Topical & Transdermal Medications in Palliative Medicine

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DISCLAIMER: This slideset does not constitute medical advice. References are provided through out, please discuss with your own doctor or consult your own references before utilizing any information found in this slideset. Presented to the University of Kansas Palliative Medicine Fellowship lecture group.

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  • By definition, topical drugs used to control pain will act locally on damaged or dysfunctional soft tissues or peripheral nerves. Topical delivery systems differ from transdermal delivery systems in that they target a site immediately adjacent to the site of delivery rather than using the skin as an alternate systemic delivery system. FDA identifies 111 official routes of medication administration: http://www.fda.gov/cder/dsm/DRG/drg00301.htm including other and not applicable
  • Stratum corneum poses a formidable challenge to drug delivery systems
  • Also CaJo Anes compared dicolfenac versus EMLA 54:196-200
  • Cochrane database – amethocaine is better Also lmx which is lidocaine only
  • Cochrane review Lander JA, Weltman BJ, So SS. EMLA and Amethocaine for reduction of children's pain associated with needle insertion. Art. No.: CD004236. DOI: 10.1002/14651858.CD004236.pub2.
  • http://www.eperc.mcw.edu/FastFactPDF/Concept%20185.pdf
  • Pain. 1999 Mar;80(1-2):121-5.Links Potential uses of topical opioids in palliative care--report of 6 cases. Krajnik M , Zylicz Z , Finlay I , Luczak J , van Sorge AA . Department of Palliative Care, The Ludwig Rydygier Medical University, Bydgoszcz, Poland. Opioids used topically may exercise several useful clinical effects. Opioids may cause immediate local analgesia and also may work indirectly through decreasing the inflammation process. In this article we describe six patients treated with topical opioids because of cutaneous pain due to tumor infiltration. skin ulcers of malignant and non-malignant origin, severe oral mucositis, pain due to knee arthrosis and severe tenesmoid pain. In all but one case, topical morphine provided rapid relief which lasted usually for 7-8 h. The side effects of topical opioids were none or minimal. Possible mechanisms of topical analgesia are discussed. 2% morphine solution
  • Morphine Bioavailability from a Topical Gel Formulation in Volunteers .  Journal of Pain and Symptom Management , Volume 35 , Issue 3 , Pages 314 - 320 J . Paice , J . Von Roenn , J . Hudgins , L . Luong , T . Krejcie , M . Avram Although available therapies provide relief to many patients with cancer-related pain, swallowing difficulties or intestinal obstruction may preclude oral analgesic delivery in some. Topical morphine might provide an alternate delivery form but morphine bioavailability from a topical gel formulation has not been reported in humans. We conducted a randomized, placebo-controlled, double-blind, crossover study of five volunteers after they provided institutionally-approved, written, informed consent. They were admitted to the Northwestern University General Clinical Research Center twice, being randomly assigned to receive either 1mL of morphine compounded at 10mg/mL in pluronic lecithin organogel (PLO) base applied to the wrist and 1mL of normal saline administered subcutaneously, or 1mL of topical drug-free PLO base and 1mL of subcutaneous morphine, 3mg/mL, the first time and the opposite combination the second. Seventeen blood samples were collected from 5minutes to 10hours after dose administration for morphine concentration determination. Plasma samples were prepared by solid-phase extraction and morphine concentrations measured by a mass spectrometric technique with a linear range of 0.5–500ng/mL. Bioavailability of the topical formulation relative to the subcutaneous dose was to be estimated from doses and the plasma morphine concentration versus time relationships. Because morphine was seldom detected in plasma samples after topical administration and was unquantifiable when it was, the low bioavailability of topical morphine was unquantifiable. These results suggest that topical administration of morphine compounded in a PLO base for transdermal drug delivery is unlikely to provide relief of cancer-related pain.
  • 3 patients had dementia, and the patients could not use pain scales, so the staff rated their pain.
  • Case reports of toxicity in children with VZV Bernhardt DT. Related Articles , Links Topical diphenhydramine toxicity. Wis Med J. 1991 Aug;90(8):469-71. PMID: 1926887 [PubMed - indexed for MEDLINE] 4: Chan CY, Wallander KA. Related Articles , Links Diphenhydramine toxicity in three children with varicella-zoster infection. DICP. 1991 Feb;25(2):130-2. Review. PMID: 2058184 [PubMed - indexed for MEDLINE] 5: 2: Int J Pharm. 2001 Oct 9;228(1-2):79-87. Links Evaluation of in vitro percutaneous absorption of lorazepam and clonazepam from hydro-alcoholic gel formulations. Puglia C , Bonina F , Trapani G , Franco M , Ricci M . Department of Pharmaceutical Sciences, School of Pharmacy, University of Catania, Viale Andrea Doria no. 6, 95125, Catania, Italy. boninaf@mbox.unict.it Nokhodchi A , Shokri J , Dashbolaghi A , Hassan-Zadeh D , Ghafourian T , Barzegar-Jalali M . School of Pharmacy, Tabriz Medical Sciences University, Tabriz, Iran. nokhodchia@hotmail.com Huston RL, Cypcar D, Cheng GS, Foulds DM. Related Articles , Links Toxicity from topical administration of diphenhydramine in children. Clin Pediatr (Phila). 1990 Sep;29(9):542-5. No abstract available. PMID: 2242650 [PubMed - indexed for MEDLINE] 2003 albino rats in india with a TDDS Drug Dev Ind Pharm. 2003 Apr;29(4):405-15.Links Transdermal drug delivery system of haloperidol to overcome self-induced extrapyramidal syndrome. Samanta MK , Dube R , Suresh B .
  • Topical capsaicin preparations of 0.025 and 0.075% Postherpetic neuralgia Bernstein et al., 1989;Watson et al., 1993 Diabetic neuropathy Capsaicin Study Group, 1992 Postmastectomy pain syndrome Watson and Evans, 1992; Dini et al., 1993 Oral neuropathic pain, Trigeminal neuralgia, and TMJ disorders Epstein and Marcoe, 994; Hersh et al., 1994 Cluster headache (following intranasal application) Marks et al., 1993 Osteoarthritis McCarthy and McCarthy, 1992 Dermatological/cutaneous conditions Hautkappe et al., 1998
  • Topical & Transdermal Medications in Palliative Medicine

    1. 1. Topical & Transdermal Medications Christian Sinclair, MD Kansas City Hospice & Palliative Care October 8, 2008
    2. 2. Medication Routes <ul><li>Oral </li></ul><ul><li>Intravenous </li></ul><ul><li>Rectal </li></ul><ul><li>Intraosseous </li></ul><ul><li>Intrathecal </li></ul><ul><li>Inhaled </li></ul><ul><li>Optical </li></ul><ul><li>Topical </li></ul><ul><li>Sublingual/Buccal </li></ul><ul><li>Subcutaneous </li></ul><ul><li>Intravesical </li></ul><ul><li>Intramuscular </li></ul><ul><li>Epidural </li></ul><ul><li>Insuffluation </li></ul><ul><li>Intravitreal </li></ul><ul><li>Transdermal </li></ul>
    3. 3. Indications for Alternate Route <ul><li>Unwilling or unable to swallow meds </li></ul><ul><li>Cancers of the head, neck and GI tract </li></ul><ul><li>Compromise of the GI tract </li></ul><ul><ul><li>Mucositis </li></ul></ul><ul><ul><li>Bowel obstruction </li></ul></ul><ul><li>Intolerable side effects during administration </li></ul><ul><li>Treating localized pain </li></ul><ul><li>Avoiding systemic side effects </li></ul><ul><li>Neonatal/pediatric populations </li></ul>
    4. 4. Topical versus Transdermal <ul><li>Topical </li></ul><ul><ul><li>Treats at the site of medication placement </li></ul></ul><ul><ul><li>Usually compounded, often non-branded </li></ul></ul><ul><ul><li>Antibiotics for skin infection </li></ul></ul><ul><ul><li>Steroid creams for rashes </li></ul></ul><ul><li>Transdermal </li></ul><ul><ul><li>Treats via systemic delivery of the medication </li></ul></ul><ul><ul><li>Usually branded and not compounded </li></ul></ul><ul><ul><li>Hormone replacement, nicotine addiction, Duragesic </li></ul></ul>
    5. 6. Variations
    6. 7. Factors affecting absorption <ul><li>Flow increases with </li></ul><ul><ul><li>Increased concentration </li></ul></ul><ul><ul><li>Increased surface area </li></ul></ul><ul><ul><li>Decreasing skin thickness </li></ul></ul><ul><ul><li>Lipophillic compounds </li></ul></ul><ul><ul><li>Low molecular weights </li></ul></ul>
    7. 8. Available Brand Medications <ul><li>• Contraceptives/HRT </li></ul><ul><li>• Lidocaine </li></ul><ul><li>• Clonidine </li></ul><ul><li>• Nicotine </li></ul><ul><li>• EMLA </li></ul><ul><li>• Nitroglycerin </li></ul><ul><li>• Methylphenidate </li></ul><ul><li>• Estradiol </li></ul><ul><li>• Oxybutynin </li></ul><ul><li>• Estrogen </li></ul><ul><li>• Scopolamine </li></ul><ul><li>• Fentanyl </li></ul><ul><li>• Testosterone </li></ul>
    8. 9. Compounding Vehicles <ul><li>PLO – Pluronic Lecithin Organogel </li></ul><ul><li>Can hold guest molecules which are solubilized in the gel </li></ul><ul><li>DMSO </li></ul><ul><li>Other proprietary gels </li></ul>
    9. 10. Other topical meds in Pubmed <ul><li>Hormones-estriol and estradiol, DHEA, progesterone, testosterone </li></ul><ul><li>NSAIDs-ketoprofen, diclofenac, piroxicam </li></ul><ul><li>SSRIs –fluoxetine, paroxetine </li></ul><ul><li>Antipsychotics-haloperidol, prochlorperazine </li></ul><ul><li>Levodopa </li></ul><ul><li>Morphine </li></ul><ul><li>Dexamethasone </li></ul><ul><li>Calcium channel blockers-diltiazem, nifedipine </li></ul><ul><li>Clonidine with gabapentin and ketamine </li></ul><ul><li>Lidocaine, tetracaine </li></ul>
    10. 11. Evidence for Topical Meds <ul><li>Poor to Fair </li></ul><ul><li>Animal studies (cats) in small numbers </li></ul><ul><li>Many are single dose studies </li></ul><ul><li>Rare human drug level studies </li></ul><ul><li>Rare human symptom studies </li></ul>
    11. 12. Topical Diclofenac <ul><li>OA, lateral epicondylitis </li></ul><ul><li>2% topical dicoflenac </li></ul><ul><li>n=74, 14 </li></ul><ul><li>Improved pain, stiffness, physical function </li></ul><ul><li>J Rheum 1999, Clin J Sport Med 1998 </li></ul>
    12. 13. Topical NSAIDs <ul><li>Stay mostly in the dermis </li></ul><ul><li>Can reach synovial fluid </li></ul><ul><li>Efficacy ranges from 18-92% </li></ul>
    13. 14. EMLA Cream/Disc <ul><li>Typically used in the pediatric population </li></ul><ul><li>1G for 60 mins before efficacy </li></ul><ul><li>Localized effect </li></ul><ul><li>5% emulsion preparation </li></ul><ul><li>Combination of lidocaine and prilocaine </li></ul><ul><li>Strong evidence base </li></ul><ul><li>Patch 60 minutes provides 2 hours of relief </li></ul>
    14. 15. Amethocaine <ul><li>1G amethocaine gel 30 mins </li></ul><ul><li>Better results then EMLA in less time </li></ul>
    15. 16. Topical Ketamine <ul><li>No to minimal effect </li></ul><ul><ul><li>With neuropathic or capsacin induced pain </li></ul></ul><ul><li>Ionotopheresis assisted delivery </li></ul><ul><li>Open label showed long term effectiveness </li></ul><ul><li>Often combined with amitriptyline </li></ul>
    16. 17. Lidocaine Patch <ul><li>5% Lidocaine </li></ul><ul><li>Topical not transdermal </li></ul><ul><li>Indicated for Post-herpetic Neuralgia </li></ul><ul><li>Tried in </li></ul><ul><ul><li>CTS, OA, vaccinations, venipuncture </li></ul></ul><ul><li>Also available as lidocaine gel </li></ul>
    17. 18. Topical Opioids <ul><li>Opioid receptors on: </li></ul><ul><ul><li>Peripheral nerves </li></ul></ul><ul><ul><li>Inflammed skin </li></ul></ul><ul><li>Morphine and metabolites not found systemically </li></ul><ul><li>? Wound healing mechanism </li></ul><ul><ul><li>Up-regulate nitric oxide synthase </li></ul></ul>
    18. 19. Topical Opioids <ul><li>Skin infiltration of tumor </li></ul><ul><li>Nonmalignant skin ulcers </li></ul><ul><li>Severe oral mucositis </li></ul><ul><li>Knee arthritis </li></ul><ul><li>Tenesmoid pain. </li></ul>Pain. 1999 Mar;80(1-2):121-5.
    19. 20. Topical Opioids <ul><li>Mostly used for pressure ulcer pain </li></ul><ul><li>Relief modest for about 7-8 hours </li></ul><ul><li>Gel form </li></ul><ul><ul><li>10 mg of morphine sulfate injection (10mg/ml) </li></ul></ul><ul><ul><li>in 8 gm of Intrasite gel </li></ul></ul><ul><ul><li>or gel infused dressing </li></ul></ul><ul><li>Also for burn wounds </li></ul><ul><ul><li>MISS->Morphine Infused Silver Sulfadiazene </li></ul></ul>
    20. 21. http://www.supportiveoncology.net/journal/articles/0506289.pdf
    21. 22. Topical Methadone <ul><li>Methadone 100mg in 10g Stomadhesive powder </li></ul><ul><li>Varied results in wound application </li></ul><ul><li>Analgesic effects of topical methadone: a report of four cases. </li></ul>Clin J Pain. 2005 Mar-Apr;21(2):190-2.
    22. 23. Topical antidepressants <ul><li>Topical Doxepin combined with capsacin for chronic neuropathic pain </li></ul><ul><li>Doxepin mouthwash improved oral mucosal pain in cancer patients </li></ul>
    23. 24. Transdermal Medications
    24. 25. Testosterone <ul><li>Transdermal Patch </li></ul><ul><li>Transdermal Cream/Gel </li></ul><ul><ul><li>Testim or Androgel 1% QD </li></ul></ul><ul><li>Injectable, oral, and buccal forms </li></ul><ul><li>Indicated for testosterone replacement therapy </li></ul><ul><ul><li>Increased lean body mass, decreased fat mass, increased bone mineral density, increased sexual activity and desire </li></ul></ul>
    25. 26. Transdermal Nicotine <ul><li>Approved for nicotine replacement therapy </li></ul><ul><li>Effects of nicotine </li></ul><ul><ul><li>Increases glucose, epinephrine </li></ul></ul><ul><ul><li>Enhances serotonin and opiate receptors? </li></ul></ul><ul><ul><li>Stimulant, but also anxiolytic </li></ul></ul><ul><ul><li>Appetite suppressant </li></ul></ul><ul><li>Not indicated in naïve patients </li></ul>
    26. 27. Fentanyl Transdermal Patch <ul><li>Well studied </li></ul><ul><li>92% bioavailable </li></ul><ul><li>Strong mu opioid agonist </li></ul><ul><li>Lipophillic -> High CNS Concentration </li></ul><ul><li>Reservoir and Matrix patches </li></ul><ul><li>Affected by skin thickness and temperature </li></ul><ul><li>Less constipating </li></ul>
    27. 28. Fentanyl Transdermal Patch
    28. 29. Source: Duragesic package insert
    29. 30. Source: Duragesic package insert
    30. 31. Scopolamine Transdermal Patch <ul><li>Motion sickness </li></ul><ul><li>Opioid induced nausea </li></ul><ul><li>Smooth muscle spasm </li></ul><ul><li>Parkinson’s </li></ul><ul><li>Drying secretions </li></ul><ul><li>Pyrexia/Sweating </li></ul>
    31. 32. Scopolamine Transdermal Patch <ul><li>Belladonna alkaloid (Hyoscine) </li></ul><ul><li>Anti-cholinergic </li></ul><ul><li>Side effects: </li></ul><ul><ul><li>Drowsiness, dilated pupils, increased HR </li></ul></ul><ul><li>Initial bolus, then 120mcg/d x 3d </li></ul><ul><li>Plasma – 4hrs, Peak 24hrs </li></ul><ul><li>Post-auricular? </li></ul><ul><li>Cost: $8/patch </li></ul>
    32. 33. Transdermal ABHR <ul><li>Ativan (lorazepam) </li></ul><ul><ul><li>2 articles </li></ul></ul><ul><li>Benadryl (diphenhydramine) </li></ul><ul><ul><li>Case reports </li></ul></ul><ul><li>Haldol (haloperidol) </li></ul><ul><ul><li>One study </li></ul></ul><ul><li>Reglan (metoclopramide) </li></ul><ul><ul><li>No studies </li></ul></ul>
    33. 34. <ul><li>“ Yes, you’re changed; you’ve got new ideas over here,” her friend continued. </li></ul><ul><li>“ I hope so,” said Isabel; “one should get as many new ideas as possible.” </li></ul><ul><li>“ Yes; but they shouldn’t interfere with the old ones when the old ones have been the right ones.” </li></ul><ul><li>Henry James, Portrait of a Lady </li></ul>
    34. 35. The Future <ul><li>More studies </li></ul><ul><li>Med-Tats </li></ul><ul><li>Micro-needles </li></ul><ul><li>Needless jet injectors </li></ul><ul><li>Ionotophoresis </li></ul><ul><li>Phonophoresis </li></ul><ul><li>Liposomal delivery </li></ul>
    35. 36. Review <ul><li>Topical vs. Transdermal </li></ul><ul><li>Know the drug </li></ul><ul><li>If it is branded, likely some efficacy </li></ul>
    36. 37. Bibliography <ul><li>Carnel SB, Blakesless DB, Oswald SG, Barnes M. Treatment of radiation and chemotherapy-induced stomatitis. Otolaryngol Head Neck Surg. 1990;102:326-30. </li></ul><ul><li>Cerchietti LC, Navigante AH, Bonomi MR et al. Effect of topical morphine for mucositis-associated pain following concomitant chemoradiotherapy for head and neck carcinoma. Cancer. 2002;95:2230-2236. </li></ul><ul><li>Flock P. Pilot study to determine the effectiveness of diamorphine gel to control pressure ulcer pain. J Pain and Symptom Management. 2003;25:547-554. </li></ul><ul><li>Gallagher RE, Arndt DR, Hunt K. Analgesic effects of topical methadone; a report of four cases. Clin J Pain. 2005;21:190-192. </li></ul><ul><li>5. Kalso E, Tramer MR, Carroll D et al. Pain relief from intra-articular morphine after knee surgery: a qualitative systematic review. Pain. 1997;71:127-34. </li></ul>
    37. 38. Bibliography <ul><li>Krajnik M, Zylicz Z, Finlay I et al. Potential uses of topical opioids in palliative care – report of 6 cases. Pain. 1999;80:121-125. </li></ul><ul><li>Picard PR, Tramer MR, McQuay HJ et al. Analgesic efficacy of peripheral opioids (all except intra-articular): a qualitative systematic review of randomized controlled trials. Pain. 1997;72:309-318. </li></ul><ul><li>Poonawala T, Levay-young BK, Hebbel RP, Gupta K. Opioids heal ischemic wounds in the rat. Wound Repair Regen. 2005;13:165-74. </li></ul><ul><li>Porzio G, Marchetti P. Topical morphine in the treatment of painful ulcers. J Pain and Symptom Management. 2005;30:304-305. </li></ul>
    38. 39. Bibliography <ul><li>Twillman RK, Long TD, Cathers TA. Treatment of painful skin ulcers with topical opioids. J Pain and Symptom Management. 1999;17:288-292. </li></ul><ul><li>Vernassiere C, Cornet C, Trechot P et al. Study to determine the efficacy of topical morphine on painful chronic skin ulcers. J Wound Care. 2005;14:289-93. </li></ul><ul><li>Zeppetella G, Paul J, Ribeiro MDC. Analgesic efficacy of morphine applied topically to painful ulcers. J Pain and Symptom Management. 2003;25:555-558. </li></ul><ul><li>Zeppetella G, Joel SP, Ribeiro MD. Stability of morphine sulphate and diamorphine hydrochloride in intrasite gel. Palliat Med. 2005;19:131-6. </li></ul><ul><li>Zeppetella G, Ribeiro MDC. Morphine in Intrasite gel applied topically to painful ulcers. J Pain and Symptom Management. 2005;29:118-119. </li></ul>
    39. 40. Topical CCB <ul><li>Diltiazem with lidocaine (PLO) for anal fissures </li></ul><ul><li>Also for anal fissures/hemorrhoids </li></ul><ul><ul><li>Preparation H (phenylepherine) </li></ul></ul><ul><ul><li>0.2% glyceryl trinitrate </li></ul></ul>
    40. 41. Topical Capsacin <ul><li>Topical capsaicin preparations of 0.025 and 0.075% </li></ul><ul><li>Postherpetic neuralgia </li></ul><ul><li>Diabetic neuropathy </li></ul><ul><li>Postmastectomy pain syndrome </li></ul><ul><li>Oral neuropathic pain, Trigeminal neuralgia, and TMJ disorders </li></ul><ul><li>Cluster headache (following intranasal application) </li></ul><ul><li>Osteoarthritis </li></ul><ul><li>Dermatological/cutaneous conditions </li></ul>

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