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



Subcutaneous



<2ml volumes
Much more rapid absorption than ID
Intramuscular




Small volumes  0.1ml
Absorption is slow  slow onset of action
2 – 5ml volumes
More rapid absorption than by SC
Can formulate a delayed response
Intravenous


Sterile Dosage Forms: S.
Turco, R. King
Small to large volumes
No absorption of drug  directly in vein
Pharmacokinetics for Absorption
IV 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


Epinephrine  vasoconstriction   drug absorption
Heat  blood flow   drug absorption
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;581-584
Vehicles Used1

PLO – Pluronic Lecithin Organobase









Pluronic  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
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-inflammatory’s, dexamethasone,
lidocaine

Phonophoresis
ultrasound to  transcutaneous drug
absorption
 NSAID’s, 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 first-pass
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 used as an anesthetic agent

Given 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


Phantom limb pain (Knox et al., 1995)
Post-operative pain and other post-traumatic pain

Control control pain during dressing changes

Low doses of ketamine have minimal adverse effects on
cardiovascular or respiratory function (Miller et al., 2000)
(Edie et al., 1994, 1995; Jackson et al., 2001; Kannan et al.,
2002; Kjepstad & Borchgrevnik., 1997; Mercandante et al., 1995, 2000; Mercandante & Arcuri, 1998)
(Dick-Neilsen et
al.,1992; Gurmani et al., 1996; Hirlinger & Dick, 1984; Hirlinger & Pfenninger, 1987; Lauretti &
Azevedo, 1996; Owen et al., 1987)
(Bookwalter, 1994;
Humphries et al, 1997; Kulbe, 1998; Pal et al, 1997)
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
Bretylium
Bupivicaine
Capsaicin
Carbamazepine
Clonidine
Cyclobenzaprine
Dextromethorphan
Strength
1-5%
2-5%
1-5%
0.25-10%
Mechanism
NE Reuptake inhibitor
GABA Agonist
Sympathetic Inhibition
Anesthetic
0.025-0.1% Substance P Blockade
2-5%
NMDA Na+ Blocker
0.1-0.3% Alpha -2 Agonist
1-4%
Muscle Relaxant
5-10% NMDA Receptor Antagonist
Medications Used in
Transdermal Delivery
Drug
Diclofenac
Diphenhydramine
Gabapentin
Guaifenesin
Ibuprofen
Indomethacin
Strength
Mechanism
2-10% Cyclooxygenase Inhibitor
5-10% Voltage Regulated Na+ &
Ca++ Blockade
5-10% Voltage Regulated Na+ &
Ca++ Blockade
Glutamate Antagonist
5-10% Muscle Relaxant
10-30% Propionic Acid NSAID
15-20% Methylated Indole NSAID
Drug
Strength
Mechanism
Ketamine
5-15%
NMDA Receptor Antagonist
Ketoprofen
5-10%
Propionic Acid NSAID
Lidocaine
2-10%
Anesthetic
Lipoic Acid
2-3%
Antioxidant
Loperamide
5-10%
Mu agonist
Naproxen
10-20%
Propionic Acid NSAID
Nifedipine
0.2-16% Non-NMDA Ca+2 Channel
Antagonist
Pentoxifylline
5-15%
TNF Inhibitor, Peripheral
Vasodilator
Phenytoin
0.5-2%
NMDA Na+ Blocker
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
disc
prevent sciatica caused by a herniated
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

depth up to 50mm
Tx 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 0.2% Ointment

Less side effects than NTG



HA’s, dizziness, lightheadedness hypotension
Ca++ antagonist   O2 demand and mechanical
contraction of smooth muscle
One study 95% complete healing rate in 21 days
Myofascial Pain
Topical Magnesium

Magnesium Chloride 10% PLO
 Use
twice daily
 Applied across whole “taught” band
 Can cause diarrhea

Magnesium 10%/ Pyridoxine 5% PLO
 Pyridoxine
  pain thresholds and
 serotonin levels
Diabetic Neuropathy
Ketamine 15%, Amitriptyline 2-5%,
Clonidine 0.1-0.3%%, Nifedipine 2-10%,
 Diclofenac 2-4%
 Burning sensation 
Alpha Lipoic Acid PO 600-1800mg/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%

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 _______