Topical Pain Control

Medication
Gregory Harochaw
Pharmacy Manager
Tache Pharmacy
Phone 204-233-3469
tache@mts.net

Goals and Objectives

Understand

the pharmacokinetics of
transdermal delivery
Advantages/disadvantages of
transdermal route
Medications used for some different
situations

Metabolism

Cytochromes

Parenteral Routes
Intradermal
Small

volumes 0.1ml
Absorption is slow slow onset of action
Subcutaneous
<2ml

volumes
Much more rapid absorption than ID
Intramuscular
2

5ml volumes
More rapid absorption than by SC
Can formulate a delayed response
Intravenous
Small

Sterile Dosage Forms: S.

Turco, R. King

to large volumes
No absorption of drug directly in vein

 IV

Pharmacokinetics for
Absorption

route immediate & total access to

active drug molecules
IM, SC, ID require an absorption
step
The

vascularity of the IM route is greater

than the SC route absorption

Sterile Dosage Forms:

S. Turco, R. King

 SC

injections active drug absorbed by

diffusion of drug into the capillary network
The

greater the blood flow in the capillary

network the greater the absorption of the drug

vasoconstriction drug absorption

Heat blood flow drug absorption
Epinephrine

Stratum Corneum (horny

layer)
Compared

to bricks & mortar

10-15 layers of flattened cornified cells
constitute the bricks
Lipid-rich intercellular matrix constitutes
the mortar
form

an effective barrier to transdermal water

loss & external chemical access
If a drug is to pass through the skin & into
general circulation, it must 1st traverse this
barrier

Factors for Drug

Absorption

Transcutaneous

flow of compounds across

the stratum corneum is directly
proportional to the concentration gradient
& therefore can be attributed to passive
diffusion
As surface area & thickness of epidermis
, the rate of transdermal flux
The underlying epidermal layers & the
dermis area are an aqueous environment

Factors for Drug

Absorption
Highly

hydrophilic drugs will absorb

poorly through the stratum corneum
but better in the aqueous layers of
the epidermis
Highly lipophilic drugs will absorb
better through the stratum corneum
but slowed when they reach the
aqueous layers of epidermis

Finding a Suitable Carrier

For

compounds used exclusively for the

treatment of a skin condition, passive
diffusion into the superficial epidermis
may be sufficient
Using

a vehicle such as Glaxal Base or

Vaseline

For

a drug to be delivered to the general

circulation, the drug/vehicle must
maintain affinity for both aqueous and
lipid environments to absorb effectively

Site Permeability
Generalized

rank order of site

permeabilities:
genitals

> head/neck > trunk > arm

> leg
Preterm infant > term infant > young
adult
> elderly Klein & collegues,. Transdermal
Clonidine Therapy in Elderly Mild Hypertensives; Hypertension Suppl 1985:3;581584

Vehicles Used1
PLO

Pluronic Lecithin Organobase

hydrophilic phase
Lecithin Isopropyl Palmitate lipophilic phase
Mixing Pluronic Gel & Lecithin Isopropyl Palmitate
under pressure (with the drug) will form an amphiphilic
phase containing drug micelles
Pluronic

Gold

standard available most Rx

Provides good penetration into skin
Works well with a variety of lipophilic/hydrophilic
agents
Need to rub in well???
Greasy base
The 2 phases can separate under cold conditions

Electronic and Electro Mortar &

Pestles
The electronic
mortar &
pestle provide
pharmacists
with the
modern way
to compound
creams,gels,
ointments
and
suspensions.

Ointment Mill

The ointment mill mixes powders, crystals and

creams into a smooth, finished product

Bases To Be Used1
Lipoderm
Creamier

base than PLO

Cosmetically

more elegant

Less

sticky
Less smell
Not

as temperature sensitive as PLO

Cold

Less

temperatures PLO may separate

chance of rash vs PLO

Only compounding pharmacies can make

Bases To Be Used1
Penetration

rates:

Pentravan,VanPen,

PLO 5-20mm
PCCA Gel 2058 1-3mm (Intradermal)
PCCA Gel 4038 10-20mm
PCCA Gel 6633 +30mm
Speed Gel up to 50mm

Sports Medicine
Iontophoresis
Enhance

absorption of ions by the use of

an electrical current
Anti-inflammatorys, dexamethasone,
lidocaine
Phonophoresis

ultrasound to transcutaneous
drug absorption
NSAIDs, dexamethasone
Uses

Reasons for Topical Route

Oral route not desirable
Mucositis
Inability to swallow
Nausea/vomiting
Obstruction
Poor taste of product
Dry mouth

Can produce a more localized action

Also can be used for systemic use
GH

Topical Route: Advantages

Avoids the GI tract and hepatic firstpass metabolism
Reduces systemic side effects
Improves compliance
Allows concentration of Rx at site of
application
Plasma concentrations of <10%
compared to oral route
Heir, Gary DMD, et al. IJPC 2004; 8:337-343

Topical Route: Drawbacks

Variations in the stratum corneum
barrier
Delivery dosing may require
adjustment
Rate of absorption may vary

Rash most common SE

May be incumbent when using larger
areas
Heir, Gary DMD, et al. IJPC 2004; 8:337-343

Prostaglandins
Bradykinin

Step 1: Peripheral
Stimulation &
Nociceptor
Sensitization

Histamine

Leukotrienes

Substance P
Glutamate
Aspartic Acid
+

Nitric Oxide
-

Step 2: Signal
Transmission
Enkephalins
Endorphins

Step 3: Pain
Perception

Medication

NMDA and AMPA Receptors

Na+ influx exacerbates the Ca++ influx in absence of Mg++
This results in wind up pain, LTP and Allodynia

Drugs That Effect Ion

Channels
NMDA-Ca++

channel blockers:

Ketamine,

orphenadrine,
amantadine,DM, magnesium,
haloperidol, nylidrin, methadone

AMPA-Na+

channel blockers:

Anticonvulsants
Gabapentin,

carbamazepine

Antiarrythmics:
Lidocaine,

mexilitine

Ketamine
Widely
Given

used as an anesthetic agent

IV, IM, PO, PR, intranasally or spinally

(Chia et al.,
1998; Gehling and Tryba, 1998; Malinovsky et al., 1996; Mercandante et al., 2000;
Walker et al., 2002)

Safety

and efficacy of ketamine and analgesic

well documented (Malinovsky et al., 1996; Reich & Silvay. 1989; White et
al., 1982)

Tx in neuropathic pain (Edie et al., 1994, 1995; Jackson et al., 2001;

Kannan et al., 2002; Kjepstad & Borchgrevnik., 1997; Mercandante et al., 1995, 2000;
Mercandante & Arcuri, 1998)

Phantom limb pain (Knox et al., 1995)

Post-operative pain and other post-traumatic pain
(Dick-Neilsen et al.,1992; Gurmani et al., 1996; Hirlinger & Dick, 1984; Hirlinger &
Pfenninger, 1987; Lauretti & Azevedo, 1996; Owen et al., 1987)

Control control pain during dressing changes

(Bookwalter,

1994; Humphries et al, 1997; Kulbe, 1998; Pal et al, 1997)

Low doses of ketamine have minimal adverse effects

on cardiovascular or respiratory function (Miller et al., 2000)

Ketamine2

REQUIRES A
TRIPLICATE

Medications Used in
Transdermal Delivery
Drugs listed in percentages
1% Solution = 1000mg/100ml
OR
10mg/ml
Hydromorphone 1% solution
10mg/ml

Medications Used in
Transdermal Delivery
Drug
Amitriptyline
Baclofen

Strength
Mechanism
1-5%
NE Reuptake inhibitor
2-5%
GABA Agonist

Bretylium
Bupivicaine

1-5%
0.2510%

Sympathetic Inhibition
Anesthetic

Capsaicin

0.0250.1%

Substance P Blockade

Carbamazepin
e
Clonidine

2-5%

NMDA Na+ Blocker

0.1-0.3% Alpha -2 Agonist

Drug
Diclofenac

Medications Used in
Transdermal Delivery

Strength
Mechanism
2-10% Cyclooxygenase
Inhibitor
Diphenhydrami 5-10% Voltage Regulated Na+
ne
& Ca++ Blockade
Gabapentin
5-10% Voltage Regulated Na+
& Ca++ Blockade
Glutamate Antagonist
Guaifenesin
5-10% Muscle Relaxant
Ibuprofen
10-30% Propionic Acid NSAID
Indomethacin
15-20% Methylated Indole

Drug
Ketamine

Strength
Mechanism
5-15% NMDA Receptor

Ketoprofen
Lidocaine
Lipoic Acid
Loperamide
Naproxen
Nifedipine

5-10%
2-10%
2-3%
5-10%
10-20%
0.2-16%

Propionic Acid NSAID

Anesthetic
Antioxidant
Mu agonist
Propionic Acid NSAID
Non-NMDA Ca+2
Channel Antagonist

Pentoxifylline

5-15%

Phenytoin

0.5-2%

TNF Inhibitor,
Peripheral Vasodilator
NMDA Na+ Blocker

Antagonist

Quirks
Ketamine

has highest affinity for NMDA

receptors of products given
Amitriptyline has a synergistic effect
with ketamine
Fibromyalgia baclofen works well as an
add on
Complex regional pain amitriptyline and
bretylium
Diclofenac > pruritis than ketoprofen

Arthritic Pain
Diclofenac

2 4 % used for years

Pennsaid 1.5%
Add
Amitriptyline

2 5% bone pain
Capsaicin 0.025 1% Substance P
blocker
Gabapentin 6 10% Neuropathic pain
Lidocaine 2-10% Na channel blocker

Sciatica
Gabapentin

6%, Clonidine 0.1%,

Diclofenac 2% & Lidocaine 2%
Above mixture + Pentoxyfylline 5%
May

prevent sciatica caused by a

herniated disc

Yabuki et al. Prevention of compartment syndrome in dorsal root ganglia

caused
by exposure to nucleus pulposus. Spine 2001;26:870-875

Shingles
Ketamine

15%, amitriptyline 2-5%,

loperamide 5-10%, lidocaine 2-10%
Topical spray
Ketamine

10%, bupivicaine 0.3-0.75%

Ketamine 4%, morphine sulfate 4%
2-Deoxy-D-Glucose

2%,
Diphenhydramine 2%, Lidocaine 4%

Shingles
Capsaicin

0.025-0.1% substance P

blockade
Speed gel???
Penetration

Tx

depth up to 50mm

may take up to 8 weeks to get

maximum relief

Sensory Neuropathy
Tingling Sensation
Gabapentin

6%, loperamide 10% &

lidocaine 2%
Amitriptyline

2%
Clonidine 0.1%
Apply

to affected areas for 2 4

weeks

Treatment of Anal Fissures

Nitroglycerin

0.2% Ointment

Success

rates 48-78% in treating anal fissures

NTG metabolized it releases nitric oxide an
inhibitory neurotransmitter for smooth muscle
Given 3 5 times daily
Nifedipine
Less

0.2% Ointment

side effects than NTG

HAs,

dizziness, lightheadedness hypotension

antagonist O2 demand and mechanical

contraction of smooth muscle
One study 95% complete healing rate in 21 days
Ca++

Myofascial Pain

Topical Magnesium
Magnesium

Chloride 10% PLO

Use

twice daily
Applied across whole taught band
Can cause diarrhea
Magnesium
Pyridoxine

10%/ Pyridoxine 5% PLO

pain thresholds and
serotonin levels

Diabetic Neuropathy
Ketamine

15%, Amitriptyline 2-5%,

Clonidine 0.1-0.3%%, Nifedipine 210%,
Diclofenac
2-4%
Burning sensation
Alpha Lipoic Acid PO 6001800mg/day
Topically 0.5-3%

Fibromyalgia
Ketoprofen

10%, cyclobenzaprine 3%,

lidocaine 5%
Amitriptyline 5%, baclofen 2%, diclofenac
2%, lidocaine 2%
Ketoprofen 10% & baclofen 5%
lidocaine 5%

 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% __1

Menthol
__ 0.5%

Camphor
__0.25%
dditional Ingredients: _________________ _____% _________________
_____%

ections:

Apply _____mL to affected area(s) (specify) _____________________

(frequency) _______________________.
Mitte:
_______mL
Refill x _______