenous opioids
o Admin to effect vs predetermined dose
Nalbuphine, butorphanol as opioid R antagonists
reverse MOR effects but maintain some analgesia DT kappa agonism
Naloxone
–primarily as MOR antag, but antagonistic effects also at KOR, DOR
–Can elicit convulsions DT GABA antag actions, not usually clinical consideration
–High doses: antagonize central effects of opioid agonists, may cause animal to experience acute pain, associated SNS stimulation with serious consequences = tachycardia, hypertension, pulmonary edema, cardiac arrhythmias
Admin of Naloxone
o Best to admin by careful titration
Multiple doses may be needed DT short DOA
Dose range: 0.001-0.04mg/kg IV diluted, repeat q1-2min until desired effect achieved
Other Effects of Naloxone
effects as Toll-like 4 (TLR4) R antag
R appears to be stimulated by morph, resulting in allodynia at some doses
Low-dose naloxone can block TLR4 allodynia assoc with morph admin in rodent models of peripheral nerve injury
Naltrexone
o Opioid antag at MOR, DOR, KOR
o Often admin to reverse sedative effects of carfentanil in wildlife, zoo animals
Would be effective in reversing opioids as well
o DOA 2x longer than naloxone
Desirable in wildlife, zoo animals where repeat dosing not possible
Dosing of Naltrexone with Carfentanil
100mg per 1mg carfentanil administered with typically one quarter of the dose administered IV, remainder admin subcutaneously
Methylnaltrexone
o Quaternary derivative of naltrexone
o Only acts peripherally DT greater polarity, lower lipid solubility (excluded from CNS)
o Primary indication: controlling GI SE including ileus w/o affecting analgesic effects
Some beneficial use in preventing GI motility problems assoc with opioid use
Costly, further studies needed
Low Dose Naltrexone, Naloxone
admin to humans prior to/after sx to reduce potential for SE (ie constipation, urine retention) without interfering with analgesia but SE not as common as in dogs and cats
