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.
The theory regarding topical agents:
- Oral analgesics can contain intolerable adverse effects that are bypassed with topical administration
- They can be customized specifically to patient’s pain management need
- There is a faster onset of action with topically administered products
- The medication can be applied directly to pain source
- There are fewer systemic side effects, drug interactions, and risk of systemic accumulation typically associated with topically administered medications
- Patients can cut down on medication burden by combining agents together
- These compounds can help decrease opioid consumption
Concerns regarding these compounded agents include:
- Limited clinical trial evidence; most research conducted for other indications not chronic pain management, many trials conducted only in animal models
- No FDA oversight to prove both safety and efficacy
- Limited data regarding stability of agents combined into a single topical product
- Many ingredients ineffective when administered topically; some require metabolism in the liver to the active drug for effect, and topical application eliminates this step (e.g., tramadol)
- No consensus regarding appropriate bases to mix the active ingredients
- No oversight to assess the accuracy of ingredients in the compounds; no quality control requirements
Topical vs. Transdermal
- Transdermal is intended to penetrate the dermal layer into systemic circulation with a systemic effect
- Topical is intended to penetrate the epidermis (top layer of the skin) for local action
- Topical products are not intended for systemic absorption therefore, ideally less adverse systemic effects
- Of note, damage or heat can increase the extent and rate of absorption and produce systemic effects in a product intended for topical use only (e.g., the topical fentanyl patches were big in the news a few years back due to overdose if used with a heating pad)
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.
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|