Compounded Pain Formulations: What is the Evidence?

Pain syndromes are among the most widespread, costly, and debilitating of all neurological disorders. The number of patients living with chronic pain is expected to increase with the aging population and with the rise in obesity and diabetes across the nation. This type of pain is often insensitive to the traditional pain pharmacopeia or surgical intervention. Over the last 10 years the number of prescriptions that have been compounded by pharmacists has increased dramatically. There are a number of drugs in the area of pain management that have been formulated and compounded by pharmacists to treat conditions such as diabetic neuropathy, fibromyalgia, postherpetic neuralgia, joint pain, arthritis, and a variety of other conditions. A significant portion of these compounded analgesic preparations is made up of topical/transdermal dosage forms such as gels and creams. While the efficacy and doses of these drugs in systemic dosage forms have been widely established, little is known about the permeation and efficacy of these compounds from topical/transdermal gels. This review will provide an overview of chronic pain as a disease, the mechanisms of chronic pain, current treatment approaches to chronic pain, and a discussion of the drugs that are typically compounded into these topical formulations and studied in clinical trials.

Effects of JWH015 in cytokine secretion in primary human keratinocytes and fibroblasts and its suitability for topical/transdermal delivery.

Background JWH015 is a cannabinoid (CB) receptor type 2 agonist that produces immunomodulatory effects. Since skin cells play a key role in inflammatory conditions and tissue repair, we investigated the ability of JWH015 to promote an anti-inflammatory and pro-wound healing phenotype in human primary skin cells. Methods Human primary keratinocytes and fibroblasts were stimulated with lipopolysaccharide. The mRNA expression of cannabinoid receptors was determined using RT-PCR. The effects of JWH015 (0.05, 0.1, 0.5, and 1 µM) in pro- and anti-inflammatory factors were tested in lipopolysaccharide-stimulated cells. A scratch assay, using a co-culture of keratinocytes and fibroblasts, was used to test the effects of JWH015 in wound healing. In addition, the topical and transdermal penetration of JWH015 was studied in Franz diffusion cells using porcine skin and LC-MS. Results The expression of CB1 and CB2 receptors (mRNA) and the production of pro- and anti-inflammatory factors enhanced in keratinocytes and fibroblasts following lipopolysaccharide stimulation. JWH015 reduced the concentration of major pro-inflammatory factors (IL-6 and MCP-1) and increased the concentration of a major anti-inflammatory factor (TGF-ß) in lipopolysaccharide-stimulated cells. JWH015 induced a faster scratch gap closure. These JWH015'seffects were mainly modulated through both CB1 and CB2 receptors. Topically administered JWH015 was mostly retained in the skin and displayed a sustained and low level of transdermal permeation. Conclusions Our findings suggest that targeting keratinocytes and fibroblasts with cannabinoid drugs could represent a therapeutic strategy to resolve peripheral inflammation and promote tissue repair.

Debating the Effectiveness and Necessity of Tenure in Pharmacy Education.

Academic tenure is a controversial and highly debated topic. Is tenure truly outdated or does it simply need to be reformed? On one hand, the tenure system has shortcomings including deincentivizing productive faculty members, inconsistent application of tenure policies and procedures, and the potential for discrimination during tenure decisions. On the other hand, the tenure system is a long held tradition in the academy, essential in higher education to ensure academic standards and values are upheld in the best interest of students. It provides faculty members with the academic freedom to try innovative teaching strategies and conduct research and assists with faculty retention and recruitment. Regardless of one's opinion, the tenure debate is not going away and warrants further discussion. This paper represents the work of a group of academic leaders participating in the 2014-2015 AACP Academic Leadership Fellowship Program. This work was presented as a debate at the 2015 AACP Interim Meeting in Austin, TX in February 2015.

Skin Permeation and Antinociception of Compounded Topical Cyclobenzaprine Hydrochloride Formulations.

Cyclobenzaprine has been commonly compounded by pharmacists into topically applied dosage forms for the treatment of pain disorders. However, the efficacy and transdermal penetration of topically applied compounded cyclobenzaprine is currently unknown. In this study, the transdermal penetration of cyclobenzaprine was studied in Franz diffusion cells using porcine skin. Cyclobenzaprine was compounded in two commercially available bases; Lipobase, Lipoderm, and a standard poloxamer lecithin organogel. In addition, cyclobenzaprine was tested in an in vivo formalin pain model. Cyclobenzaprine 5% compounded into all three bases yielded significant transdermal penetration and results in modest levels of cyclobenzaprine being retained in the skin tissue. Systemically administered cyclobenzaprine (10 mcg/kg), but not topically administered cyclobenzaprine (1% and 5%), attenuated nociception in a rodent formalin pain model.

Analgesic Efficacy and Transdermal Penetration of Topical Gabapentin Creams: Finding an Optimal Dose and Pre-treatment Time.

Many patients with chronic neuropathic pain continue to suffer despite traditional pharmacotherapy. As a result, pharmacists commonly compound gabapentin into creams, gels, and ointments as an alternative treatment option. In this study, various concentrations (1%, 5%, and 10%) of topical gabapentin compounded in Lipoderm were applied at various pre-treatment times (30 minutes, 1 hour, and 4 hours) to investigate what gabapentin concentration and pre-treatment time best attenuates formalin-induced nociceptive behaviors in a rodent model. A 30-minute pre-treatment with 5% gabapentin demonstrated maximum attenuation of nociceptive behaviors in this in vivo preclinical pain model. Nociceptive behaviors unexpectedly increased when gabapentin concentration or pre-treatment time was increased, suggesting both antinociceptive and pronociceptive effects of transdermal gabapentin administration. Gabapentin permeation into the skin and deeper tissues of the hindpaw was measured following the in vivo study. Skin and deep tissue permeation of gabapentin was both dose and time-dependent. Maximum deep-tissue permeation occurred within 30 minutes of topical application. Skin concentrations increased with a longer 1-hour pre-treatment. Minimal skin and deeper tissue levels were found following a 4-hour pre-treatment. These results suggest that topical gabapentin may be antinociceptive in a rodent formalin model at specific doses and pre-treatment intervals.

Peripherally Restricted Cannabinoids for the Treatment of Pain.

The use of cannabinoids for the treatment of chronic diseases has increased in the United States, with 23 states having legalized the use of marijuana. Although currently available cannabinoid compounds have shown effectiveness in relieving symptoms associated with numerous diseases, the use of cannabis or cannabinoids is still controversial mostly due to their psychotropic effects (e.g., euphoria, laughter) or central nervous system (CNS)-related undesired effects (e.g., tolerance, dependence). A potential strategy to use cannabinoids for medical conditions without inducing psychotropic or CNS-related undesired effects is to avoid their actions in the CNS. This approach could be beneficial for conditions with prominent peripheral pathophysiologic mechanisms (e.g., painful diabetic neuropathy, chemotherapy-induced neuropathy). In this article, we discuss the scientific evidence to target the peripheral cannabinoid system as an alternative to cannabis use for medical purposes, and we review the available literature to determine the pros and cons of potential strategies that can be used to this end.

Naegleria fowleri: pathogenesis, diagnosis, and treatment options.

Naegleria fowleri has generated tremendous media attention over the last 5 years due to several high-profile cases. Several of these cases were followed very closely by the general public. N. fowleri is a eukaryotic, free-living amoeba belonging to the phylum Percolozoa. Naegleria amoebae are ubiquitous in the environment, being found in soil and bodies of freshwater, and feed on bacteria found in those locations. While N. fowleri infection appears to be quite rare compared to other diseases, the clinical manifestations of primary amoebic meningoencephalitis are devastating and nearly always fatal. Due to the rarity of N. fowleri infections in humans, there are no clinical trials to date that assess the efficacy of one treatment regimen over another. Most of the information regarding medication efficacy is based on either case reports or in vitro studies. This review will discuss the pathogenesis, diagnosis, pharmacotherapy, and prevention of N. fowleri infections in humans, including a brief review of all survivor cases in North America.

Compounded pain formulations: what is the evidence?

Pain syndromes are among the most widespread, costly, and debilitating of all neurological disorders. The number of patients living with chronic pain is expected to increase with the aging population and with the rise in obesity and diabetes across the nation. This type of pain is often insensitive to the traditional pain pharmacopeia or surgical intervention. Over the last 10 years the number of prescriptions that have been compounded by pharmacists has increased dramatically. There are a number of drugs in the area of pain management that have been formulated and compounded by pharmacists to treat conditions such as diabetic neuropathy, fibromyalgia, postherpetic neuralgia, joint pain, arthritis, and a variety of other conditions. A significant portion of these compounded analgesic preparations is made up of topical/transdermal dosage forms such as gels and creams. While the efficacy and doses of these drugs in systemic dosage forms have been widely established, little is known about the permeation and efficacy of these compounds from topical/transdermal gels. This review will provide an overview of chronic pain as a disease, the mechanisms of chronic pain, current treatment approaches to chronic pain, and a discussion of the drugs that are typically compounded into these topical formulations and studied in clinical trials.

Skin permeation and antinociception of topical gabapentin formulations.

Chronic pain affects greater than 116 million Americans each year. Even with the best pain management approaches, many chronic pain patients still suffer from moderate to severe pain. An alternative therapy to treat chronic pain includes compounded topical formulations of common analgesics. Compounded dosage forms of gabapentin are commonly used for pain management, however, the penetration and efficacy of gabapentin in these compounded topical formulations has not been fully studied. In this study, the transdermal penetration of gabapentin was studied in Franz diffusion cells using porcine skin. Gabapentin was compounded in two commercially available bases; Lipobase, Lipoderm, and a standard poloxamer lecithin organogel. The penetration and retention of gabapentin in the skin was dependent upon the base. The most rapid and greatest penetration and retention of gabapentin in the skin occurred with a poloxamer lecithin organogel base. Lipobase and Lipoderm bases produced slow and smaller penetration and retention of gabapentin as compared to poloxamer lecithin organogel base. Gabapentin 1% and 5% compounded in Lipoderm were tested in the in vivo preclinical formalin pain model. Topical 5% gabapentin produced a similar reduction in nociception in both Phase 1 and Phase 2 of the formalin response as systemic subcutaneous gabapentin (100 mg/kg). Topical 1% gabapentin reduced Phase 2, but not Phase 1 formalin-induced nociceptive behaviors. These findings suggest that topical administration of gabapentin may produce local antinociception.

In vitro skin penetration and skin content of progesterone from various topical formulations.

Progesterone has been compounded by pharmacists over the last decade using a variety of different dosage forms including, suppositories, troches, solutions, capsules, nasal sprays, creams, ointments, and gels. In particular, the topical/transdermal route has become very popular among physicians, compounders, and patients. There are a few studies in the medical literature that address the transdermal permeation of progesterone from topically applied dosageforms. The results are typically controversial with some studies showing permeation and others showing little to no permeation. Coupled with the high saliva levels that are often seen in patients undergoing topical/transdermal treatment with progesterone and the accompanying lack of progesterone blood levels, the transdermal route of delivery for progesterone is controversial. In this study, we examined the transdermal penetration of progesterone from four different formulations and the skin retention of progesterone in porcine skin. Our results indicate that only minute quantities of progesterone transdermally penetrated through the porcine skin. However, there was significant partitioning of progesterone in the skin tissues. Consequently, these results suggest that the lymphatic circulation that exists in the skin may potentially account for the systemic delivery of topically applied progesterone that is often observed clinically.

The release and transdermal penetration of baclofen formulated in a poloxamer lecithin organogel.

The purpose of this study was to evaluate the in vitro release and ex vivo penetration of baclofen following incorporation into a 2% poloxamer lecithin organogel. Franz cells were utilized for both the release and penetration studies. Semi-permeable dialysis membranes were used as the model skin for the penetration study. Baclofen release and penetration at predetermined time points were assessed using high-performamce liquid chromatographic analysis. Results demonstrated that baclofen release from the poloxamer lecithin organogel was significantly higher than its penetration through porcine skin. The amount of baclofen released by the poloxamer lecithin organogel was linear up to 12 hours. Approximately 20% of applied drug was released over the duration of the study period. In comparison with drug released, the ex vivo penetration of baclofen through porcine skin was very low with only minute detectable quantities (significantly less than 1%) after the 12-hour study period. These results suggest that the request to include baclofen into a compounded poloxamer lecithin organogel should be approached cautiously by compounding pharmacists.