1. Topical Pain Control Medication
Gregory Harochaw
Pharmacy Manager
Tache Pharmacy
Phone

2. Goals and Objectives
Understand the pharmacokinetics of transdermal delivery
Advantages/disadvantages of transdermal route
Medications used for some different situations

3. Clearly all PPIs are effective
We need to understand how they get into the body and reach the target site – the parietal cell

4. Metabolism Cytochromes Once absorbed, metabolism is an issue
A large portion of the initial PPI dose is processed off by the cytochromes in the liver
Cytochromes

6. Parenteral Routes Intradermal Subcutaneous Intramuscular Intravenous
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 to large volumes
No absorption of drug  directly in vein
Sterile Dosage Forms: S. Turco, R. King

7. 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

8. 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

11. 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

12. 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

13. 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

14. 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

15. 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;

16. 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

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

18. Ointment Mill The ointment mill mixes powders, crystals and
creams into a smooth, finished product

19. Bases To Be Used1 Lipoderm Creamier base than PLO
Cosmetically more elegant
Less sticky
Less smell
Not as temperature sensitive as PLO
Cold temperatures PLO may separate
Less chance of rash vs PLO
Only compounding pharmacies can make

20. 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

21. Sports Medicine Iontophoresis Phonophoresis
Enhance absorption of ions by the use of an electrical current
Anti-inflammatory’s, dexamethasone, lidocaine
Phonophoresis
Uses ultrasound to  transcutaneous drug absorption
NSAID’s, dexamethasone

22. 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

23. 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:

24. 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:

25. Medication Step 1: Peripheral Stimulation & Nociceptor Sensitization
Prostaglandins
Bradykinin
Histamine
Leukotrienes
Step 1: Peripheral Stimulation & Nociceptor Sensitization +
Substance P
Glutamate
Aspartic Acid
Nitric Oxide +
Step 2: Signal Transmission -
“Opioids” refer to all medications which stimulate opioid receptors (mu, kappa, delta). At therapeutic concentrations, opioids mimic endogenous endorphins and enkephalins, thereby decreasing pain signal transmission from the nociceptor to the spinal cord and from the spinal cord to the brain.
Enkephalins
Endorphins
Medication
Step 3: Pain Perception -

27. NMDA and AMPA Receptors
Na+ influx exacerbates the Ca++ influx in absence of Mg++
This results in “wind up” pain, LTP and Allodynia
Influx of Ca++ ions after Mg++ ions dislodged
Na+ ions influx will exacerbate the Ca++ ion influx

28. 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

29. 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 (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)

30. Ketamine2
REQUIRES A TRIPLICATE

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

32. Medications Used in Transdermal Delivery
Drug
Strength
Mechanism
Amitriptyline
1-5%
NE Reuptake inhibitor
Baclofen
2-5%
GABA Agonist
Bretylium
Sympathetic Inhibition
Bupivicaine %
Anesthetic
Capsaicin %
Substance P Blockade
Carbamazepine
NMDA Na+ Blocker
Clonidine %
Alpha -2 Agonist
Cyclobenzaprine
1-4%
Muscle Relaxant
Dextromethorphan
5-10%
NMDA Receptor Antagonist

33. Medications Used in Transdermal Delivery
Drug
Strength
Mechanism
Diclofenac
2-10%
Cyclooxygenase Inhibitor
Diphenhydramine
5-10%
Voltage Regulated Na+ & Ca++ Blockade
Gabapentin
Glutamate Antagonist
Guaifenesin
Muscle Relaxant
Ibuprofen
10-30%
Propionic Acid NSAID
Indomethacin
15-20%
Methylated Indole NSAID

34. Non-NMDA Ca+2 Channel Antagonist Pentoxifylline
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
Mu agonist
Naproxen
10-20%
Nifedipine
0.2-16%
Non-NMDA Ca+2 Channel Antagonist
Pentoxifylline
TNF Inhibitor, Peripheral Vasodilator
Phenytoin
0.5-2%
NMDA Na+ Blocker

35. 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

36. Arthritic Pain Diclofenac 2 – 4 % used for years Pennsaid 1.5% Add
Amitriptyline 2 – 5%  bone pain
Capsaicin – 1%  Substance P blocker
Gabapentin 6 – 10%  Neuropathic pain
Lidocaine 2-10%  Na channel blocker

37. 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:

38. Shingles
Ketamine 15%, amitriptyline 2-5%, loperamide 5-10%, lidocaine 2-10%
Topical spray
Ketamine 10%, bupivicaine %
Ketamine 4%, morphine sulfate 4%
2-Deoxy-D-Glucose 2%, Diphenhydramine 2%, Lidocaine 4%

39. 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

40. Sensory Neuropathy “Tingling” Sensation
Gabapentin 6%, loperamide 10% & lidocaine 2%
Amitriptyline 2%
Clonidine 0.1%
Apply to affected areas for 2 – 4 weeks

41. 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

42. Myofascial Pain

43. 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

44. Diabetic Neuropathy
Ketamine 15%, Amitriptyline 2-5%, Clonidine %%, Nifedipine 2-10%,  Diclofenac 2-4%
Burning sensation  Alpha Lipoic Acid PO mg/day
Topically 0.5-3%

45. Fibromyalgia Ketoprofen 10%, cyclobenzaprine 3%, lidocaine 5%
Amitriptyline 5%, baclofen 2%, diclofenac 2%, lidocaine 2%
Ketoprofen 10% & baclofen 5%  lidocaine 5%

46. Mitte: _______mL Refill x _______
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 _______