slap it on! topical medications in palliative...

Paul Daeninck MD, MSc, FRCPCLindsay Lemanski, BSc Pharm

University of Manitoba/CancerCare MBSt. Boniface Hospital

Slap It On!Topical Medications

in Palliative Care

I currently have, or I have had in the past two years, an affiliation with/or financial interests in a business corporation, or I receive remuneration, royalties, or research grants from a business corporation.

Valeant Pharmaceuticals CanadaConsultant

Wyeth PharmaceuticalsConsultant and Advisory Board member

GW Pharmaceutical Clinical Trial Investigator and Advisory Board member

Learning ObjectivesDiscuss the options of using the topical or

transdermal route of drug administrationList indications for use of topical medicationsReview the science and the evidence behind

topical medicationsDiscuss initial clinical use and results

Delivery Routes for MedicationsStandardOralIntravenousInhalation (nebulized)Subcutaneous

AlternativeSublingual

transmucosalmouthwashes

IntranasalTransdermal (topical)RectalVaginalIntraosseus

Reasons for Topical RouteOral route not desirable

MucositisInability to swallowNausea/vomitingGastric/ bowel obstructionPoor taste of product/taste alterations

More localized actionEasily accessibleSystemic adverse effects

Topical Route: AdvantagesAvoids the GI tract and hepatic first-pass

metabolismDelivers to a specific siteControls absorption rateProvides constant dosing depot effect

with anhydrous gelsReduces systemic side effects

Heir G et al. IJPC 2004; 8:337-343

Improves complianceAllows ↑ concentration of Rx at site of

applicationPlasma concentrations of <10% compared

to oral route

Topical Route: Advantages

Heir G et al. IJPC 2004; 8:337-343

Topical Route: DrawbacksVariations in the stratum corneum barrier

Delivery dosing may require adjustmentRate of absorption may vary

Rash most common AECumbersome when using larger areasPatient complianceCost

Heir G et al. IJPC 2004; 8:337-343

Topical RouteOphthalmology

topical meds commonplace

Dermatologylotions, ointments, gels, etc.

Internal medicineblood pressure, pain control, infections, etc.

Gynecologyhormone patches, antibiotic creams

Topical Route

Transdermal RouteFentanyl, scopolamine, estrogen, nitrate patchesTransdermal gels (Pennsaid®)Ointments (Flamazine®)Lotions/creams (steroids or antibiotics)Sunblock (local blockade, ?absorption)

Topical Opioids

Classically, opioids active on CNS receptors mu (μ) kappa (κ) delta (δ) receptorsNow found on:

peripheral neuronsimmune cellsinflamed tissuerespiratory tissueGI tract

Why Topical Opioids?Opioid receptors on peripheral neurons &

dorsal root gangliaInflammation ↑ receptors, activationMacrophages produce opioid peptidesPeptides ↓ neuron excitabilityExogenous opioids ↓ pain, inflammationActivated receptors respond to topical Rx

Stein C. NEJM 1995; 332:1685-1690

Peripheral Sensory Neuron

Stein C. NEJM 1995; 332:1685-1690

Symptom Prevalence:Wounds

Pain ~50%Other symptoms ?

Lindholm et al. J Wound Care 1999;8:5-10

Clinical Concerns: Malignant Wounds

PainEmotional stressOdorExudateBleeding Functional compromiseSocial concernsEdemaComplications

21%18%16%11%10%7%6%5%5%

Schulz V et al. JPSM 2002;24 572-77

Causes of Wound Pain

WUWHS, 2004

Chronic Wound InflammationAlters nerves:

excitability, expression of transmitters and receptors

Alters immune system:blood flow, vascular permeability, immune cells, chemicals

Alters spinal processing of pain

Why Topical Opioids?Inflammation ↑ peripheral receptors,

activationMacrophages, lymphocytes produce opioid

peptides (in turn,↓ neuron excitability)Exogenous opioids ↓ pain, inflammationActivated receptors respond to topical Rx

Stein C. NEJM 1995; 332:1685-1690

Topical Opioids: BenefitsSmall doses, little systemic absorptionHigh local concentrationLess side effects↓ constipation, N/V, sedationdecreased risk of toxicityno known drug interactions

Ease of use → better compliance

Twillman R et al. JPSM 1999; 17:288-92Sawynok J.Pharmacol Rev 2003; 55:1-20

Topical OpioidsCase seriesDiamorphine 10 mg in IntraSite® gel

relief in 3 ptsduration 1 wk to 2 mo

Morphine 0.1% in IntraSite® (1 mg/ml )

8/9 reported reliefduration few days to > 1 yr

Back IN & Findlay I. JPSM 1995;10:493Twillman RK et al. JPSM 1999; 17:288-92

Topical OpioidsZylicz et al

Series of papers, 7 patientsMorphine gel (0.08%-0.5%)Pain rapidly ↓ , lasted up to 8 hrsDuration of up to 2 moMinimal side effects

Krajnik M et al. Pain 1999; 80:121-25Krajnik M, Zylicz Z. Pall Med 1997; 11:325-26Krajnik M, Zylicz Z. Prog Pall Care 1997; 5:101-06

Topical OpioidsDiamorphine in IntraSite® gelRCT, double-blind, 13 pts, II/III decubitus ulcersPlacebo x 3/diamorphine (0.1% w:w) x 3; switchPain assess before, 1 h & 12 h after applicationSignificant relief in tx group (n=6) vs placeboA/E: pruritis, skin irritationNo significant systemic effects seen

Flock P. JPSM 2003; 25:547-554

Topical OpioidsMorphine in IntraSite® gelRCT, double-blind, 5 pts, painful sacral ulcersMorphine 10 mg/ml in 8 g IntraSite®

Placebo x 3/morphine x 3 or opposite (2 d w/o)Pain twice daily using VASSignificant relief in tx group vs placeboA/E: pruritis, burning, skin discomfort

Zeppetella G et al. JPSM 2003; 25:555-8

Topical Opioids: BioavailabilityOpen label study, X-over, 6 hospice in-ptsTopical vs SC morphineSerial blood levels post therapyMorphine, M6G, M3G in SC ptsOnly detected 1 topical pt (largest ulcer)No AEs in topical pts, drowsiness in SCTopical opioids act locally, no systemic

absorptionRibeiro MDC et al. JPSM 2004:27:434-39

Topical Opioids: BioavailabilityRCT, X-over, 5 volunteersTopical morphine (10 mg/ml) in PLO 1 ml + SC

placeboTopical placebo + morphine (3mg/ml) 1 ml SC Serial blood levels (16) post therapyMorphine detected in SC samples onlyTopical opioids not systemically absorbed

Paice JA et al. JPSM 2008:35:314-20

Topical OpioidsMethadone in Stomahesive® powderCase series, 4 pts, 3 non-malignant woundsTopical morphine gel not effectiveMethadone 100mg / 10g Stomahesive®

Dry powder worked in open, exudativewounds

Absorption measured via serum levelsEffective in 3 cases, esp. with open wounds

Gallagher R et al. Clin J Pain 2005; 21:190-2pd

Topical Analgesics

Science? Rationale?LL

Structure of SkinLargest organ of the human bodySkin is composed of 3 primary layers

Epidermis 5 strataDermisHypodermis (Subcutaneous adipose layer)

Structure of Skin

EpidermisStratum Corneum (Horny layer)

Final product of epidermal cell differentiation“Bricks & mortar”Regulates transdermal water loss & prevents

external accessThickness varied

Structure of SkinDermis

Major component of skinNetwork of connective tissue Hydrophilic = challenging for lipophillic drugs

Regulation of body temperatureBlood supply maintains [gradient]? “Shunt routes” for early permeation3 main appendages

Williams A. Transdermal and topical drug delivery: from theory to clinical practice, 2003

Structure of Skin


Permeation Pathways(Stratum Corneum)

Transappendageal transportTranscellular routeIntercellular pathwayRelative contributions of these pathways to

the gross flux will depend on the physico-chemical properties of the permeant


Transcellular Intercellular Transappendageal

ENLARGED: stratum corneum

Physiological Factors

Physiological factors that influence the rate of drug delivery include:

Skin ageBody SiteEthnicityOther Factors


Other Factors

HydrationSkin water content ~15-20% of tissue

dry weight⇑ water content with occlusion In stratum corneum 25-35 % of water is

‘bound’ within this layer


Other Factors


Liphophilic

Hydrophilic Hydrophilic

Hydrophilic

Factors for Drug Absorption

Physico-Chemical PropertiesSolubility

Lipophilic agents penetrate well across the stratum corneum

Hydrophilic agents absorb better in aqueous layers of the epidermis


Factors for Drug Absorption

Skin CharacteristicsPhysico-Chemical PropertiesChemical Penetration EnhancersVehicle Base


Chemical Penetration Enhancers

Act reversiblyPotencies appear to be drug specificWork well with co-solvents Concentration dependent effectPotential mechanism of action of enhancers

are varied


Finding a Suitable VehiclePassive diffusion into superficial epidermis

sufficient for skin penetration

Drug/vehicle must maintain affinity for aqueous & lipid environments to absorb effectively into systemic circulation

G Harochaw, Personal communication

Vehicles UsedPLO – Pluronic Lecithin Organogel

Pluronic → hydrophilic phaseLecithin Isopropyl Palmitate → lipophilic phase

Wiler’s PCCA

Vehicles Used

Gold StandardPLO

Template VehicleProcess BenefitsStructural/Physical StabilityTopical Delivery PotentialSafety

Kumar R et al. AAPS PharmSciTech 2005; 6:1-47

Vehicles UsedChange PLO Lipoderm

Less chance of rash vs PLOProducts don’t separate as easily Only compounding pharmacies can make

Hydro-Alcoholic GelsDisappears into the skin much faster than PLO Agents used in gel must dissolve completely in

water or alcohol (Not with PLO)

Wiler’s PCCA

Vehicles To Be UsedPenetration rates:

Pentravan,VanPen, PLO 5-20mmPCCA Gel 2058 1-3mmPCCA Gel 4038 10-20mmPCCA Gel 6633 +30mmSpeed Gel up to 50mm

Wiler’s PCCA

Pain Physiology

Pain PATHWAYPain perception

EnkephalinsEndorphins

BradykininProstaglandins Nitric Oxide

GlutamateAspartateSubstance P

LeukotrienesHistamine

Spinal cord

Descendin

g

Inhibition of Neurotransmitters

Voltage-Gated Na+ Channel Antagonistα2-Adrenoceptor AgonistNE Reuptake InhibitorGlutamate AntagonistNMDA Antagonist

NMDA

Presynaptic Neuron

V-G Na

+

Release

V-G Na

+

Cytoplasm

Postsynaptic

Neuron

AMPAAMPA AMPA

AMPA

DEPOLARIZATION

NMDANMDA NMDA

NMDA

α2 α2

V-G

Ca2+

V-G

Ca2+

μ μ

Ca2+

Ca2+

Mg2+

Ca2+

Ca2+

Glu

Glu

Na+Na+

GluGlu

μ μ

5HTNE

Na+

Voltage-Gated Na+ Channel Antagonist

LidocaineAlters depolarization in neurons by blocking

the voltage gated Na+ channels in the cell membrane

Inhibits depolarization = NO action potential = anesthetic effects

Katzung B Basic & Clinical Pharmacology, 7th ed 1998

NMDA

Presynaptic Neuron

V-G Na

+ V-G Na

+

Cytoplasm

Postsynaptic

Neuron

AMPAAMPA AMPA

AMPA

DEPOLARIZATION

NMDANMDA NMDA

NMDA

α2 α2

V-G

Ca2+

V-G

Ca2+

μ μ

Ca2+

Ca2+

Mg2+

Ca2+

Ca2+

Glu

Glu

Na+Na+

NE5HT

μ μLidocaine

Na+

α2-Adrenoceptor AgonistClonidineSpecificity towards presynaptic α2 receptorsα2 receptors located in peripheral and

central terminals↓ Ca2+ levels = ↓ neurotransmissionLipophilic


NE Reuptake InhibitorTricyclic Antidepressants

AmitriptylineInhibition of nociceptive transmission via ↑ in

synaptic NE, 5-HT3

Blockade of α-adrenergic receptors?Anticholinergic effectsExtremely lipophilic


NMDA

Presynaptic Neuron

V-G Na

+

Release

V-G Na

+

Cytoplasm

Postsynaptic

Neuron

AMPAAMPA AMPA

AMPA

NMDANMDA NMDA

NMDA

α2 α2

V-G

Ca2+

V-G

Ca2+

μ μ

Ca2+

Ca2+

Mg2+

Ca2+

Ca2+

Glu

Glu

Na+Na+

NE5HT

μ μ

Clon

idine

TCA

Glutamate Antagonist

GabapentinAnalog of gamma-aminobutyric acid

Works via binding to the α2δ subunit of the voltage-gated N-type Ca++ ion channel

Modulates the Ca++ channel & ↓ Ca++ influx↓ presynaptic glutamate release

Davies A et al. Trends Pharmacol Sci 2007;28:220-8Taylor CP. CNS Drug Rev 2004;10:183-188

NMDA AntagonistKetamineN-methyl-D-aspartate antagonist Ionotropic receptor for glutamateBoth ligand-gated & voltage-gatedActivation results in opening of an ion

channelCalcium flux may be critical for synaptic

plasticityKatzung B Basic & Clinical Pharmacology, 7th ed 1998

NMDA

V-G Na

+

Release

V-G Na

+

Cytoplasm

Postsynaptic

Neuron

AMPAAMPA AMPA

AMPA

DEPOLARIZATION

NMDANMDA NMDA

NMDA

α2 α2

V-G

Ca2+

V-G

Ca2+

μ μ

Ca2+

Ca2+

Mg2+

Ca2+

Ca2+

Glu

Glu

Na+Na+

GluGlu

μ μ

Gaba

pent

in

Ketamine

Presynaptic Neuron

General Formulation “Rules”Select a DrugEstimate Drug PenetrationSelect a Vehicle?Role of Chemical Penetration EnhancerBe Realistic

LL

Jones M IJPC 2002; 6:4-6

Transdermal DeliveryDrugs listed in percentages

1% Solution = 1000mg/100ml(10mg/ml)

Morphine 1% solutionKetamine 5% in gel

Transdermal Delivery: Meds

Cyclo-oxygenase inhibitor2-10%Diclofenac α2-Adrenoceptor agonist0.1-0.3%ClonidineSubstance P blockade0.025-0.1%CapsaicinGABAβ agonist2-5%BaclofenNE reuptake inhibitor1-5%Amitriptyline

MechanismStrengthDrug

Glutamate antagonist5-10%Gabapentin

Mu (µ) agonist5-10%Loperamide

NMDA-receptor antagonist5-15%KetaminePropionic acid NSAID5-10%KetoprofenAnaesthetic2-10%Lidocaine

MechanismStrengthDrug

Transdermal Delivery: Meds

Transdermal NeuropathicsFour way X-over study, 20 pts c neuropathic pain2 d blinded trial Amitriptyline(A) 1% vs ketamine(K) 0.5% vs

A 1% + K 0.5% vs PLO gelNo relief for any patient11 pts in open label cohort

Topical A 1% + K 0.5% gel applied QID x 7 d

Lynch M et al. Clin J Pain 2003;19:323-28

Significant pain response noted with use of combination gelRash, burning at site in 2 pts No significant systemic absorption of any of the medicationsTopical meds need time to work

Lynch M et al. Clin J Pain 2003;19:323-28

Retrospective, orofacial pain pts (n=39)Systemic Rx, topical, bothTopical (apply 4-6 x daily) contains:

carbamazepine 4% lidocaine 1%ketoprofen 4% ketamine 4%gabapentin 4%

Pain measured baseline and at clinic visitsVAS, 30% reduction = good result

Transdermal Neuropathics

Heir G et al. OOOOE 2008:105:446-9

Best relief with combined therapiesShortest time to relief c topicalsAEs? Standard Rx? doses?Good start for line of researchProspective trials needed

Heir G et al. OOOOE 2008:105:446-9

Pain & Symptom Management Clinic

Multidisciplinary assessment/treatment of pts with symptoms related to cancer or its treatment(s)

Provide consultation, follow-up/evaluation of interventions

Symptoms suitable for clinicReferral from several sources

Pharmacy CollaborationImproved patient outcomes through:

Education of patients/family/allied healthcare membersMonitoring of adverse effectsDrug information/counselingMedication management

Date: __________________________Patient Name__________________________Address: __________________________Date of Birth:__________________________PHIN: __________________________Base: □ Lipoderm □ PLO □ Speed Gel

□ Other (specify) _____________________Check the Ingredient & Strength: Other Strength:Ketamine __5% __10% __15% ______%

(requires a duplicate Rx)Gabapentin __6% __8% __10% ______%Clonidine __0.1% __0.2% ______%Lidocaine __2% __4% __5% ______%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% ______%Camphor __0.25% Menthol __0.5%

Additional Ingredients: ____________________ ______%____________________ ______%

Sig: Apply _____mL to affected area(s)____________(frequency) _______________________.

Mitte: _______mL Refill x _______Physician Name (Print): _______________________________Address: _______________________________Phone: _______________________________Signature: _______________________________

G HarochawD WongP Daeninck

Transdermal Neuropathics

1st combination we use:Ketamine 5-15% Gabapentin 6-8%Lidocaine 2-6%

1st time use success rate ~ 30%Adjust %, add others, add DMSO Success after “fine tuning” gel ~ 70%

G Harochaw, Personal Communication

Clinical ChallengesFollow-up with patients after initial use:If able to contact, can adjust topical to work 70% of

timeIncorrect application (regardless of counselling)

too small an amountapplying to wrong arearubbing too aggressively → creating pain

Poor compound selectionCommunication/compliance issues

physicianspatients

G Harochaw, Personal Communication

Results from ClinicReferrals to P & S clinic13 patients

8 post therapy neuropathy (CT, RT, surgery)4 due to disease (breast ca)1 other (Zoster infection)

Ketamine/lidocaine common to allOther Rx: ketoprofen, gabapentin, loperamidePLO or lipodermTID to QID application

Complete information in 11 ptsAll had some benefit (↓VAS)1 stopped: worsening painAdjustments often improved pain control5 concomitant Rx (opioids, pregabalin)

Compliance may be a problemA/E: nilPts complaints: cost, greasy feeling, inconv.

Results from Clinic

Results from Clinic66 yo male, Stage III Colon, FOLFOX x 12Hands/feet neuropathy (8-9/10 baseline)

Several oral drugs (opioids, TCA, anti-epileptics)

Methadone (6/10 best result)

PLO gel with ketamine 5%, lidocaine 2%, gabapentin 4%, apply TID

Improved 4/10, ↑ gabapentin to 6%Present pain rated as 2/10

Where are we going?Which patients benefit most?Treatment algorithm?

which drugs?which carriers?condition specific?topical alone or with systemic therapy?

Formalize a protocolmeds, follow-up, timing

?Clinical trial

Synthetic cannabinoids20-30 x more potent

than Δ9-THCBenefits seen in emesis,

glaucoma, pain

SummaryPts with advanced diseases may require

alternative routes for Rx administrationTopical compounds gaining popularityEvidence for opioids, topicals emergingClinical trial support lackingCollaboration with pharmacy invaluable

ReferencesBack IN, Findlay I. JPSM 1995;10:493Twillman RK et al. JPSM 1999; 17:288-292Krajnik M, Zylicz Z et al. Pain 1999; 80:121-125Krajnik M, Zylicz Z. Palliative Med 1997; 11:325-326Krajnik M, Zylicz Z. Prog Palliative Care 1997; 5:101-106Jepson BA. Lancet 1992;339:503-504Stein C. NEJM 1995; 332:1685-1690Flock P. JPSM 2003; 25:547-554Zeppetella G, Paul J, Ribeiro MDC. JPSM 2003; 25:555-558Heir G et al. IJPC 2004; 8:337-343Schulz V et al. JPSM 2002;24 572-77Sawynok J. Pharmacol Rev 2003; 55:1-20Ribeiro MDC et al. JPSM 2004:27:434-39

ReferencesPaice JA et al. JPSM 2008:35:314-20Gallagher R et al. Clin J Pain 2005;21:190-2Jones M. IJPC 2002; 6:4-6Lynch M et al. Clin J Pain 2003;19:323-28Heir G et al. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:466-9

Valiveti S et al. Intl J of Pharmaceuticals 2004;278:173-80Kumar R et al. AAPS PharmSciTech 2005; 6 (2)Davies A et al. Trends Pharmacol Sci 2007 May;28(5):220-8 Taylor CP. CNS Drug Rev 2004;10:183-188Williams AC. Transdermal and topical drug delivery: from theory to

clinical practice, Pharmaceutical Press, London, 2003Katzung B. Basic & Clinical Pharmacology, 7th ed. 1998

slap it on! topical medications in palliative...

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