A Healthesystems publication

Fall 2012

Compounds: The Topical, Transdermal and Oral Debate

The use of compound medications continues to require scrutiny by both payers and PBMs as these questionable formulations continue to be utilized. Compounds – drugs composed of several ingredients compounded in a pharmacy with questionable, if any, quality control measures – can often be prescribed to workers’ comp patients. Payers must determine if approving a compound provides real patient benefits, if the compound is therapeutically necessary, or even if it could potentially pose a danger to the patient. A recent fungal meningitis outbreak resulting from an injectable steroid product made by a compounding pharmacy is a prime example of the dangers inherent in this practice.

Until recently, it was difficult for payers and PBMs to even determine the ingredients contained in a compound. In 2012 retail pharmacies implemented NCPDP Data Standard D.0 which provided the necessary tools for being able to record all ingredient level detail of compound drugs. Now there’s an opportunity for deeper scrutiny of these ingredients, and the chance to effectively evaluate each ingredient for safety and efficacy. This is helpful when considering whether compounded agents are appropriate for the treatment of chronic pain.

Topical Application
The theory regarding topical agents:

The Truth
Concerns regarding these compounded agents include:

Topical vs. Transdermal

Separating the Theory from the Facts

There is a significant amount of variability in compounded agents. Limited data exists regarding the interactivity/stability of combined ingredients; interaction with the base compounds (which can affect stability and absorption), patient skin integrity, patient climate, and the overall stability of product.

Beyond the issues of stability and patient variability are the ingredients and their appropriateness for use topically or in transdermal compounds. The table on the following page shows some of the more common ingredients found in compounds prescribed for workers’ comp patients.

The Future

A few topical compounds are currently in clinical trial stage. At the moment, EpiCept NP-1 (4% Amitriptyline/ 2% Ketamine) Topical Cream is currently being studied. Also, baclofen/amitriptyline/ketamine and ketamine clonidine are being studied.

Even with current clinical trials underway, their applicability to workers’ comp and chronic pain management is in question. Current clinical trials are looking at compounded agents for either PHN (post-herpetic neuralgia), DPN (diabetic peripheral neuropathy), or chemo/radiation induced neuropathy. These trials are not studying long-term use for chronic pain related to injury or trauma.

Additionally, branded compounds such as the agents Medrox® (medroxicin), Dendracin® (Neurodendraxin®), and Terocin® (terodoloricin) are all proprietary compounds with their formulated generic name and expensive price tag for ingredients that are available at local pharmacies for pennies on the dollar. These agents are available in a virtually identical formulation such as Ultra Strength Muscle Rub; a combination of menthol, methyl salicylate, camphor, and capsaicin. Compare the cost of Medrox AWP $201.00 for a 6 oz (168g) container with Ultra Strength Muscle Rub at AWP $5.99 per container (114g).

These agents have the look and appeal of a commercially available prescription topical agent. They are combined in concentrations so that they are considered a proprietary blend, thus manufacturers can set their price for these Branded Compounds and circumvent price hits that are in play with the ingredient prices of an individually compounded agent.

While there are trials under way for a few select commercial compounds, currently the supporting data for use of these extemporaneously compounded agents is limited to small populations, poorly conducted studies, or isolated case reports. The pricey container of ingredients may stand out, but the evidence does not.

The table below lists some of the more common ingredients found in compounds prescribed for workers’ comp patients and denotes issues that exist with topical application of the agents.

Generic Medication Name Drug Category Issues with Topical Application
Amitriptyline Tricyclic antidepressant No topical dose yet available

Data is gleaned from small, poorly designed clinical trials and case studies

Currently being studied for its reaction when combined with ketamine
Baclofen Oral skeletal muscle relaxant Centrally acting; has not shown therapeutic effect in topical application
Clonidine Sympatholytic medication Blocks apha-2 receptors on skin nerve terminals

Found effective in diabetic peripheral neuropathy, but has stability questions when in combination with other ingredients
Cyclobenzaprine Muscle relaxant Relieves muscle spasms with no direct action on the muscle involved

No evidence of transdermal efficacy
Diclofenac Nonsteroidal anti-inflammatory (NSAID) Readily available in topical and transdermal formulations; no rationale for compounding

Reports of adverse liver toxicity, including topical applications

Safety concerns exist with lower concentrations
Doxepin Tricyclic antidepressant Only TCA approved for topical use in itching secondary to eczema

Not indicated for pain management
Gabapentin Gabapentin Seizure treatment drug Binds proteins confined to brain and spinal cord without altering skeletal muscle tissue1

Topical use not supported by literature or clinical justification
Ketamine Dissociative anesthetic Used as general anesthetic and can be used intravenously for severe, refractory pain

Studies concluded no significant difference between treatment groups, including placebos
Ketoprofen Nonsteroidal anti-inflammatory (NSAID) Remains popular despite failed topical NSAID trials over last decade2

Drug delivery system critical to clinical effectiveness of topical anti-inflammatory therapy9

Topical dosing yielded inconsistent concentrations in muscle tissue4

Topical use has been associated with high number of adverse events5

No FDA-approved topical products marketed
Lidocaine Local anesthetic and antiarrhythmic drug Commercially available as topical cream, ointment, jelly

Lidoderm (lidocaine patch) available as topical analgesic. FDA-approved for post-herpectic neuralgia; also used off-label for various neuropathic pain conditions

Not effective nor recommended for non-neuropathic pain6
Nifedipine Dihydropyridine calcium channel blocker Studied for treatment of thrombosed hemorrhoids; however no data to support topical use in pain treatment, and 2011 review did not support topical use7
Tramadol Centrally acting synthetic analgesic Required hepatic metabolism to be effective8; as such, topical use bypasses hepatic circulation and is not expected to be effective topically

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SOURCES

1 -Taylor CP. Mechanism of analgesic by gabapentin and pregabalin: calcium channel alpha2-delta ligands. Pain. 2009;142:13-16.
2 -Diaz RL, Gardeazabal J, Manrique P, et al. Greater allergenicity of topical ketoprofen in contact dermatitis confirmed by use. Contact Dermatitis. 2006;54(5):239-243.
3 -DeCarli A, Volpi P, Pelosini I, et al. New therapeutic approaches for management of sport-induced muscle strains. Adv Ther. 2009;26(12):1072-1083.
4 -Tegeder I, Lotsch J, Kinzig-Schippers M, et al. Comparison of tissue concentrations after intramuscular and topical administration of ketoprofen. Pharm Res. 2001;18(7):980- 986.
5 -Diaz RL, Gardeazabal J, Manrique P, et al. Greater allergenicity of topical ketoprofen in contact dermatitis confirmed by use. Contact Dermatitis. 2006;54(5):239-243.
6 -Scudds RA, Janzen V, Delaney G, et al. The use of topical 4% lidocaine in spheno-palatine ganglion blocks for the treatment of chronic muscle pain syndromes: a randomized, controlled trial. Pain. 1995;62:69-77.
7 -Chiu HY, Tsai, TF. Topical use of systemic drugs in dermatology: a comprehensive review. J Am Acad Dermatol. 2011:65(5):1048.e1—e22.
8 -Ultram [package insert]. Raritan, NJ: Ortho-McNeil Pharmaceutical; 2009.
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