Treatment with transdermal unlicensed medication for complex regional pain syndrome — is there enough evidence?

Case-based learning: management of complex regional pain syndrome with a transdermal unlicensed medication‘ describes the successful treatment of complex regional pain syndrome (CPRS) with an extemporaneous topical formulation and a positive patient outcome. However, while the observations are noteworthy, pharmacists reading this article should reflect on whether some of the conclusions drawn are sufficiently supported by the evidence presented.

The ‘Treatment with transdermal unlicensed medication’ section concludes: “Application directly to the affected site… allowed [delivery] of ketamine and amitriptyline into and through the epidermal and dermal layers of the skin, leading to high drug concentrations at the target site, while maintaining low [systemic levels] and… decreased systemic side effects. The enhanced skin permeation enables topical medications to include active pharmaceutical ingredient (APIs) in higher concentrations than [otherwise] prescribed orally, potentially resulting in increased efficacy without compromising [safety].”

Three assertions merit careful consideration. First, there are no data or measurements showing ketamine and amitriptyline delivery into/through the epidermis and dermis, nor that high-drug concentrations are achieved at the site of action, nor that low systemic drug levels resulted. Rather, these are conclusions based solely on the fact that the patient got better.

Second, concerning ‘enhanced’ skin permeation, no comparator formulation is provided to justify increased absorption and no definition of ‘enhancement’ and its significance is offered.

Third, it is well-known that, although percutaneous absorption through intact skin is slow and limited, effective levels at the skin target can be achieved for potent drugs with low systemic exposure. The case study of Jean et al.; however, presents no measurements or data to confirm these presumptions.

The report also raises other questions. For example, how were the drug concentrations formulated in the presumed permeation-enhancing base selected and optimised to achieve which target levels in the skin? Given the frequency and duration of treatment, can one be sure that the regimen adopted (four times a day application of formulation prior to physiotherapy) was responsible for the patient’s improvement; might this have occurred spontaneously anyway, or perhaps a placebo formulation and physiotherapy would have been equally effective?

Finally, when reading the final key point of this article — “a transdermal unlicensed medication … has proven effective in CRPS by providing optimal pain relief” — pharmacists must remind themselves that this statement is true for a single subject who received this particular treatment. Extrapolation more generally, to other patients, to other extemporaneous drug products, should be undertaken with considerable care.

Richard Guy, professor of pharmaceutical science, University of Bath

Response from the authors of the article:

On behalf of all authors, I would like to thank you for taking time to provide feedback on our case study. CPRS is a complex condition and patients often struggle to manage their symptoms. This individual patient had a remarkable improvement in her condition and we believe that the evidence presented may be a benefit to other patients suffering from the same condition.

The patient was not subjected to laboratory tests to check data or measurements. Nevertheless, there are several in vitro studies published in the literature that demonstrate the percutaneous absorption of ketamine and amitriptyline across epidermis and dermis.

This case study was presented to us while the treatment was ongoing. The authors did not interfere in the treatment nor in the feedback provided. Likewise, the authors did not make suggestions such as including a comparator or placebo formulations. As stated by the patient alongside the after treatment questionnaire: “Relief from pain is profound for approximately 30 minutes after application of cream, allowing physiotherapy four times daily, with residual pain reduction between applications. Without this cream I could not possibly have made the improvement that I have achieved thus far.”

The prescription was provided and there was no interference in the drug concentrations by the authors. Previous oral treatment options were not well tolerated owing to the side effects profile, as opposed to the transdermal formulation, as reported by the patient. 

Thanks again for the valuable points raised. For further discussion, please contact the corresponding author Linda Jean at: or

Linda Jean, Craig Urwin, Maria Carvalho and Michael Robson-Laws

Last updated
The Pharmaceutical Journal, PJ, November 2022, Vol 309, No 7967;309(7967)::DOI:10.1211/PJ.2022.1.166567

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