Administering medications via off-label routes is common in hospice and palliative care despite lack of published evidence. Patients’ ability to swallow diminishes or is lost completely as they approach end of life requiring the need for alternative routes of administration. Some oral medications are administered rectally, but this may not be feasible or desired by all patients or caregivers. A topical route can be used to manage local symptoms such as muscle aches, arthritic pain or certain types of neuropathic pain. The transdermal route is used for systemic effects, however, commercially available products are lacking for most symptoms. The introduction of pluronic lecithin organogel (PLO) to the compounding world promised to improve the systemic absorption of medications through the skin. Over the years, many medications and combinations have been incorporated into PLO gels and prescribed despite the lack of human bioavailability studies.
WHAT IS A TOPICAL PLO FORMULATION AND HOW, IN THEORY, DOES IT WORK?
PLO is a type of topical dosage form that represents a means of administering medications once the oral, rectal or parenteral routes can no longer be utilized or are no longer appropriate.1,2
Topical compounds in PLO are composed of the active drug(s) suspended in a vehicle consisting of water and two plant derivatives, pluronic acid and lecithin. In theory, these components work together to temporarily disorganize the outermost layer of the skin to provide maximum absorption of the drug, but without causing skin damage.3
Topical compounds in PLO differ from other types of topical creams, gels or ointments in that they generally work systemically rather than locally. This means that when applied, medications incorporated in PLO gel should penetrate the skin to allow absorption by the bloodstream. However, these systemic effects are not supported by evidence; most topical PLOs work best when applied directly to the affected area for local symptom control.4-8
WHERE AND HOW SHOULD A PLO COMPOUND BE APPLIED?
Although there are no specific guidelines/regulations on how gels should be used, general directions include:
- PLO compounds used for systemic effects should be applied topically to a thin, hairless area of the skin to increase the likelihood of reaching the vasculature. In the majority of patients, the inner wrist or forearm is acceptable.9,10 Other sites that have been reported anecdotally include behind the knee, inner thigh and the carotid (very light rubbing to avoid carotid massage).
- PLO compounds used for their local effects, such as ketoprofen4-6 and ketamine,7,11,12 should be applied directly to the affected area. However, patients with several affected areas or a very large affected area should consider an alternative therapy.
- Once the gel is placed on the skin, rub in for one full minute until it is completely dissolved. If the gel disappears into the skin before the full minute has passed, add a few drops of water and continue rubbing it into the skin for the remainder of the time. The purpose of the water is to re-emulsify the gel that should help ensure maximal absorption. Another application technique is to run both wrists together after the gel is applied to the skin for 0.5 to 3 minutes until dry.10,13
PLO compounds may be very irritating to mucous membranes and to open areas or sores on the skin; therefore they should NOT be applied rectally or vaginally or to open lesions, or taken orally.
IS THERE LITERATURE TO SUPPORT THE SAFETY AND EFFICACY OF PLO COMPOUNDS?
Although the active ingredients in compounded gels were reviewed and approved by the Food and Drug Administration (FDA), compounded gels are not FDA reviewed. For most compounds, the percentage of drug absorbed from the PLO is unknown. Since PLO compounds, in general, have questionable absorption, they are considered last line therapy when the oral, rectal and parenteral routes are no longer feasible.
Studies supporting the use of PLO gels vary depending on the active ingredients. In general, human clinical trials are limited and most compounds either do not have literature to support their use or is based in animal models, case reports and anecdotal reports. Overall, the evidence for PLO’s is quite weak and/or conflicting.14 Specifically, there is evidence that ABH,9,15,16 chlorpromazine,17,18 quetiapine,19,20 promethazine,13 morphine,21-24 and dexamethasone25 PLO gels ARE NOT reliably absorbed across the skin (systemically absorbed). This leads to the conclusion that they are likely ineffective when applied topically. Topical drugs, such as topical non-steroidal anti-inflammatory drugs for local arthritis symptoms (e.g., ketoprofen) and topical anesthetics (e.g., ketamine), are thought to be safe and effective.
In particular, the evidence for anti-nausea PLO gels has not been proven effective in any large, well-designed or placebo-controlled trials.26
- The active ingredients in ABH are not absorbed to systemic levels that could be effective. Only diphenhydramine (Benadryl®) is absorbed via the skin, and then only after several hours and erratically at sub-therapeutic levels.16 It is therefore not appropriate for “as needed” use.
- Some believe that the use of PLO’s produces a placebo effect of symptom relief. Others speculate that the site and method of application are keys to their effects, not the systemic absorption and action of the active medication(s).
- Rubbing the wrists innervates an acupressure point that alleviates nausea and perhaps other symptoms. The PC 6 acupressure point is located in the groove between the two large tendons on the inside of the wrist that start at the base of the palm. Special wristbands that are sold over the counter press on similar pressure points and work for some people.27-29
Due to the lack of evidence supporting, use of PLO’s with intention of systemic absorption may delay or prevent the use of more effective interventions. Careful consideration is imperative prior to initiating.
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For additional information on this topic, please review these references:
- Murdan S. A review of pluronic lecithin organogel as a topical and transdermal drug delivery system. Hospital Pharmacist 2005;12:267-271.
- Kumar R, Katare OP. Lecithin organogels as a potential phospholipid-structured system for topical drug delivery: A review. AAPS PharmSciTech 2005;6(2):E298-310.
- Willimann H, Walde P, Luisi PL, et al. Lecithin organogel as matrix for transdermal transport of drugs. J Pharm Sci Sep 1992;81(9):871-874.
- Dowling TC, Arjomand M, Lin ET, et al. Relative bioavailability of ketoprofen 20% in a poloxamer-lecithin organogel. Am J Health Syst Pharm 2004;61(23):2541-2544.
- White RL. Ketoprofen gel as an adjunct to physical therapist management of a child with Sever disease. Phys Ther 2006;86(3):424-433.
- Nguyen T, Ashworth J. Ketoprofen 10% in pluronic lecithin organogel for heel pain. IJPC Rx Triad 2003;6(2).
- Gammaitoni A, Gallacher RM, Welz-Bosna M. Topical ketamine gel: Possible role in treating neuropathic pain. Pain Med 2000;1(1):97-100.
- Crowley KL, Flores JA, Hughes CN, Iacono RP. Clinical application of ketamine ointment in the treatment of sympathetically maintained pain. Int J Pharm Compound 1998;2(2):122-127.
- Herr J, Farkus J. Ativan, Benadryl and Haldol (ABH) gel and Ativan, Benadryl, Haldol and metoclopramide (ABHM) gel in the treatment of nausea. IJPC Rx Triad 2001;4(3).
- Bleicher J, Bhaskara A, Huyck T, et al. Lorazepam, diphenhydramine, and haloperidol transdermal gel for rescue from chemotherapy‐induced nausea/vomiting: results of two pilot trials. J Support Oncol 2008; 6(1):27‐32.
- Quan D, Wellish M, Gilden DH. Topical ketamine treatment of postherpetic neuralgia. Neurol 2003;60(8):1391‐1392.
- Kopsky DJ, Hellelink JMK, Bhaskar A, et al. Analgesic effects of topical ketamine. Minerva Anestesiol 2015;81:440-9.
- Glisson JK, Wood RL, Kyle PB, Cleary JD. Bioavailability of promethazine in a topical pluronic lecithin organogel: A pilot study. Int J Pharm Compound 2005;9(3):242‐246.
- Alsaab H, Bonam SP, Bahl D, et al. Organogels in drug delivery: A special emphasis on organogels. J Pharm Pharm Sci 2016;19(2): 252-273.
- Fletcher DS, Coyne PJ, Dodson PW, et al. A randomized trial of the effectiveness of topical “ABH Gel” (Ativan®, Benadryl®, Haldol®) vs. placebo in cancer patients with nausea. J Pain Symptom Manage 2014 Nov;48(5):797-803.
- Smith TJ, Ritter JK, Poklis JL, et al. ABH gel is not absorbed from the skin of normal volunteers. J Pain Symptom Manage 2012;43(5):961‐
- Hirsch J. Chlorpromazine bioavailability from a topical gel formulation in volunteers. J Support Oncol. 2013;11:144-8.
- Alsaab H, Alzhrani RM, Boddu SH. Evaluation of the percutaneous absorption of chlorpromazine from PLO gels across porcine ear and human abdominal skin. Drug Development and Industrial Pharmacy. 2015:1-9
- Kayhart B, Lapid MI, Nelson S, et al. A lack of systemic absorption following the repeated application of topical quetiapine in healthy adults. Am J Hosp Palliat Med35(8):1076-1080.
- Leung JG, Nelson S, Cunningham JL, et al. A single-dose crossover pharmacokinetic comparison study of oral, rectal and topical quetiapine in healthy adults. Clin Pharmacokinet 2016;55(8):971-976.
- Ribeiro MDC, Joel SP, Zeppetella G. The bioavailability of morphine applied topically to cutaneous ulcers. J Pain Symptom Manage 2004;27(5):434‐439.
- Paice JA, Von Roenn JH, Hudgins JC, et al. Morphine bioavailability from a topical gel formulation in volunteers. J Pain Symptom Manage 2008;35(3):314-20.
- Roy SD, Flynn GL. Transdermal delivery of narcotic analgesics: comparative permeabilities of narcotic analgesics through human cadaver skin. Pharmaceutical Research 1989;6(10):825-32.
- Krotscheck U, Boothe DM, Boothe H. Evaluation of transdermal morphine and fentanyl pluronic lecithin organogel administration in dogs. Veterinary Therapeutics: Research in Applied Veterinary Medicine 2003;5(3):202-11. 88.
- Willis-Goulet HS, Schmidt BA, Nicklin CF, et al. Comparison of serum dexamethasone concentrations in cats after oral or transdermal administration using pluronic lecithin organogel (PLO): a pilot study. Vet Dermatol 2003 Apr;14(2):83-9.
- Fischberg D, Bull J, Casarett D, et al; HPM Choosing Wisely Task Force. Five things physicians and patients should question in hospice and palliative medicine. J Pain Symptom Manage 2013;45(3):595-605.
- Warner J. Wristbands ease chemo-related nausea. Published Aug 29, 2003. http://www.webmd.com/cancer/news/20030829/wristbands-ease-chemo. Accessed Oct 10, 2018.
- Ratini M. Acupressure points and massage treatment. Reviewed 2018. http://www.webmd.com/balance/guide/acupressure-points-and-massage-treatment#. Accessed Oct 10, 2018.
- Bao T. Use of acupuncture in the control of chemotherapy-induced nausea and vomiting. J Natl Compr Canc Netw 2009;7:606-612.