topical pain control medication gregory harochaw pharmacy manager tache pharmacy phone 204-233-3469...
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Topical Pain Control Topical Pain Control MedicationMedication
Gregory HarochawGregory Harochaw
Pharmacy ManagerPharmacy Manager
Tache PharmacyTache Pharmacy
Phone 204-233-3469Phone 204-233-3469
[email protected]@mts.net
Goals and ObjectivesGoals and Objectives
Understand the Understand the pharmacokineticspharmacokinetics of of transdermal deliverytransdermal delivery
Advantages/disadvantages of Advantages/disadvantages of transdermal routetransdermal route
Medications used for some different Medications used for some different situationssituations
Metabolism
Cytochromes
Parenteral RoutesParenteral Routes IntradermalIntradermal
Small volumes Small volumes 0.1ml 0.1ml Absorption is slow Absorption is slow slow onset of action slow onset of action
SubcutaneousSubcutaneous <2ml volumes<2ml volumes Much more rapid absorption than IDMuch more rapid absorption than ID
IntramuscularIntramuscular 2 – 5ml volumes2 – 5ml volumes More rapid absorption than by SCMore rapid absorption than by SC Can formulate a delayed responseCan formulate a delayed response
IntravenousIntravenous Small to large volumesSmall to large volumes No absorption of drug No absorption of drug directly in vein directly in vein
Sterile Dosage Forms: S. Turco, R. King
Pharmacokinetics for Pharmacokinetics for AbsorptionAbsorption
IV route IV route immediate & total access to immediate & total access to active drug moleculesactive drug molecules
IM, SC, ID IM, SC, ID require an absorption require an absorption stepstep
The vascularity of the IM route is greater The vascularity of the IM route is greater than the SC route than the SC route absorptionabsorption
Sterile Dosage Forms: S. Turco, R. King
SC injections SC injections active drug absorbed by active drug absorbed by diffusion of drug into the capillary diffusion of drug into the capillary networknetworkThe greater the blood flow in the capillary The greater the blood flow in the capillary
network the greater the absorption of the network the greater the absorption of the drugdrug
Epinephrine Epinephrine vasoconstriction vasoconstriction drug absorptiondrug absorption Heat Heat blood flow blood flow drug absorptiondrug absorption
Stratum Corneum (horny Stratum Corneum (horny layer)layer)
Compared to “bricks & mortar”Compared to “bricks & mortar” 10-15 layers of flattened cornified cells 10-15 layers of flattened cornified cells
constitute the bricksconstitute the bricks Lipid-rich intercellular matrix constitutes Lipid-rich intercellular matrix constitutes
the mortarthe mortar form an effective barrier to transdermal water form an effective barrier to transdermal water
loss & external chemical accessloss & external chemical access If a drug is to pass through the skin & into If a drug is to pass through the skin & into
general circulation, it must 1st traverse this general circulation, it must 1st traverse this barrierbarrier
Factors for Drug Factors for Drug Absorption Absorption
Transcutaneous flow of compounds across Transcutaneous flow of compounds across the stratum corneum is directly the stratum corneum is directly proportional to the concentration gradient proportional to the concentration gradient & therefore can be attributed to passive & therefore can be attributed to passive diffusiondiffusion
As surface area As surface area & thickness of epidermis & thickness of epidermis , the rate of transdermal flux , the rate of transdermal flux
The underlying epidermal layers & the The underlying epidermal layers & the dermis area are an aqueous environmentdermis area are an aqueous environment
Factors for Drug Factors for Drug AbsorptionAbsorption
Highly hydrophilic drugs will absorb Highly hydrophilic drugs will absorb poorly through the stratum corneum poorly through the stratum corneum but better in the aqueous layers of but better in the aqueous layers of the epidermisthe epidermis
Highly lipophilic drugs will absorb Highly lipophilic drugs will absorb better through the stratum corneum better through the stratum corneum but slowed when they reach the but slowed when they reach the aqueous layers of epidermisaqueous layers of epidermis
Finding a Suitable CarrierFinding a Suitable CarrierFor compounds used exclusively for the For compounds used exclusively for the
treatment of a skin condition, passive treatment of a skin condition, passive diffusion into the superficial epidermis diffusion into the superficial epidermis may be sufficient may be sufficient Using a vehicle such as Glaxal Base or Using a vehicle such as Glaxal Base or
VaselineVaselineFor a drug to be delivered to the general For a drug to be delivered to the general
circulation, the drug/vehicle must circulation, the drug/vehicle must maintain affinity for both aqueous and maintain affinity for both aqueous and lipid environments to absorb effectivelylipid environments to absorb effectively
Site PermeabilitySite Permeability
Generalized rank order of site Generalized rank order of site permeabilities:permeabilities:genitals > head/neck > trunk > arm genitals > head/neck > trunk > arm
> leg> legPreterm infant > term infant > young Preterm infant > term infant > young
adult adult > elderly > elderly Klein & collegues,. Transdermal Klein & collegues,. Transdermal
Clonidine Therapy in Elderly Mild Hypertensives; Hypertension Suppl 1985:3;581-Clonidine Therapy in Elderly Mild Hypertensives; Hypertension Suppl 1985:3;581-
584584
Vehicles UsedVehicles Used11
PLO – PLO – PPluronic luronic LLecithin ecithin OOrganobaserganobasePluronic Pluronic hydrophilic phase hydrophilic phaseLecithin Isopropyl Palmitate Lecithin Isopropyl Palmitate lipophilic phase lipophilic phaseMixing Pluronic Gel & Lecithin Isopropyl Palmitate Mixing Pluronic Gel & Lecithin Isopropyl Palmitate
under pressure (with the drug) will form an under pressure (with the drug) will form an amphiphilic phase containing drug micellesamphiphilic phase containing drug micelles
Gold standard Gold standard available most Rxavailable most Rx Provides good penetration into skin Provides good penetration into skin Works well with a variety of Works well with a variety of
lipophilic/hydrophilic agents lipophilic/hydrophilic agents Need to rub in well???Need to rub in well??? ““Greasy” baseGreasy” base The 2 phases can separate under cold The 2 phases can separate under cold
conditionsconditions
Electronic and Electro Mortar & Electronic and Electro Mortar & PestlesPestles
The electronic The electronic mortar & mortar & pestle providepestle provide
pharmacists pharmacists with the with the modern way modern way to compound to compound creams,gels, creams,gels, ointments ointments and and suspensions.suspensions.
Ointment MillOintment Mill
The ointment mill mixes powders, crystals andThe ointment mill mixes powders, crystals andcreams into a smooth, finished productcreams into a smooth, finished product
Bases To Be UsedBases To Be Used11
LipodermLipodermCreamier base than PLOCreamier base than PLO
Cosmetically more elegantCosmetically more elegantLess stickyLess stickyLess smellLess smell
Not as temperature sensitive as PLONot as temperature sensitive as PLOCold temperatures PLO may separateCold temperatures PLO may separate
Less chance of rash vs PLOLess chance of rash vs PLOOnly compounding pharmacies can makeOnly compounding pharmacies can make
Bases To Be UsedBases To Be Used11
Penetration rates:Penetration rates:Pentravan,VanPen, PLO Pentravan,VanPen, PLO 5-20mm 5-20mmPCCA Gel 2058 PCCA Gel 2058 1-3mm (Intradermal) 1-3mm (Intradermal)PCCA Gel 4038 PCCA Gel 4038 10-20mm 10-20mmPCCA Gel 6633 PCCA Gel 6633 +30mm +30mmSpeed Gel Speed Gel up to 50mm up to 50mm
Sports MedicineSports Medicine
IontophoresisIontophoresisEnhance absorption of ions by the use of Enhance absorption of ions by the use of
an electrical currentan electrical currentAnti-inflammatory’s, dexamethasone, Anti-inflammatory’s, dexamethasone,
lidocainelidocainePhonophoresisPhonophoresis
Uses ultrasound to Uses ultrasound to transcutaneous transcutaneous drug absorptiondrug absorption
NSAID’s, dexamethasoneNSAID’s, dexamethasone
Reasons for Topical RouteReasons for Topical Route
Oral route not desirableOral route not desirableMucositisMucositisInability to swallowInability to swallowNausea/vomitingNausea/vomitingObstructionObstructionPoor taste of productPoor taste of productDry mouthDry mouth
Can produce a more localized action Can produce a more localized action Also can be used for systemic useAlso can be used for systemic use
GH
Topical Route: AdvantagesTopical Route: Advantages
Avoids the GI tract and hepatic first-Avoids the GI tract and hepatic first-pass metabolismpass metabolism
Reduces systemic side effectsReduces systemic side effectsImproves complianceImproves complianceAllows Allows ↑ ↑ concentration of Rx at site of concentration of Rx at site of
applicationapplicationPlasma concentrations of <10% Plasma concentrations of <10%
compared to oral route compared to oral route
Heir, Gary DMD, et al. IJPC 2004; 8:337-343
Topical Route: DrawbacksTopical Route: Drawbacks
Variations in the stratum corneum Variations in the stratum corneum barrierbarrier Delivery dosing may require Delivery dosing may require
adjustmentadjustment Rate of absorption may varyRate of absorption may vary
Rash most common SERash most common SE
May be incumbent when using larger May be incumbent when using larger areasareas
Heir, Gary DMD, et al. IJPC 2004; 8:337-343
Prostaglandins
Bradykinin
Histamine
Leukotrienes+
Step 1: Peripheral Stimulation & Nociceptor Sensitization
Step 2: Signal Transmission
Step 3: Pain Perception
Substance P
Glutamate
Aspartic Acid
Nitric Oxide+
Enkephalins
Endorphins
Medication-
-
NMDA and AMPA ReceptorsNMDA and AMPA ReceptorsNa+ influx exacerbates the Ca++ influx in absence of Mg++
This results in “wind up” pain, LTP and Allodynia
Drugs That Effect Ion Drugs That Effect Ion ChannelsChannels
NMDA-CaNMDA-Ca++++ channel blockers: channel blockers:Ketamine, orphenadrine, Ketamine, orphenadrine,
amantadine,DM, magnesium, amantadine,DM, magnesium, haloperidol, nylidrin, methadonehaloperidol, nylidrin, methadone
AMPA-NaAMPA-Na++ channel blockers: channel blockers:AnticonvulsantsAnticonvulsants
Gabapentin, carbamazepineGabapentin, carbamazepineAntiarrythmics:Antiarrythmics:
Lidocaine, mexilitineLidocaine, mexilitine
KetamineKetamine Widely used as an anesthetic agent Widely used as an anesthetic agent
Given IV, IM, PO, PR, intranasally or spinally Given IV, IM, PO, PR, intranasally or spinally (Chia et (Chia et al., 1998; Gehling and Tryba, 1998; Malinovsky et al., 1996; Mercandante et al., al., 1998; Gehling and Tryba, 1998; Malinovsky et al., 1996; Mercandante et al., 2000; Walker et al., 2002)2000; Walker et al., 2002)
Safety and efficacy of ketamine and Safety and efficacy of ketamine and analgesic well documented analgesic well documented (Malinovsky et al., 1996; Reich & (Malinovsky et al., 1996; Reich & Silvay. 1989; White et al., 1982)Silvay. 1989; White et al., 1982)
Tx in neuropathic pain Tx in neuropathic pain (Edie et al., 1994, 1995; Jackson et al., 2001; (Edie et al., 1994, 1995; Jackson et al., 2001; Kannan et al., 2002; Kjepstad & Borchgrevnik., 1997; Mercandante et al., 1995, 2000; Kannan et al., 2002; Kjepstad & Borchgrevnik., 1997; Mercandante et al., 1995, 2000; Mercandante & Arcuri, 1998)Mercandante & Arcuri, 1998)
Phantom limb pain Phantom limb pain (Knox et al., 1995)(Knox et al., 1995)
Post-operative pain and other post-traumatic pain Post-operative pain and other post-traumatic pain (Dick-Neilsen et al.,1992; Gurmani et al., 1996; Hirlinger & Dick, 1984; Hirlinger & (Dick-Neilsen et al.,1992; Gurmani et al., 1996; Hirlinger & Dick, 1984; Hirlinger & Pfenninger, 1987; Lauretti & Azevedo, 1996; Owen et al., 1987)Pfenninger, 1987; Lauretti & Azevedo, 1996; Owen et al., 1987)
Control control pain during dressing changes Control control pain during dressing changes (Bookwalter, 1994; Humphries et al, 1997; Kulbe, 1998; Pal et al, 1997)(Bookwalter, 1994; Humphries et al, 1997; Kulbe, 1998; Pal et al, 1997)
Low doses of ketamine have minimal adverse Low doses of ketamine have minimal adverse effects on cardiovascular or respiratory functioneffects on cardiovascular or respiratory function (Miller (Miller et al., 2000)et al., 2000)
KetamineKetamine22
REQUIRES A REQUIRES A TRIPLICATETRIPLICATE
Medications Used in Medications Used in Transdermal DeliveryTransdermal Delivery
Drugs listed in percentagesDrugs listed in percentages
1% Solution = 1000mg/100ml1% Solution = 1000mg/100ml
OROR
10mg/ml10mg/ml
Hydromorphone 1% solutionHydromorphone 1% solution
10mg/ml10mg/ml
Medications Used in Medications Used in Transdermal DeliveryTransdermal Delivery
DrugDrug StrengthStrength MechanismMechanism
AmitriptylineAmitriptyline 1-5%1-5% NE Reuptake inhibitorNE Reuptake inhibitor
BaclofenBaclofen 2-5%2-5% GABAGABA AgonistAgonist
BretyliumBretylium 1-5%1-5% Sympathetic InhibitionSympathetic Inhibition
BupivicaineBupivicaine 0.25-0.25-10%10%
AnestheticAnesthetic
CapsaicinCapsaicin 0.025-0.025-0.1%0.1%
Substance P BlockadeSubstance P Blockade
CarbamazepinCarbamazepinee
2-5%2-5% NMDA NaNMDA Na++ Blocker Blocker
ClonidineClonidine 0.1-0.3%0.1-0.3% Alpha -2 AgonistAlpha -2 Agonist
CyclobenzapriCyclobenzaprinene
1-4%1-4% Muscle RelaxantMuscle Relaxant
DextromethorphaDextromethorphann
5-10%5-10% NMDA Receptor AntagonistNMDA Receptor Antagonist
Medications Used in Medications Used in Transdermal DeliveryTransdermal Delivery
DrugDrug StrengthStrength MechanismMechanism
Diclofenac Diclofenac 2-10%2-10% Cyclooxygenase Cyclooxygenase InhibitorInhibitor
DiphenhydramiDiphenhydraminene
5-10%5-10% Voltage Regulated NaVoltage Regulated Na++ & Ca& Ca++ ++ BlockadeBlockade
GabapentinGabapentin 5-10%5-10% Voltage Regulated NaVoltage Regulated Na++ & Ca& Ca++ ++ BlockadeBlockade
Glutamate AntagonistGlutamate Antagonist
GuaifenesinGuaifenesin 5-10%5-10% Muscle RelaxantMuscle Relaxant
IbuprofenIbuprofen 10-30%10-30% Propionic Acid NSAIDPropionic Acid NSAID
IndomethacinIndomethacin 15-20%15-20% Methylated Indole Methylated Indole NSAIDNSAID
DrugDrug StrengthStrength MechanismMechanism
KetamineKetamine 5-15%5-15% NMDA Receptor NMDA Receptor AntagonistAntagonist
KetoprofenKetoprofen 5-10%5-10% Propionic Acid NSAIDPropionic Acid NSAID
LidocaineLidocaine 2-10%2-10% AnestheticAnesthetic
Lipoic AcidLipoic Acid 2-3%2-3% AntioxidantAntioxidant
LoperamideLoperamide 5-10%5-10% Mu agonistMu agonist
NaproxenNaproxen 10-20%10-20% Propionic Acid NSAIDPropionic Acid NSAID
NifedipineNifedipine 0.2-16%0.2-16% Non-NMDA CaNon-NMDA Ca+2+2 Channel AntagonistChannel Antagonist
PentoxifyllinePentoxifylline 5-15%5-15% TNFTNF Inhibitor, Inhibitor, Peripheral VasodilatorPeripheral Vasodilator
PhenytoinPhenytoin 0.5-2%0.5-2% NMDA NaNMDA Na++ Blocker Blocker
QuirksQuirks
Ketamine has highest affinity for NMDA Ketamine has highest affinity for NMDA receptors of products givenreceptors of products given
Amitriptyline has a synergistic effect Amitriptyline has a synergistic effect with ketaminewith ketamine
Fibromyalgia baclofen works well as an Fibromyalgia baclofen works well as an add onadd on
Complex regional pain amitriptyline Complex regional pain amitriptyline and bretyliumand bretylium
Diclofenac > pruritis than ketoprofenDiclofenac > pruritis than ketoprofen
Arthritic PainArthritic Pain
Diclofenac 2 – 4 % used for yearsDiclofenac 2 – 4 % used for yearsPennsaid 1.5%Pennsaid 1.5%AddAdd
Amitriptyline 2 – 5% Amitriptyline 2 – 5% bone pain bone painCapsaicin 0.025 – 1% Capsaicin 0.025 – 1% Substance P Substance P
blockerblockerGabapentin 6 – 10% Gabapentin 6 – 10% Neuropathic pain Neuropathic painLidocaine 2-10% Lidocaine 2-10% Na channel blocker Na channel blocker
SciaticaSciatica
Gabapentin 6%, Clonidine 0.1%, Gabapentin 6%, Clonidine 0.1%, Diclofenac 2% & Lidocaine 2%Diclofenac 2% & Lidocaine 2%
Above mixture + Pentoxyfylline 5%Above mixture + Pentoxyfylline 5%May prevent sciatica caused by a May prevent sciatica caused by a
herniated discherniated discYabuki et al. Prevention of compartment syndrome in dorsal root ganglia Yabuki et al. Prevention of compartment syndrome in dorsal root ganglia
caused caused
by exposure to nucleus pulposus. Spine 2001;26:870-875by exposure to nucleus pulposus. Spine 2001;26:870-875
ShinglesShingles
Ketamine 15%, amitriptyline 2-5%, Ketamine 15%, amitriptyline 2-5%, loperamide 5-10%, lidocaine 2-10%loperamide 5-10%, lidocaine 2-10%
Topical sprayTopical sprayKetamine 10%, bupivicaine 0.3-0.75%Ketamine 10%, bupivicaine 0.3-0.75%Ketamine 4%, morphine sulfate 4% Ketamine 4%, morphine sulfate 4%
2-Deoxy-D-Glucose 2%, 2-Deoxy-D-Glucose 2%, Diphenhydramine 2%, Lidocaine 4%Diphenhydramine 2%, Lidocaine 4%
ShinglesShingles
Capsaicin 0.025-0.1% Capsaicin 0.025-0.1% substance P substance P blockadeblockade
Speed gel???Speed gel???Penetration depth up to 50mmPenetration depth up to 50mm
Tx may take up to 8 weeks to get Tx may take up to 8 weeks to get maximum reliefmaximum relief
Sensory NeuropathySensory Neuropathy“Tingling” Sensation“Tingling” Sensation
Gabapentin 6%, loperamide 10% & Gabapentin 6%, loperamide 10% & lidocaine 2% lidocaine 2% Amitriptyline 2%Amitriptyline 2%Clonidine 0.1%Clonidine 0.1%
Apply to affected areas for 2 – 4 Apply to affected areas for 2 – 4 weeksweeks
Treatment of Anal FissuresTreatment of Anal Fissures
Nitroglycerin 0.2% OintmentNitroglycerin 0.2% Ointment Success rates 48-78% in treating anal fissuresSuccess rates 48-78% in treating anal fissures NTG metabolized it releases nitric oxide NTG metabolized it releases nitric oxide an an
inhibitory neurotransmitter for smooth muscleinhibitory neurotransmitter for smooth muscle Given 3 – 5 times dailyGiven 3 – 5 times daily
Nifedipine 0.2% OintmentNifedipine 0.2% Ointment Less side effects than NTG Less side effects than NTG
HA’s, dizziness, lightheadedness hypotensionHA’s, dizziness, lightheadedness hypotension CaCa++++ antagonist antagonist O O22 demand and mechanical demand and mechanical
contraction of smooth muscle contraction of smooth muscle One study 95% complete healing rate in 21 daysOne study 95% complete healing rate in 21 days
Myofascial PainMyofascial Pain
Topical MagnesiumTopical Magnesium
Magnesium Chloride 10% PLOMagnesium Chloride 10% PLOUse twice dailyUse twice dailyApplied across whole “taught” band Applied across whole “taught” band Can cause diarrhea Can cause diarrhea
Magnesium 10%/ Pyridoxine 5% PLOMagnesium 10%/ Pyridoxine 5% PLOPyridoxine Pyridoxine pain thresholds and pain thresholds and
serotonin levels serotonin levels
Diabetic NeuropathyDiabetic Neuropathy
Ketamine 15%, Amitriptyline 2-5%, Ketamine 15%, Amitriptyline 2-5%, Clonidine 0.1-0.3%%, Nifedipine 2-Clonidine 0.1-0.3%%, Nifedipine 2-10%, 10%, Diclofenac 2-4%Diclofenac 2-4%
Burning sensation Burning sensation Alpha Lipoic Acid PO Alpha Lipoic Acid PO 600-1800mg/day600-1800mg/day
Topically 0.5-3%Topically 0.5-3%
FibromyalgiaFibromyalgia
Ketoprofen 10%, cyclobenzaprine 3%, Ketoprofen 10%, cyclobenzaprine 3%, lidocaine 5%lidocaine 5%
Amitriptyline 5%, baclofen 2%, diclofenac Amitriptyline 5%, baclofen 2%, diclofenac 2%, lidocaine 2%2%, lidocaine 2%
Ketoprofen 10% & baclofen 5% Ketoprofen 10% & baclofen 5% lidocaine 5%lidocaine 5%
Base: □ Lipoderm □ PLO □ Speed Gel □ Other (specify)_________________Check the Ingredient & Strength: Other Strength:
□ Ketamine __5% __10% __15% ______%(requires a triplicate Rx with this Rx)
□ Gabapentin __6% __8% __10% ______% □ Clonidine __0.1% __0.2% ______% □ Lidocaine __2% __4% __5% __10% ______% □ Loperamide __5% __10% ______% □ Ketoprofen __5% __10% __20% ______% □ Diclofenac __2% __4% __5% ______%
□ Carbamazepine __2% __5% __10% ______% □ Baclofen __2% __5% ______%
□ Amitriptyline __2% __5% ______% □ Pentoxifylline __5% __10% __15% ______% □ Bretylium __1% __2% ______% □ Nifedipine __2% __5% __10% ______%
□ Dextromethorphan __10% □ Guaifenesin __5% __10% □ Menthol __ 0.5% □ Camphor __0.25%
Additional Ingredients: _________________ _____% _________________ _____%
Directions: Apply _____mL to affected area(s) (specify) ________________________ (frequency) _______________________.
Mitte: _______mL Refill x _______