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

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

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

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

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 temperatures PLO may separate Less 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 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

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

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 -

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

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 (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

Medications Used in Transdermal Delivery Drug Strength Mechanism Amitriptyline 1-5% NE Reuptake inhibitor Baclofen 2-5% GABA Agonist Bretylium Sympathetic Inhibition Bupivicaine 0.25-10% Anesthetic Capsaicin 0.025-0.1% Substance P Blockade Carbamazepine NMDA Na+ Blocker Clonidine 0.1-0.3% Alpha -2 Agonist Cyclobenzaprine 1-4% Muscle Relaxant Dextromethorphan 5-10% NMDA Receptor Antagonist

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

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

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 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%

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 _______