Topical Pain Control Topical Pain Control MedicationMedication

Gregory HarochawGregory Harochaw

Pharmacy ManagerPharmacy Manager

Tache PharmacyTache Pharmacy

Phone 204-233-3469Phone 204-233-3469

tache@mts.nettache@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 _______