THE PCCA BLOG

Chronic Pain, Hormones and Inflammation: Connecting the Dots at CONNEXT 2026

Thu, 05 Mar 2026 20:21:34 GMT

Featuring Sarah Zielsdorf, MD, MS, ABIM, IFMCP

Some patients don’t fit neatly into diagnostic categories. They’ve collected labels over time: fibromyalgia, endometriosis, mast cell activation, dysautonomia. Their labs fluctuate. Their symptoms overlap. They react to medications that are supposed to help. And too often, they leave appointments feeling unheard.

At CONNEXT 2026, Dr. Sarah Zielsdorf will address these complex intersections head-on — not as isolated conditions but as interconnected patterns across the endocrine, immune and inflammatory systems.

She’ll open the week alongside Sebastian Denison, RPh, in a live “Morning Warm-Up” session designed to answer unfiltered questions and fill education gaps for newer practitioners. It’s a practical starting point for a deeper conversation, grounded in real-world clinical uncertainty rather than textbook simplicity.

From there, Dr. Zielsdorf will move into one of the most challenging areas in modern medicine: chronic pain in women’s health. Conditions like adenomyosis, endometriosis and fibromyalgia are often treated as separate diagnoses. But she invites clinicians to look at what links them, including the spectrum of mast cell activation disorders, from MCAS to systemic mastocytosis, and their associations with dysautonomia and hypermobility spectrum disorders such as Ehlers-Danlos syndrome.

For many patients, these are not isolated problems but overlapping systems under stress. Supporting them requires compassion — and often compounded, individualized therapeutics due to sensitivities, allergies and trigger reactivity. Dr. Zielsdorf will discuss practical strategies, including low-dose naltrexone (LDN), bioidentical hormone therapy (bHRT), ketotifen and oral peptides — not as trends, but as tools that require thoughtful dosing, inclusion and exclusion criteria, and careful patient selection.

This theme will continue in her session on autoimmune and rheumatologic conditions, where inflammation is not simply a symptom but a driving force. She'll explore the expanding spectrum of autoinflammatory and autoimmune disorders and the mediators that fuel them: diet, trauma, microbial influences and environmental triggers. LDN’s mechanisms of action and clinical applications will be examined in detail, alongside safety profiles and practical implementation considerations.

Inflammation is also central to hormonal transitions. During perimenopause, menopause and andropause, Dr. Zielsdorf frames the conversation around inflammaging — the chronic, low-grade inflammation that accelerates age-related disease — and metaflammation, the metabolic inflammation tied to metabolic dysfunction. She'll explore the role of the gut microbiome, intestinal hyperpermeability, circadian rhythm disruption, HPA axis dysregulation, thyroid imbalance, mitochondrial dysfunction and weight gain — all through a systems-based lens.

The message is clear: Endocrine systems do not function in silos. As the science of bioidentical hormone replacement therapy continues to evolve, compounding pharmacies play a critical role in delivering precision therapeutics, especially for patients who cannot tolerate standard formulations or require individualized dosing strategies. Sebastian Denison’s complementary lectures will reinforce how these therapies translate into practical compounding solutions, bridging clinical insight with pharmacy application.

At its core, Dr. Zielsdorf’s presence at CONNEXT 2026 represents something bigger than a series of lectures: a shift toward integrative, systems-informed care that recognizes complexity rather than flattening it. If you treat patients navigating chronic pain, autoimmune disorders, inflammatory conditions or hormonal transitions, these sessions will provide both clarity and direction.

Join us at CONNEXT 2026 and be part of the conversations redefining individualized care.

Illuminating Stealth Syndromes

Wed, 29 Jan 2025 17:08:00 GMT

A forthcoming documentary from the LDN Research Trust gives compounding pharmacists, physicians and prescribers an opportunity to learn about a group of complex and debilitating syndromes that affect one in six Americans — syndromes that occur in almost every part of the body, often accompany each other and collectively exacerbate the patient’s pain and other symptoms. This article briefly summarizes these syndromes and their overlapping symptoms and discusses how you can help educate providers in your community — as well as your staff and patients — about their effects, along with the potential use of low-dose naltrexone (LDN) in compounding preparations.

Summary of Syndromes

Stealth syndromes include mast cell activation syndrome (MCAS), postural orthostatic tachycardia syndrome (POTS) and Ehlers-Danlos syndrome (EDS), each of which is discussed below.

MCAS (Mast Cell Activation Syndrome)

Found in most organs of the body, mast cells are part of the immune system and are responsible for immediate allergic reactions that are triggered by allergic substances such as medications, infections, chemicals and insect bites. Mediators stored in or created by mast cells are released and create allergic reactions. A trigger from an allergen is called activation and the release of mediators is called degranulation.

MCAS is caused by dysfunction of mast cells; patients afflicted by MCAS experience repeated episodes of allergic reactions with accompanying symptoms:

Fatigue, headache, tingling, chills
Rapid pulse (tachycardia), low blood pressure (hypotension) and fainting
Itching (pruritus), hives (urticaria), swelling (angioedema) and skin flushing
Wheezing, shortness of breath and harsh noise when breathing (stridor) due to throat swelling
Diarrhea, nausea with vomiting and cramping abdominal pain^1,2

POTS (Postural Orthostatic Tachycardia Syndrome)

POTS (also referred to as dysautonomia) is caused by a malfunction in part of the autonomic nervous system, which controls involuntary body functions such as breathing and heart rate. The syndrome is considered one of a group of disorders that present symptoms of orthostatic intolerance (OI). OI is a condition where an excessively reduced volume of blood returns to the heart after an individual stands up after laying down.

Patients afflicted with POTS often experience:

Lightheadedness or fainting when standing
A rapid increase in heartbeat (more than 30 beats per minute or exceeds 120 beats per minute)
Low blood pressure
Digestive and bladder problems
Temperature and sweating dysregulation
The syndrome often prevents individuals from exercising due to onset of fainting spells or dizziness. POTS is often associated with EDS.³

EDS (Ehlers-Danlos Syndrome)

EDS is a group of disorders that affect connective tissues that support the skin, tendons, ligaments, bone, blood vessels and many organs and tissues. An unusually large range of joint movement (hypermobility) occurs in most forms and is the hallmark feature of the hypermobile type.

Patients afflicted with hypermobile EDS (hEDS) may present some or all of the following symptoms:

Joint hypermobility
Loose, unstable joints that easily dislocate
Joint pain and clicking joints
Extreme fatigue
Skin that bruises easily
Digestive problems, such as heartburn and constipation
Dizziness and an increased heart rate after standing up
Problems with internal organs, such as mitral value issues or organ prolapse (types include bladder, pelvic and rectal prolapse)
Urinary incontinence (bladder control)⁴

Compassion and Concern: The LDN Research Trust

Linda Elsegood, Chief Executive Officer and founder of the LDN Research Trust, refers to the collection of MCAS, POTS and EDS as “Stealth Syndromes.” Keenly aware of the debilitating impacts and empathetic for patients who suffer from these syndromes, Linda shared her concerns during The Mortar & Pestle podcast. “Patients with MCAS are also susceptible to having EDS and POTS; they tend to go hand-in-hand,” Linda said. “Some of these patients come into the doctor’s office with 40 different symptoms and practitioners have no idea where to start. Some physicians just throw up their hands and walk away. Others just treat one or two individual issues. But until you get down to the root cause — it’s nothing more than a Band-Aid.”

Adding insult to injury, many conventionally prescribed tests return with negative results, which add to the growing pile of doubts among family and friends.

“A lot of the tests, they do come back negative, which leads family and friends to thinking, ‘Well, if the doctors can't find anything wrong with you, there is nothing really wrong with you!’” Linda said. “I know one lady whose parents wouldn't talk to her anymore because they thought she was just a hypochondriac, that there was nothing really wrong with her. And that is so isolating for the patient.” Although considered a rare disease, Dr. Leonard Weinstock, a gastroenterologist and leading expert on MCAS, estimates one-in-six people are afflicted with the syndrome in the Northern Hemisphere; most are unaware.

During the podcast, Linda likened the lack of awareness to Lyme disease. “There were no reported cases of Lyme disease anywhere in the United States because there was no true diagnosis. And so they couldn't gather the data. And then very quickly, they said Lyme disease existed in the United States.”

Help Spread Awareness

Linda is calling on compounding pharmacists — notably PCCA members — to raise awareness of Stealth Syndromes and the potential use of low-dose naltrexone (LDN) in preparations.

The LDN Research Trust developed a documentary, “Understanding Stealth Syndromes,” that sheds light on these esoteric conditions. The documentary, which airs for 24 hours on February 27 (to accommodate global time zones), explains the underlying root causes, why most doctors miss these conditions, potential treatments and more.

Compounding pharmacies are urged to help raise awareness by:

Purchasing a documentary license — $100 for up to 50 individuals
Hosting an event at their pharmacy or a local venue
Inviting community physicians, prescribers and patients to view the documentary

“We’re aiming to raise awareness and connect individuals suffering from undiagnosed Stealth Syndromes with knowledgeable local providers,” Linda said. “Compounding pharmacists, technicians and staff are compassionate — many are aware of the benefits of LDN — and are adept at providing personalized preparations to these patients.

“They are positioned to develop awareness in their communities and can purchase as many licenses to the documentary as needed. Once we have sold the license, they can do whatever they like.”

This includes selling tickets to and/or publicizing the event on their respective pharmacy websites.

“We are happy to help them publicize or advertise the event,” Linda said. “On our website and throughout our social media platforms, we list all pharmacies who purchased licenses for the documentary, as well as their locations, so people know who to contact to attend viewings. We also hope to invite local media to these events; if an event is sold out, many become really interested and will send reporters who will broadcast or write about it.”

Watch the compelling trailer for “Understanding Stealth Syndromes”. Click Here.

To purchase one or more licenses for the documentary, Click Here.

For additional information, email contact@ldnresearchtrust.org.

Listen as Linda shares her personal struggles and the impetus for creating the LDN Research Trust, as well as the need for public awareness of Stealth Syndromes, in The Mortar & Pestle Podcast.

PCCA is recognized as the leader of quality products, education and advocacy in the compounding industry. Find out how a PCCA membership can benefit your compounding practice.

References

American Academy of Allergy, Asthma & Immunology. Mast Cell Activation Syndrome (MCAS). August 2024. Accessed January 2025 at https://www.aaaai.org/conditions-treatments/related-conditions/mcas#:~:text=Idiopathic%20Mast%20Cell%20Activation%20Syndrome,are%20released%20during%20those%20episodes
POTS UK. Mast Cell Activation Syndrome. Version 3. Last reviewed July 2024. Accessed January 2025 at https://www.potsuk.org/about-pots/associated-conditions/mcas/
National Institute of Neurological Disorders and Stroke. Postural Tachycardia Syndrome (POTS). Last reviewed July 2024. Accessed January 2025 at https://www.ninds.nih.gov/health-information/disorders/postural-tachycardia-syndrome-pots
National Health Service UK. Ehlers-Danlos Syndromes. Last reviewed October 2022. Accessed January 2025 at https://www.nhs.uk/conditions/ehlers-danlos-syndromes/#:~:text=types%20of%20EDS-,Hypermobile%20EDS,with%20bladder%20control%20(urinary%20incontinence)

These statements are provided for educational purposes only. They have not been evaluated by the Food and Drug Administration, and are not to be interpreted as a promise, guarantee or claim of therapeutic efficacy or safety. The information contained herein is not intended to replace or substitute for conventional medical care or encourage its abandonment.

What’s in Store at the LDN Virtual Conference

Fri, 15 Nov 2024 03:53:03 GMT

Individuals who suffer from symptoms of gastrointestinal, autoimmune, dermatological and pain conditions make up 80% of the patient population. But here’s the good news: multiple studies indicate that low-dose naltrexone (LDN) may potentially help many of these conditions. Take a sneak peek at topics our Clinical Services team will discuss during the Low-Dose Naltrexone One-Day Virtual Conference on Thursday, November 21, 2024.

The Immune System — Autoimmune Conditions and the Benefits of LDN

by Catherine Henderson, PharmD, PCCA Clinical Compounding Pharmacist

LDN has long been touted for its effects in autoimmune disorders. Understanding the mechanisms of LDN action involves diving deeper into immune system function and the irregularities that occur in autoimmune disorders. We’ll explore the data related to LDN’s various mechanisms for improving disease symptomatology and quality of life, as well as review real world published studies and cases of LDN use in various autoimmune disorders.

Dermatological Inflammatory Diseases and LDN

by Nat Jones, RPh, FAPC, PCCA Clinical Compounding Pharmacist

LDN is growing in popularity in the dermatology world. It has proven to be beneficial for pruritus and inflammation due to its ability to attenuate toll-like receptors found in the skin. We’ll discuss two cases: one of a tattoo allergic reaction and one of hidradenitis suppurativa (HS). Tattoo reactions to the coloring agents can be intense and difficult to treat. HS is a chronic inflammatory, potentially scarring, skin disease primarily affecting apocrine gland-rich areas of the body (axillary, groin, perianal, perineal regions and abdominal folds), often mediating pain and considerable morbidity, both physical and psychological.

The Use of LDN in Veterinary Patients

by Katy Hecker, PharmD, PCCA Clinical Compounding Pharmacist

As pet owners, we lovingly share many things with our pets including treats, affection and half of the bed. Research suggests we also share similarities in physiological function, disease state manifestation and treatment modalities utilized. Join in the discussion and learn more about the science behind LDN for veterinary clinical indications including behavioral disorders, atopic dermatitis, osteoarthritis, cancer, inflammatory bowel disease (IBD) and more!

Perimenopause and Menopause Are Inflammatory Conditions: The Use of LDN for Hormones and Weight Loss

by Sara Hover, RPh, FAARM, PCCA Director of Clinical Services

Understanding the inflammatory processes that characterize perimenopause and menopause will shed light on how the hormonal changes contribute to weight gain and obesity. Central to this discussion is the shift in estrogen profiles — from estradiol, which possesses anti-inflammatory properties, to estrone, a pro-inflammatory estrogen that becomes predominant during menopause. This hormonal transition fosters an inflammatory state that can disrupt metabolism and promote adiposity. Additionally, the presentation will explore various options aimed at reducing inflammation and managing weight effectively. Key strategies include optimizing sleep quality, utilizing probiotics to support gut health and implementing LDN as an innovative therapeutic approach. Attendees will gain a comprehensive understanding of the biological mechanisms linking menopause to inflammation and weight gain, along with practical interventions to enhance health and well-being during this pivotal life stage.

Using LDN for Chronic Pain Conditions

by Tricia Heitman, PharmD, PCCA Clinical Compounding Pharmacist

LDN is gaining attention for its anti-inflammatory properties and its ability to manage pain and opioid addiction. By acting on the opioid receptors at lower doses, LDN enhances endorphin production, which can help reduce inflammation and alleviate pain associated with various conditions such as arthritis, fibromyalgia and autoimmune disorders. Many patients report significant relief from chronic pain and inflammation while taking LDN. We will discuss the appropriate doses and review the literature associated with LDN and pain.

LDN for Gut Inflammatory Disorders

by Ranel A. Larsen, PharmD, PCCA Clinical Compounding Pharmacist

LDN is emerging as a promising therapeutic option for enhancing gut health, particularly in the context of IBD and irritable bowel syndrome (IBS). LDN helps to regulate immune responses, improve epithelial barrier function and reduce inflammation within the gut, all of which are critical for maintaining intestinal homeostasis. In IBD, LDN may lower disease activity and enhance quality of life, while in IBS, it can alleviate symptoms such as pain and bloating. Overall, LDN's role in improving gut health underscores its therapeutic potential to support management of complex gastrointestinal disorders.

How to Market LDN Studies

by Mark Gonzalez, PharmD, PCCA Clinical Compounding Pharmacist

Today’s compounding pharmacist wanting to effectively market LDN to practitioners and patients has access to tools that were not as available 20 years ago when LDN started to become popular. Clinical studies, therapeutic reviews and case series are now readily available to substantiate what were once only theories on the effectiveness of naltrexone in autoimmune disorders. These studies span a wide array of specialties and medical conditions. Research groups such as the LDN Research Trust, publications such as the series of three LDN books and many of the clinical presentations given on the subject of LDN all reference these studies. The pharmacist and marketer must leverage the power of this data as part of their communication to both the practitioner and the patient they are marketing to. With the additional aid of social media, positive patient stories can accompany the data from these clinical studies to make for attractive and effective marketing.

Register for the Low-Dose Naltrexone One-Day Virtual Conference today and get more details — plus more information — on the potentials of LDN. We look forward to additional discussions and answering your questions!

Potential Options for Migraine Patients

Wed, 12 Jun 2024 14:54:28 GMT

June is National Migraine and Headache Awareness Month and we want you to be well equipped to care for your migraine and headache patients.

by Catherine Henderson, PharmD, PCCA Clinical Compounding Pharmacist

Migraines affect roughly 14-15% of people globally each year and is just one of more than 200 headache disorders.¹ If you’ve ever been a migraine patient or treated a migraine patient, you know how challenging it can be to find the right treatment for acute migraines and the best prophylaxis for chronic migraines.

Acute Migraines

The current standard of care for acute migraine involves use of NSAIDs, ergotamine derivatives, triptans, gepants and ditans. Combination therapy with antiemetics and/or caffeine is also a mainstay of treatment.² With the loss of isometheptene from the market, many compounders have been searching for a replacement. Since there are so few options for treating migraines, losing an agent that is effective for some patients leaves a gap that can be difficult to fill.

In the PCCA Clinical Services department, we have recently helped many members find an alternative option for patients who were previously using isometheptene. The way that isometheptene is thought to work is by constricting the cranial arteries. Caffeine is another cranial vasoconstrictor, often used in migraine headache formulations.³For patients who were previously experiencing relief with isometheptene, caffeine would be a reasonable inclusion in their formula.

One of my favorite formulas to recommend for acute migraine is piroxicam 40 mg/ondansetron 2 mg/caffeine troches. The combination of ingredients treats pain and nausea associated with migraine headaches and may provide faster relief due to the route of administration. As an anhydrous formula, both compounders and patients can benefit from the potential of longer beyond-use dates (BUDs).*

Another unique compounding option for acute migraine is intranasal lidocaine, which has been shown to decrease pain intensity and the need for rescue medications. It has been used in varying concentrations of 4-10% in each nostril. The benefit of this formula is that it provides a non-oral, non-injectable route of administration that can be useful in patients experiencing significant nausea. Combining lidocaine with ketorolac in a nasal spray is another option that has been studied and found to have even greater pain relief than lidocaine alone.⁴ Before choosing this combination, it is important to remember that the use of ketorolac is limited to five days, regardless of route of administration. Evaluating the number of headache days per month that a patient has can help determine if this is an appropriate treatment.⁵

Migraine Prophylaxis

While the goals of therapy for acute migraine are to relieve symptoms as quickly as possible — with as few side effects as possible — we also need to avoid medication overuse headaches (a headache that results from the frequent use of acute medicines or painkillers).⁶ In any migraine patient, prevention is an important piece of the puzzle. Current migraine prophylaxis medications include beta-blockers (propranolol), anticonvulsants (valproate, topiramate), antidepressants (amitriptyline) and calcitonin gene-related peptide receptors (CGRPs) (erenumab).⁷ These prophylactic medications have varying success rates, with the new class of CGRPs having the greatest efficacy.⁸ Unfortunately, all of these medications come with the risk of adverse events and some come with a significant financial burden.

Alpha-lipoic acid and riboflavin are two agents that have been shown to help with migraine prophylaxis. A study found that a dose of riboflavin 400 mg/day for three months reduced headache days, as well as the duration, frequency and pain score of migraine attacks.⁹ Another study found similar results with alpha-lipoic acid 300 mg twice daily for 12 weeks.¹⁰ Alpha-lipoic acid has also been studied as a preventative agent in adolescents.¹¹A benefit of these two agents is that they are generally well-tolerated and may be less expensive than other options. These agents can be used alone or as an adjunct to other prophylactic measures.

Treatment Success

In helping your patients navigate migraine treatment and prophylactic options, there are some key strategies and counseling points to consider. Many patients expect full resolution of their migraine symptoms and frequency and may give up on a treatment option too soon if those expectations aren’t managed. Most prophylactic measures must be taken daily for at least two months before a determination can be made about the success of the treatment. Encourage patients to keep a headache diary to collect data about their headache days, severity and other details related to their migraines.⁶

As pharmacists, we are also uniquely placed to screen for potential medication overuse. Medication overuse headaches are typically seen in patients with 15 or more headache days per month. Most migraine prophylactics won’t be effective in these patients until they go through a detox period from acute migraine treatments.¹²The most effective detox programs for medication overuse headaches include complete withdrawal from acute treatments and initiation of preventative medications.^13,14

You have the opportunity to make a significant impact on the lives of your patients who suffer with debilitating headache disorders. This article covered just a few of the creative ways that compounding pharmacists are contributing to solutions for migraines.

PCCA members with clinical services access may contact our Clinical Services team for help when compounding for patients with migraines and other compounding concerns.

*USP 795 establishes BUD limits by type of preparation in the absence of a USP−NF Compounded Preparation Monograph or CNSP-specific stability information.

References

Steiner, T. J., & Stovner, L. J. (2023). Global epidemiology of migraine and its implications for public health and health policy. Nature reviews. Neurology, 19(2), 109–117. Accessed May 2024 at https://doi.org/10.1038/s41582-022-00763-1
Ailani, J., Burch, R. C., & Robbins, M. S. (2021). The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice. Headache: The Journal of Head and Face Pain, 61(7), 1021–1039. Accessed May 2024 https://doi.org/10.1111/head.14153
Drugs.com (Last updated June 2023). Isometheptene, Caffeine, and Acetaminophen Tablets. Accessed May 2024 at https://www.drugs.com/pro/isometheptene-caffeine-and-acetaminophen-tablets.html
Chi, P. W., Hsieh, K. Y., Chen, K. Y., et al. (2019). Intranasal lidocaine for acute migraine: A meta-analysis of randomized controlled trials. PloS one, 14(10), e0224285. Accessed May 2024 at https://doi.org/10.1371/journal.pone.0224285
Pfaffenrath, V., Fenzl, E., Bregman, D., et al. (2012). Intranasal ketorolac tromethamine (SPRIX®) containing 6% of lidocaine (ROX-828) for acute treatment of migraine: Safety and efficacy data from a phase II clinical trial. Cephalalgia, 32(10), 766–777. Accessed May 2024 at https://doi.org/10.1177/0333102412451359
The Migraine Trust. (2021). Medication overuse headache. Accessed May 2024 at https://migrainetrust.org/understand-migraine/types-of-migraine/medication-overuse-headache/
Kumar, A., & Kadian, R. (2020). Migraine Prophylaxis. PubMed; StatPearls Publishing. Accessed May 2024 at https://www.ncbi.nlm.nih.gov/books/NBK507873/
Lampl, C., MaassenVanDenBrink, A., Deligianni, C.I. et al. The comparative effectiveness of migraine preventive drugs: a systematic review and network meta-analysis. J Headache Pain 24, 56 (2023). Accessed May 2024 at https://doi.org/10.1186/s10194-023-01594-1
Chen, Y.-S., Lee, H.-F., Tsai, C.-H., et al. (2021). Effect of Vitamin B2 supplementation on migraine prophylaxis: a systematic review and meta-analysis. Nutritional Neuroscience, 1–12. Accessed May 2024 at https://doi.org/10.1080/1028415X.2021.1904542
Kelishadi, M.R., Naeini, A.A., Khorvash, F. et al. The beneficial effect of Alpha-lipoic acid supplementation as a potential adjunct treatment in episodic migraines. Sci Rep 12, 271 (2022). Accessed May 2024 at https://doi.org/10.1038/s41598-021-04397-z
Puliappadamb, H. M., Satpathy, A. K., Mishra, et al. (2023). Evaluation of Safety and Efficacy of Add-on Alpha-Lipoic Acid on Migraine Prophylaxis in an Adolescent Population: A Randomized Controlled Trial. Journal of clinical pharmacology, 63(12), 1398–1407. Accessed May 2024 at https://doi.org/10.1002/jcph.2331
D'Amico, D., & Tepper, S. J. (2008). Prophylaxis of migraine: general principles and patient acceptance. Neuropsychiatric disease and treatment, 4(6), 1155–1167. Accessed May 2024 at https://doi.org/10.2147/ndt.s3497
Carlsen, L. N., Munksgaard, S. B., Jensen, R. H. et al. (2018). Complete detoxification is the most effective treatment of medication-overuse headache: A randomized controlled open-label trial. Cephalalgia : an international journal of headache, 38(2), 225–236. Accessed May 2024 at https://doi.org/10.1177/0333102417737779
Nielsen, M., Carlsen, L. N., Munksgaard, S. B., et al. (2019). Complete withdrawal is the most effective approach to reduce disability in patients with medication-overuse headache: A randomized controlled open-label trial. Cephalalgia, 39(7), 863–872. Accessed May 2024 at https://doi.org/10.1177/0333102419828994

The Value of Topically Applied Compounds for Patients in Pain

Wed, 12 Jan 2022 14:55:09 GMT

By Beau Harger, PharmD, PCCA Clinical Compounding Pharmacist

I remember my first experience with compounding, which interestingly turned out to be a topical pain preparation using a permeation-enhancing base. I was a pharmacist intern at a compounding pharmacy back in the summer of 1998, in a small town on the Mississippi Gulf Coast. We were using a combination of ibuprofen, piroxicam and cyclobenzaprine in PLO (PCCA Formula #3444) for patients with inflammatory conditions.

I couldn’t believe that it would be possible to drive these drugs through the skin to the site of inflammation. They didn’t teach this in pharmacy school. It was such an influential experience that the light bulb went on in my head, and I knew I was going to have a future in compounding. Now here I am, working at PCCA. Some of the compounding tools have changed, and the needs of patients have multiplied.

Patients in Pain

An analysis of data from the 2019 National Health Interview Survey showed that nearly 50.2 million adults (20.5%) in the United States reported pain on most days or every day. Common locations of pain were the back, hip, knee or foot.¹ Aside from the pain epidemic in general, this is especially important in the current environment of drug addiction and opioid abuse. The Centers for Disease Control and Prevention found that almost 50,000 Americans died from opioid-related overdoses in 2019 alone. It has also estimated that the total cost of prescription opioid misuse in the United States is as much as $78.5 billion per year. The National Institute on Drug Abuse characterizes opioid misuse and addiction as “a serious national crisis that affects public health as well as social and economic welfare.”²

Physicians are coming under scrutiny for prescribing opioid medications as well, and they are looking for better options for their patients. Furthermore, The BMJ recently published a meta-analysis of data on 446,763 Canadian and European patients suggesting that oral NSAID use for more than one week increases the risk of myocardial infarction, and that higher doses corresponded with greater risk.³This is where the compounding pharmacist comes in.

Also on The PCCA Blog: Lidocaine vs. Lidocaine HCl in Pharmacy Compounding

There is a need and a place for the delivery of drugs through the skin due to the side-effect profile of many oral medications, a tendency for abuse of and addiction to opioid medications, administration challenges, prescriber challenges, and lack of efficacy of traditional therapies. ⁴ Benefits of topical administration using a permeation-enhancing base may include convenience and ease of administration, improved patient compliance, and allowing for less frequent dosing.⁵

As a result, the use of permeation-enhancing topical pain medications may be considered a viable alternative to oral pain therapies in many patients. There are a multitude of studies to show that the active pharmaceutical ingredients (APIs) we use have merit and clinical relevance today. ^6,7 (For clinical information on a specific API, PCCA members can click on the Clinical References tab when viewing the API on PCCA’s website after logging in.)

Evolution of Pain Creams

Human skin has many functions, and its most apparent one is that of a defense organ, both physical and biological. Penetration of any compound into the body is primarily prevented by the corneal layer of the epidermis. This outer layer is just a few micrometers thick, but effectively forms a barrier that preserves life. The 500 Dalton rule states that when molecular weight increases to over 500 Daltons, absorption of molecules through normal skin rapidly declines.⁸ This further highlights the importance of using a base that will transverse the skin.

First Generation

The first widely recognized compounded topical base with permeation enhancement was Pluronic^® lecithin organogel (PLO). This is an oil-and-water emulsion introduced as a drug-delivery vehicle in the 1990s. ⁹ The technology was derived from studies on “organogels” created from incorporating lecithin into organic solvents.¹⁰ One study involved using Pluronic 20% with ketoprofen on carrageenan-induced paw edema in rats.¹¹ This base was quite revolutionary in the compounding world and led to many drugs being used that had never been delivered in this way before. However, PLO is considered first generation, and more advanced versions of permeation-enhancing topical bases have been introduced.

Current Generation

The Lipoderm^® family is a collection of current-generation, proprietary, permeation-enhancing bases that are improvements over PLO in consistency, stability and penetration.^12,13,14,15 In a comparison study, Lipoderm outperformed PLO when evaluating the percutaneous absorption of promethazine.¹⁵ Lipoderm also has been shown to successfully deliver four pain medications, including ketamine hydrochloride, gabapentin, clonidine hydrochloride and baclofen, simultaneously into human skin.¹² A topical cream base without permeation-enhancing properties does not have these characteristics and may stay on top of the epidermis. Physicians may be very interested in the differences and the importance of using true permeation-enhancing vehicles versus topical vehicles when considering positive patient outcomes. Topical pain management with the permeation-enhancing bases in the Lipoderm family can be used to address patients with conditions of inflammation, musculoskeletal pain and neuropathic pain, to name a few. Prescribers can review clinical data on these bases on the PCCA Science webpage .

Also on The PCCA Blog: Compounding for Patients in Hospice Care

Newest Innovation

With more recent industry changes related to stability requirements and higher workflow demands, compounders are looking for cost-effective ways to extend beyond-use dates and save money on stability testing. To help meet these needs, PermE8^® Anhydrous Gel is a base from PCCA that uses new technology to deliver drugs through the skin using an anhydrous vehicle. This will allow the compounder to use extended beyond-use dates according to USP 795 standards and still provide the same permeation-enhancing quality that compounders are used to with the Lipoderm family.¹⁶

This is an incredible opportunity for compounding pharmacists. Patients in pain can be very challenging to treat, and their quality of life is often negatively affected by their painful conditions. Compounding pharmacists can be of great value to both prescribers and their patients who are suffering.

PCCA members with Clinical Services support can access many PCCA formulas in our database that are commonly requested for patients with inflammatory pain , musculoskeletal pain , general neuropathic pain and diabetic neuropathy , among others. If they have any questions about permeation-enhancing topical compounds, they can contact our Clinical Services team.

Also on The PCCA Blog: Permeation-Enhanced Topical Pain Therapy: A Literature Review

Beau Harger, PharmD, is a graduate of the University of Mississippi. He joined the staff of PCCA in January 2015 as a full-time clinical compounding pharmacist after working as a part-time consultant for the previous year and a half. He came to PCCA with 15 years of compounding experience. He also taught pharmacology at William Carey College in Gulfport, Mississippi, and was the pharmacist in charge of Nucara Compounding Pharmacy in Austin, Texas, for eight years.

Photo by Nati Melnychuk on Unsplash.

A version of this article originally appeared in PCCA’s members-only magazine, the Apothagram.

References

Yong, R. J., Mullins, P. M., & Bhattacharyya, N. (2021). Prevalence of chronic pain among adults in the United States. Pain. Advance online publication. https://doi.org/10.1097/j.pain.0000000000002291
National Institute on Drug Abuse. (2021). Opioid overdose crisis. Retrieved December 16, 2021, from https://www.drugabuse.gov/drug-topics/opioids/opioid-overdose-crisis
Bally, M., Dendukuri, N., Rich, B., Nadeau, L., Helin-Salmivaara, A., Garbe, E., & Brophy, J. M. (2017). Risk of acute myocardial infarction with NSAIDs in real world use: Bayesian meta-analysis of individual patient data. The BMJ, 357. https://doi.org/10.1136/bmj.j1909
Branvold, A., & Carvalho, M., (2014). Pain management therapy: The benefits of compounded transdermal pain medication. Journal of General Practice, 2(6). http://dx.doi.org/10.4172/2329-9126.1000188
Paudel, K. S., Milewski, M., Swadley, C. L., Brogden, N. K., Ghosh, P., & Stinchcomb, A. L. (2010). Challenges and opportunities in dermal/transdermal delivery. Therapeutic Delivery, 1(1), 109-131. https://doi.org/10.4155/tde.10.16
PCCA. (n.d.). Drugs used in transdermal pain management: References [PCCA Document #99047]. Available from https://www.pccarx.com/Documents/M-Files/99047_PainAlgorithm_REFERENCES.pdf
PCCA. (n.d.). Information regarding drug usage – links to abstracts and research articles: Pain-focused [PCCA Document #98735]. https://www.pccarx.com/Documents/M-Files/98735_Drug_Abstracts_Pain.pdf
Bos, J. D., & Meinardi, M. M. (2000). The 500 Dalton rule for the skin penetration of chemical compounds and drugs. Experimental Dermatology, 9(3), 165-169. https://doi.org/10.1034/j.1600-0625.2000.009003165.x
Murdan, S. (2005). A review of pluronic lecithin organogel as a topical and transdermal drug delivery system. Hospital Pharmacist, 12(7), 267-270.
Willimann, H., Walde, P., Luisi, P. L., Gazzaniga, A., & Stroppolo, F. (1992). Lecithin organogel as matrix for transdermal transport of drugs. Journal of Pharmaceutical Sciences, 81(9), 871-874. https://doi.org/10.1002/jps.2600810906
Chi, S. C., & Jun, H. W. (1990). Anti-inflammatory activity of ketoprofen gel on carrageenan-induced paw edema in rats. Journal of Pharmaceutical Sciences, 79(11), 974-977. https://doi.org/10.1002/jps.2600791106
Bassani, A. S., & Banov, D. (2016). Evaluation of the percutaneous absorption of ketamine HCl, gabapentin, clonidine HCl, and baclofen, in compounded transdermal pain formulations, using the Franz finite dose model. Pain Medicine, 17(2), 230-238. https://doi.org/10.1111/pme.12899
Bassani, A. S., Banov, D., & Phan, H. (2015). In vitro characterization of the percutaneous absorption of lorazepam into human cadaver torso skin, using the Franz skin finite dose models. Journal of Pharmaceutics & Drug Delivery Research, 4(2). https://doi.org/10.4172/2325-9604.1000131
Bassani, A. S., Banov, D., & Phan, H. (2016). Characterization of the percutaneous absorption of ketoprofen using the Franz skin finite dose model. Postgraduate Medicine, 128(2), 262-267. https://doi.org/10.1080/00325481.2016.1144448
Bassani, A. S., Banov, D., & Lehman, P. A. (2008). Evaluation of the percutaneous absorption of promethazine hydrochloride,in vitro, using the human ex vivo skin model. International Journal of Pharmaceutical Compounding, 12(3), 270-273. https://ijpc.com/Abstracts/Abstract.cfm?ABS=2782
PCCA. (2019). Evaluation of the in vitro human skin percutaneous absorption of ketoprofen in PCCA PermE8 vs. PCCA Lipoderm [PCCA Document #99732]. https://www.pccarx.com/Documents/M-Files/99732_TR_Ketoprof-PermE8-Lipoderm.pdf

Compounding for Patients in Hospice Care

Wed, 06 Oct 2021 13:29:42 GMT

Bryan Prescott, PharmD, MBA, PCCA Director of Business Coaching Services

Emotional and spiritual needs are areas in which hospice care provides assistance to people who are terminally ill. Beyond those, there are the physical and therapeutic needs that are unique to hospice patients. They are often unable to tolerate many of the conventional medication dosage forms or need specialized concentrations of medications to adequately resolve their ailments. Compounding pharmacies can play a vital role in the care of these patients.

Addressing the patient’s physical needs may be the most important issue in hospice care. Since hospice strives to improve the quality of life for patients, it is important to address all symptoms they may experience. Some problems that hospice patients have are pain, constipation, nausea and vomiting, anxiety, difficult breathing (dyspnea), muscle loss and weakness (cachexia), anorexia, wounds, and terminal restlessness.

Compounding pharmacies have the ability to assist with these problems by making medications into patient-specific dosage forms and strengths. Some unique dosage forms commonly prescribed for hospice patients are capsules, sublingual drops, suppositories, oral suspensions, inhalations, sprays, troches, and topical gels and creams with permeation enhancement to deliver drugs through the skin.

Pain

Pain control is one of the best ways to comfort terminally ill patients. Pain may be overlooked or undertreated if physicians fear patients may become addicted to pain medications, but the fact is that many terminally ill patients cannot enjoy their last days with friends and family due to their uncontrolled pain.

A thorough assessment is a crucial step in achieving pain control, since pain is subjective, involves multiple aspects and can be of various origins. The three major types of pain seen in terminally ill patients are muscular, bone and neuropathic pain. These pain types differ not only in their symptoms and presentations, but also in their response to different classes of pain medications (e.g., neuropathic pain typically does not respond to opioids, while muscle pain does). When the correct type of pain is identified, treatment is based on classification of pain being responsive, semiresponsive or unresponsive to opioids.

Treatment schedules are also very important. Since most terminally ill patients have chronic pain, medications should be given around the clock instead of on an as-needed basis. Scheduled medications may reduce the incidence of “breakthrough pain,” which is a sudden increase in pain. It is better to prevent pain for hospice patients than try to control it once it starts.

Long-acting drugs are most commonly used for chronic pain while short-acting ones are used for breakthrough pain. Dosages are usually titrated up to achieve proper pain control, and then decreased as pain permits. In some circumstances, practitioners may increase patients’ medications by 25–50% to achieve proper pain management. If dosages are decreased, but the patient begins to ask for medications for breakthrough pain, the long-acting medication dose may be increased again to regain control.

Morphine, hydrocodone, fentanyl, meperidine, and methadone are some of the medications commonly prescribed to control muscular pain for hospice patients. They can be made into various dosage forms and concentrations that are specific to each patient’s need.

Bone pain is another challenge for hospice patients and is usually caused by cancer metastasis. Patients with bone pain will get the most benefit from nonsteroidal anti-inflammatory drugs (NSAIDs). Most practitioners prefer ibuprofen for bone pain; however, some prescribe other NSAIDs depending on the case.

Neuropathic pain is the third type of pain that hospice patients experience. Neuropathic pain occurs when nerves are damaged, and it is usually chronic. It is typically not opioid responsive and is usually controlled with the use of a combination of agents, including ketamine, amitriptyline, baclofen, gabapentin and clonidine.^1,2,3,4,5 These medications can be used topically directly at the site of injury or pain.

Constipation

Constipation is frequently reported in hospice patients and may be due to the use of narcotic pain medications or anticholinergics. It has been reported that up to 71% of terminal cancer patients suffer from constipation.⁶ Other causes of constipation include a low-fiber diet, reduced defecation (due to anal fissures or hemorrhoids), dehydration, depression and hypercalcemia. Treatment should include a daily stool softener and stimulant laxative (especially if a patient is on narcotic pain medications) as well as proper hydration and active movement. Bulk laxatives should be avoided since they can cause impaction. Time between bowel movements should not exceed three days.

Many patients also experience impaction with overflow, which is sometimes not seen as constipation. Some physicians see patients passing stool, so they do not recommend a laxative and stool softener, but these patients are constipated and need to have regular bowel programs.

Nausea and Vomiting

Nausea and vomiting have also been reported in patients receiving hospice care. Up to 48% of patients with terminal cancer report these symptoms. ⁶Nausea and vomiting in hospice patients can be caused by drug side effects, oral thrush, brain metastases, anxiety, gastric irritation, intestinal obstruction, constipation, small-stomach syndrome, hypercalcemia, uremia, and low-grade urinary tract or pulmonary infections. Practitioners often prescribe drugs such as promethazine, scopolamine, lorazepam, diphenhydramine, haloperidol, metoclopramide and ondansetron for patients in these situations.^7,8,9 Compounders can provide patient-specific options as needed.

Wounds

When patients are confined to bed, as many patients in hospice care are, vascular insufficiency and subsequent tissue hypoxia may lead to bedsores (decubitus ulcers). Patients with decubitus ulcers are susceptible to severe infections, so treatment should begin as soon as possible. Practitioners commonly prescribe combination medications to help with pain and soothe the tissue, prevent or treat infection, and promote healing. They may include ketoprofen, lidocaine, bupivacaine, misoprostol, metronidazole, phenytoin or diphenhydramine.^10,11

Unfortunately, most wounds will not completely heal for hospice patients, but it is important to prevent them from progressing into more painful situations. As the necrotic tissue progresses, it will produce a foul odor that may be offensive to the patient and caregivers. For patients in this situation, the focus for wound treatment will be odor control and wound irrigation. One common way to reduce the odor is applying a eucalyptus chap stick under the nose to mask the smell.

Terminal Restlessness and Anxiety

Terminal restlessness, or agitated delirium, occurs at the end of life due to shutdown of multiple body systems. Up to 85% of dying patients are reported as having this condition.¹² Some common causes of terminal restlessness include pain, dyspnea, full bladder or rectum, nausea, unresolved concerns about death, lack of personal meaning and purpose in life, dehydration, hypercalcemia, hypoglycemia, hyponatremia, and adverse drug reactions. Patients with terminal restlessness may present with thrashing or agitation, involuntary muscle twitching or jerking (myoclonus), fidgeting or tossing and turning, yelling, or moaning. This delirium is often reversible until the last 48–72 hours of life. Appropriate assessment is important since this condition differs from regular delirium and treatments are different.

There are several treatment options for patients with terminal restlessness. One of the most commonly prescribed agents is the ABH compounded gel.⁸ It’s a topical gel with permeation enhancement that contains lorazepam, diphenhydramine and haloperidol but is known by the abbreviation of their brand names: Ativan^®, Benadryl ^® and Haldol^®. It is typically applied to the forearm every 8–12 hours and produces a rapid effect for the patient. This combination can also be compounded into a suppository.

Oral Hygiene

Patients in hospice care may also have many issues related to oral hygiene. They can deal with mouth sores from radiation treatments, dry mouth from opioids, excessive secretions due to the inability to clear lung secretions, and thrush from cancer treatments. These problems can lead to inability to eat, tooth decay and pain if not properly addressed. Compounding pharmacies can provide options for all of these issues that are customized for the individual patient.

Also on The PCCA Blog: Dental Compounding: Common Issues and Potential Treatment Options

PCCA members with Clinical Services support can find commonly requested formulas for hospice patients with pain , nausea and vomiting , wounds , and oral-hygiene needs in our formula database. They can also contact our Clinical Services team to discuss any questions about helping patients receiving hospice care.

Bryan Prescott, PharmD, MBA, PCCA Director of Business Coaching Services, currently provides business coaching for compounding pharmacies, including financial analysis, marketing and human resources expertise. Before joining the staff of PCCA in 2012, he worked at Pharmcare in Pearland, Texas, for 10 years, where he was the PIC and operations manager for the long-term care department. He has been a featured speaker at many PCCA and A4M seminars focusing on pain, palliative care, wound, scar, ENT and marketing. Bryan obtained his Doctor of Pharmacy from the University of Houston in 2001 and Master of Business Administration from Texas A&M University in 2019. He is a member of the Rho Chi Society and a lifetime member of Phi Delta Chi.

References

1. Gammaitoni, A., Gallagher, R. M., & Welz-Bosna, M. (2000). Topical ketamine gel: Possible role in treating neuropathic pain. Pain Medicine, 1(1), 97–100. https://doi.org/10.1046/j.1526-4637.2000.00006.x

2. Genevois, A. L., Ruel, J., Penalba, V., Hatton, S., Petitfils, C., Ducrocq, M., Principe, P., Dietrich, G., Greco, C., & Delmas, P. (2021). Analgesic effects of topical amitriptyline in patients with chemotherapy-induced peripheral neuropathy: Mechanistic insights from studies in mice. The Journal of Pain, 22(4), 440–453. https://doi.org/10.1016/j.jpain.2020.11.002

3. Kopsky, D. J., Keppel Hesselink, J. M., & Casale, R. (2015). Walking with neuropathic pain: Paradoxical shift from burden to support? Case Reports in Medicine, 2015. https://doi.org/10.1155/2015/764950

4. Hiom, S., Patel, G. K., Newcombe, R. G., Khot, S., & Martin, C. (2015). Severe postherpetic neuralgia and other neuropathic pain syndromes alleviated by topical gabapentin. The British Journal of Dermatology, 173(1), 300–302. https://doi.org/10.1111/bjd.13624

5. Wrzosek, A., Woron, J., Dobrogowski, J., Jakowicka-Wordliczek, J., & Wordliczek, J. (2015). Topical clonidine for neuropathic pain. The Cochrane Database of Systematic Reviews. https://doi.org/10.1002/14651858.CD010967.pub2

6. Morita, T., Tsunoda, J., Inoue, S., & Chihara, S. (1999). Contributing factors to physical symptoms in terminally-ill cancer patients. Journal of Pain and Symptom Management, 18(5), 338–346. https://doi.org/10.1016/s0885-3924(99)00096-2

7. Bassani, A. S., Banov, D., & Lehman, P. A. (2008). Evaluation of the percutaneous absorption of promethazine hydrochloride, in vitro, using the human ex vivo skin model. International Journal of Pharmaceutical Compounding, 12 (3), 270–273. https://ijpc.com/Abstracts/Abstract.cfm?ABS=2782

8. Bleicher, J., Bhaskara, A., Huyck, T., Constantino, S., Bardia, A., Loprinzi, C. L., & Silberstein, P. T. (2008). Lorazepam, diphenhydramine, and haloperidol transdermal gel for rescue from chemotherapy-induced nausea/vomiting: Results of two pilot trials. The Journal of Supportive Oncology, 6(1), 27–32.

9. Moon R. B. (2006). ABHR gel in the treatment of nausea and vomiting in the hospice patient. International Journal of Pharmaceutical Compounding, 10 (2), 95–98. https://ijpc.com/Abstracts/Abstract.cfm?ABS=2351

10. Mahoney, J., Ponticello, M., Nelson, E., & Ratz, R. (2007). Topical misoprostol and wound healing in rats. Wounds, 19(12), 334–339. https://www.hmpgloballearningnetwork.com/site/wounds/article/8076

11. Shaw, J., Hughes, C. M., Lagan, K. M., & Bell, P. M. (2007). The clinical effect of topical phenytoin on wound healing: A systematic review. The British journal of dermatology, 157(5), 997–1004. https://doi.org/10.1111/j.1365-2133.2007.08160.x

12. Brajtman S. (2003). The impact on the family of terminal restlessness and its management. Palliative Medicine, 17(5), 454–460. https://doi.org/10.1191/0960327103pm779oa

Topical Compounded Treatment Options for Painful Vaginal and Vulvar Conditions

Wed, 12 May 2021 13:26:11 GMT

By Tricia Heitman, PharmD, PCCA Clinical Compounding Pharmacist

Painful vaginal and vulvar conditions can be difficult to resolve successfully without a comprehensive treatment plan. Often, that treatment plan will include physical therapy, psychological counseling and intravaginal treatment. These conditions are challenging for practitioners because age, hormonal status, dysbiosis, traumatic events, mental health, genetics and general state of health represent only a few factors that they may need to address. Depression and anxiety can complicate the pain and sexual dysfunction that can result from vaginal and vulvar conditions. Some researchers believe that the mental status causes the dysfunction, while others believe that the sexual dysfunction is the cause of the depression and anxiety.¹ We may not always know which came first in each patient, but what we do know is that this group of disorders often cause a reduction in quality of life for patients experiencing them. Fortunately, there are unique customizable treatment options that compounding pharmacies can offer to patients with atrophic vaginitis, vulvar lichen sclerosis, desquamative inflammatory vaginitis, vaginismus, vulvodynia and high-tone pelvic floor dysfunction.

In addition to the patient-specific treatment, PCCA’s recently released compounding base, Ellage^™ Anhydrous Vaginal (PCCA #30-5110), may improve patient compliance and therefore patient outcomes. Ellage is an anhydrous vaginal vehicle that can extend the default beyond-use date of compounded vulvar and intravaginal medications. This special feature is especially helpful when treating chronic conditions: A longer beyond-use date means a reduction in the number of pharmacy visits for refills. Regardless of the base used, working together with the practitioner to create an effective treatment plan with minimal side effects will provide the best outcome possible for patients.

Atrophic Vaginitis

Atrophic vaginitis, or vaginal atrophy, is possibly the most common vaginal condition facing postmenopausal and perimenopausal women. It is characterized by vaginal dryness, thinning of the vaginal mucosa, and in some cases, inflammation and bleeding. Atrophic vaginitis is a condition caused by estrogen deficiency and can also occur in patients following radiation therapy, chemotherapy, removal of one or both ovaries (oophorectomy), premature ovarian failure or endocrine disorders as well as in patients receiving antiestrogen medication. Atrophic vaginitis can cause painful intercourse (dyspareunia) and burning pain and can lead to other symptoms, including urinary symptoms if the condition is not addressed. In recent years, health care professionals have begun referring to atrophic vaginitis and its symptoms collectively as genitourinary syndrome of menopause, or GSM.

Treatment with intravaginal estrogen creams, gels and inserts (specifically estradiol) are the gold standard treatment.² Unfortunately, this therapy is not the best therapeutic option for every patient. Estriol or oxytocin may be an alternative for patients who are not good candidates for intravaginal estradiol. A small clinical trial evaluated the use of 0.03 mg estriol and Lactobacillus combination vaginal tablets. The study included 16 postmenopausal patients, all of whom had resolution of their atrophic vaginitis symptoms. The treatment caused a small increase in estriol levels in half of the patients observed but did not produce increases in estrone or estradiol. Although current regulations do not allow compounding of Lactobacillus, data from this trial can be deduced regarding the kinetics of vaginal estriol used in postmenopausal women.³ Further evidence includes a phase III study with 167 patients. Participating women received either 1 Gm of vaginal gel containing 50 μg of estriol or placebo. Patients were instructed to use the gel daily for three weeks and then twice weekly up to 12 weeks. The results of this study support the use of estriol in women with atrophic vaginitis. Estriol was superior to placebo in reducing vaginal dryness, atrophy, dyspareunia, pruritis, burning, vaginal pH and painful urination (dysuria). ⁴ This option could be a potential alternative for those patients who respond to estrogen therapy but may be sensitive to more potent estrogens such as estradiol.

“Estriol or oxytocin may be an alternative for patients who are not good candidates for intravaginal estradiol.”

Patients who have a personal history of estrogen-receptor-positive cancer, who have a high risk of such cancer types or who are receiving antiestrogen medication will need alternative treatment options. Intravaginal oxytocin has recently emerged as another option that may improve the vaginal hormone environment, improve subjective symptoms of vaginal atrophy and reduce the vaginal pH in patients suffering from atrophic vaginitis.⁵ A randomized, controlled trial studied 140 postmenopausal women who received intravaginal oxytocin gel or placebo for a period of 30 days. The oxytocin gel consisted of 600 IU oxytocin in a sodium carboxymethylcellulose gel. Of the 70 participants in the oxytocin arm, 47 improved versus no improvement in the placebo arm.⁶ Researchers in Sweden conducted a larger double-blind, randomized, controlled study in which participants used 400 IU or 100 IU oxytocin gels once daily for seven weeks. The oxytocin gel was made with sodium carboxymethylcellulose and had the pH adjusted to 3.75. The most substantial results of this study show that in the women receiving 400 IU oxytocin, there was a significant improvement in their most troublesome symptom. In fact, 53% of participants claimed complete resolution of their most troublesome symptom.⁷

Vulvar Lichen Sclerosis

Vulvar lichen sclerosis (VLS) is a chronic inflammatory disorder of unknown cause and can affect women of all ages. The risk factors for it include genetic predisposition, autoimmunity, repeated tissue trauma, infection and low hormone levels. VLS is characterized by atrophic, white plaques that cause pruritis, pain, burning, and potentially genital scarring and adhesion if not treated effectively and early. It is typically isolated to the labial, perineal and perianal areas, but in some patients, other areas such as the trunk, buttock and thigh can be involved.⁸ VLS has also been associated with an increased risk of squamous cell carcinoma. ⁹ Research has shown an increase in the inflammatory markers TNF-α and interleukin-6 in the tissue of patients with this condition. Researchers conclude that VLS has at least in part an autoimmune etiology. ¹⁰

While high-dose topical steroids such as mometasone furoate 0.05% or clobetasol propionate 0.05% are the current mainstay of treatment, there are other options for patients who do not improve with this treatment. ¹¹ In an Italian study, 12 women who were unresponsive or poorly responsive to high-potency topical corticosteroids were prescribed a 0.1% tacrolimus ointment. The ointment was applied twice daily for six weeks, then once daily for 15 days and then twice daily for the last four weeks of the trial. Of the 11 patients who completed the trial, eight had good to complete remission of symptoms.¹² Researchers conducted another trial of topical 0.1% tacrolimus including 16 total patients, 10 with anogenital and six with extragenital localization. Of the 10 patients with anogenital involvement, nine responded to therapy, while only one of the six extragenital patients saw response. Therefore, response to tacrolimus may be more likely in patients without extragenital involvement. ¹³

“While high-dose topical steroids such as mometasone furoate 0.05% or clobetasol propionate 0.05% are the current mainstay of treatment, there are other options for patients who do not improve with this treatment.”

Naltrexone may be another topical option for these patients. We know that naltrexone can inhibit the production of interleukin-6 and TNF-α, which are part of the pathogenic picture of many inflammatory conditions, including VLS.¹⁴ Although there are no large-scale clinical trials, topical naltrexone has been used successfully in other autoimmune diseases and may be worth considering for VLS patients as well.

Desquamative Inflammatory Vaginitis

Desquamative inflammatory vaginitis is a challenging, chronic condition of unknown etiology that causes purulent vaginal discharge, red vaginal inflammation, bleeding, spotted rash, dyspareunia and pain. It is associated with a vaginal pH greater than 4.5 and a near absence of vaginal Lactobacilli in almost all women.¹⁵ Some researchers have given this spectrum of symptoms the term “aerobic vaginitis” due to the severe disruption of vaginal flora.^16,17 First-line treatment of this condition with intravaginal 2% clindamycin is commonly used, although most patients also experience relapse after the treatment is discontinued.

High-dose intravaginal hydrocortisone is another widely used treatment option.¹⁷ Typically, 3–5 Gm of 10% hydrocortisone cream is inserted daily for three weeks. Alternatively, hydrocortisone acetate 25 mg suppositories twice daily have been used successfully. Maintenance therapy is recommended for all treatment options to prevent relapse. Maintenance therapy of the initial therapeutic option should be recommended three times weekly for at least two months.¹⁸

Vaginismus

Vaginismus is characterized by persistent involuntary spasm of the vaginal musculature. It is a painful condition that can make gynecological exam, sexual intercourse and tampon insertion difficult or impossible. Primary vaginismus, also called lifelong vaginismus, occurs when a woman has never been able to experience non-painful vaginal intercourse. Secondary vaginismus, also called acquired vaginismus, occurs if the woman has been able to have non-painful penetration of the vaginal opening previously but has since developed the painful condition. Both conditions are involuntary and cannot be overcome without treatment. It is not clear if the condition is caused by fear or anxiety, or if the fear and anxiety stem from the pain of the condition. In many cases, the condition is related to past sexual trauma or fear of painful intercourse.

Patients experiencing vaginismus can benefit from counseling and education as well as pharmacotherapy.^19,20 As an adjunct, lidocaine 5% gel and lubricants have been used to help with painful vaginal intercourse. Combining lidocaine with a lubricant could prove to be a successful combination for patients dealing with this condition.^20,21 Additionally, a retrospective review of 13 patient medical records revealed that a combination of ketamine 0.5% and amitriptyline 1–2% have been used to successfully treat genital pain and could be considered for patients who are unresponsive to other treatments.²² A quick improvement in symptoms will greatly improve quality of life for these patients.

Vulvodynia

Vulvodynia, also called vulvar vestibulitis syndrome, is a chronic pain condition involving the vulva. It involves complex neuropathic pain with symptoms of burning, stinging, itching or rawness typically lasting more than three months.²³ The pain can be spontaneous or provoked and can range in severity among patients. This condition is a common cause of dyspareunia and decreased quality of life.²⁴ There is currently no known cause, but risk factors include sleep disturbances, chronic pain conditions and psychological disorders such as PTSD.²⁵

While lidocaine 4% cream or gel applied to the vestibule prior to intercourse may reduce provoked pain in some patients, other treatments may be necessary in more severe pain.²⁵ Gabapentin, ketamine and amitriptyline have been used as well due to their neuromodulating effects. ^{22,26,27,28,29,30} In a multicenter, double-blind, randomized crossover trial, gabapentin improved sexual function, including arousal, desire and satisfaction in patients with vulvodynia.²⁷ The previously mentioned review of 13 patient charts where ketamine 0.5% and amitriptyline 1–2% were prescribed for rectal, perineal or genital pain revealed that 54% of patients had complete to substantial relief of pain. ²² Another treatment option, estriol 0.03% and amitriptyline 0.5% topical gel applied to the vulvar vestibule, was evaluated in a retrospective clinical audit of 1,174 patients with entry dyspareunia. This combination treatment was rated effective by 51.2% of patients less than 30 years of age, 66.7% of patients 30–50 years of age, and 58.3% of patients over 50.²⁸

“While lidocaine 4% cream or gel applied to the vestibule prior to intercourse may reduce provoked pain in some patients, other treatments may be necessary in more severe pain.”

Topical treatments for vulvodynia are typically applied at the vaginal opening nightly. Twice daily application can be of benefit in patients with spontaneous pain that causes discomfort throughout the day. Topical pain therapy for these patients could reduce side effects resulting from oral treatment.

High-Tone Pelvic Floor Dysfunction

High-tone pelvic floor dysfunction (HTPFD) in women is a condition of elevated resting tone of the pelvic floor muscles that is persistent and results in lactic acid buildup and pain that radiates to the groin, abdomen and back. HTPFD is also associated with dyspareunia, painful menstrual periods, constipation, urinary urgency and stress incontinence. Some risk factors include traumatic injury to the pelvic area, pregnancy, pelvic surgery, obesity and advancing age. Patients may find vaginal exam painful and uncomfortable as the tissues will be resistant to stretch.³¹ Muscles that contract continually generate pain, edema and inflammation due to cytokine release.

Diazepam, due to its muscle-relaxant activity, has been used to reduce pain in patients with HTPFD. Diazepam 10 mg suppositories used nightly for 30 days may improve pelvic floor function, which improves comfort with intercourse and muscle tone upon digital exam. In a study of this treatment, no patients noted adverse effects.³² Pharmacokinetic studies show that vaginal administration of diazepam results in a lower bioavailability compared to standard oral use. However, diazepam may accumulate with chronic daily intravaginal doses. Intermittent dosing following the initial course may be favorable to allow intimacy and reduce accumulation.³³ Practitioners have also prescribed compounded diazepam combined with baclofen, lidocaine, ketamine or amitriptyline to further reduce pain and dyspareunia, which has shown promise.

“Practitioners have also prescribed compounded diazepam combined with baclofen, lidocaine, ketamine or amitriptyline to further reduce pain and dyspareunia, which has shown promise.”

Vaginal and vulvar pain conditions affect quality of life for many women. Some may feel there is little help after exhausting the limit of commercially available treatment options. Depression and relationship difficulty can be a devastating consequence if not treated successfully. Equipped with supportive literature, a better understanding of each condition and formulation support, compounding pharmacists can assist practitioners with effective treatment strategies for the most challenging cases. PCCA members with Clinical Services support can find a list of related PCCA formulas in our formula database.

Patricia Heitman, PharmD, is a clinical compounding pharmacist at PCCA. She is a graduate of the University of Houston College of Pharmacy and served as a PCCA PharmD resident for one year post-graduation, which included a teaching position at her alma mater. She has been a full-time PCCA clinical compounding pharmacist since completing her residency in 2000, answering compounding-related calls daily from pharmacists in the United States and Canada. She lectures frequently at PCCA International Seminars and symposiums. Her passions include pediatric compounding—especially options for patients with autism—as well as women’s health, gastrointestinal health and pain management.

A version of this article originally appeared in PCCA’s members-only magazine, the Apothagram.

References

1. Basson, R., & Gilks, T. (2018). Women's sexual dysfunction associated with psychiatric disorders and their treatment. Women's Health. https://doi.org/10.1177/1745506518762664

2. Hainer, B. L., & Gibson, M. V. (2011). Vaginitis. American Family Physician, 83(7), 807–815. https://www.aafp.org/afp/2011/0401/p807.html

3. Donders, G., Neven, P., Moegele, M., Lintermans, A., Bellen, G., Prasauskas, V., Grob, P., Ortmann, O., & Buchholz, S. (2014). Ultra-low-dose estriol and Lactobacillus acidophilus vaginal tablets (Gynoflor^®) for vaginal atrophy in postmenopausal breast cancer patients on aromatase inhibitors: Pharmacokinetic, safety, and efficacy phase I clinical study. Breast Cancer Research and Treatment, 145, 371–379. https://doi.org/10.1007/s10549-014-2930-x

4. Cano, A., Estévez, J., Usandizaga, R., Gallo, J. L., Guinot, M., Delgado, J. L., Castellanos, E., Moral, E., Nieto, C., del Prado, J. M., & Ferrer, J. (2012). The therapeutic effect of a new ultra-low concentration estriol gel formulation (0.005% estriol vaginal gel) on symptoms and signs of postmenopausal vaginal atrophy: Results from a pivotal phase III study. Menopause, 19(10), 1130–1139. https://doi.org/10.1097/gme.0b013e3182518e9a

5. Zohrabi, I., Abedi, P., Ansari, S., Maraghi, E., Shakiba Maram, N., & Houshmand, G. (2020). The effect of oxytocin vaginal gel on vaginal atrophy in postmenopausal women: A randomized controlled trial. BMC Women’s Health, 20. https://doi.org/10.1186/s12905-020-00935-5

6. Torky, H. A., Taha, A., Marie, H., El-Desouky, E., Raslan, O., Moussa, A. A., Ahmad, A. M., Abo-Louz, A., Zaki, S., Fares, T., & Eesa, A. (2018). Role of topical oxytocin in improving vaginal atrophy in postmenopausal women: A randomized, controlled trial. Climacteric, 21(2), 174–178. https://doi.org/10.1080/13697137.2017.1421924

7. Al-Saqi, S. H., Uvnäs-Moberg, K., & Jonasson, A. F. (2015). Intravaginally applied oxytocin improves post-menopausal vaginal atrophy. Post Reproductive Health, 21(3), 88–97. https://doi.org/10.1177/2053369115577328

8. Singh, N., & Ghatage, P. (2020). Etiology, clinical features, and diagnosis of vulvar lichen sclerosus: A scoping review. Obstetrics and Gynecology International, 2020. https://doi.org/10.1155/2020/7480754

9. Carlson, J. A., Ambros, R., Malfetano, J., Ross, J., Grabowski, R., Lamb, P., Figge, H., & Mihm, M. C., Jr. (1998). Vulvar lichen sclerosus and squamous cell carcinoma: A cohort, case control, and investigational study with historical perspective; implications for chronic inflammation and sclerosis in the development of neoplasia. Human Pathology, 29(9), 932–948. https://doi.org/10.1016/s0046-8177(98)90198-8

10. Tran, D. A., Tan, X., Macri, C. J., Goldstein, A. T., & Fu, S. W. (2019). Lichen sclerosus: An autoimmunopathogenic and genomic enigma with emerging genetic and immune targets. International Journal of Biological Sciences, 15(7), 1429–1439. https://doi.org/10.7150/ijbs.34613

11. Chi, C.-C., Baldo, M., Kirtschig, G., Brackenbury, F., Lewis, F., & Wojnarowska, F. (2011). Topical interventions for genital lichen sclerosus. The Cochrane Database of Systematic Reviews. https://doi.org/10.1002/14651858.CD008240

12. Virgili, A., Lauriola, M. M., Mantovani, L., & Corazza, M. (2007). Vulvar lichen sclerosus: 11 women treated with tacrolimus 0.1% ointment. Acta Dermato-Venereologica, 87(1), 69–72. https://doi.org/10.2340/00015555-0171

13. Kim, G.-W., Park, H.-J., Kim, H.-S., Kim, S.-H., Ko, H.-C., Kim, B.-S., & Kim, M.-B. (2012). Topical tacrolimus ointment for the treatment of lichen sclerosus, comparing genital and extragenital involvement. The Journal of Dermatology, 39(2), 145–150. https://doi.org/10.1111/j.1346-8138.2011.01384.x

14. Cant, R., Dalgleish, A. G., & Allen, R. L. (2017). Naltrexone inhibits IL-6 and TNFα production in human immune cell subsets following stimulation with ligands for intracellular toll-like receptors. Frontiers in Immunology. https://doi.org/10.3389/fimmu.2017.00809

15. Murphy, R., & Edwards, L. (2008). Desquamative inflammatory vaginitis: What is it? The Journal of Reproductive Medicine, 53(2), 124–128.

16. Sonthalia, S., Aggarwal, P., Das, S., Sharma, P., Sharma, R., & Singh, S. (2020). Aerobic vaginitis — An underdiagnosed cause of vaginal discharge — Narrative review. International journal of STD & AIDS, 31(11), 1018–1027. https://doi.org/10.1177/0956462420913435

17. Murphy R. (2004). Desquamative inflammatory vaginitis. Dermatologic Therapy, 17(1), 47–49. https://doi.org/10.1111/j.1396-0296.2004.04006.x

18. Sobel, J. D., Reichman, O., Misra, D., & Yoo, W. (2011). Prognosis and treatment of desquamative inflammatory vaginitis. Obstetrics & Gynecology, 117(4), 850–855. https://doi.org/10.1097/AOG.0b013e3182117c9e

19. Pacik, P. T. (2014). Understanding and treating vaginismus: A multimodal approach. International Urogynecology Journal, 25, 1613–1620. https://doi.org/10.1007/s00192-014-2421-y

20. Harish, T., Muliyala, K. P., & Murthy, P. (2011). Successful management of vaginismus: An eclectic approach. Indian Journal of Psychiatry, 53(2), 154–155. https://doi.org/10.4103/0019-5545.82548

21. Hassel, B. (1997). Resolution of primary vaginismus and introital hyperesthesia by topical anesthesia. Anesthesia & Analgesia, 85(6), 1415–1416. https://doi.org/10.1097/00000539-199712000-00055

22. Poterucha, T. J., Murphy, S. L., Rho, R. H., Sandroni, P., Warndahl, R. A., Weiss, W. T., & Davis, M. D. P. (2012). Topical amitriptyline-ketamine for treatment of rectal, genital, and perineal pain and discomfort. Pain Physician, 15(6), 485–488. https://www.painphysicianjournal.com/current/pdf?article=MTc5Ng%3D%3D&journal=71

23. Edwards, L. (2015). Vulvodynia. Clinical Obstetrics and Gynecology, 58(1), 143–152. https://doi.org/10.1097/GRF.0000000000000093

24. Metts, J. F. (1999). Vulvodynia and vulvar vestibulitis: Challenges in diagnosis and management. American Family Physician, 59 (6), 1547–1556.

25. Reed, B. D., Legocki, L. J., Plegue, M. A., Sen, A., Haefner, H. K., & Harlow, S. D. (2014). Factors associated with vulvodynia incidence. Obstetrics & Gynecology, 123(2 Pt. 1), 225–231. https://doi.org/10.1097/AOG.0000000000000066

26. Goetsch, M. F., Lim, J. Y., & Caughey, A. B. (2015). A practical solution for dyspareunia in breast cancer survivors: A randomized controlled trial. Journal of Clinical Oncology, 33(30), 3394–3400. https://doi.org/10.1200/JCO.2014.60.7366

27. Bachmann, G. A., Brown, C. S., Phillips, N. A., Rawlinson, L. A., Yu, X., Wood, R., Foster, D. C., & Gabapentin Study Group (2019). Effect of gabapentin on sexual function in vulvodynia: A randomized, placebo-controlled trial. American Journal of Obstetrics & Gynecology, 220(1), 89.E1–89.E8. https://doi.org/10.1016/j.ajog.2018.10.021

28. Ruoss, C. M., Howard, E. A., Chan, K., Stevenson, P. G., & Vancaillie, T. (2021). Topical treatment of vulvodynia, dyspareunia and pudendal neuralgia: A single clinic audit of amitriptyline and oestriol in organogels. ANZJOG. Advance online publication. https://doi.org/10.1111/ajo.13292

29. Pagano, R., & Wong, S. (2012). Use of amitriptyline cream in the management of entry dyspareunia due to provoked vestibulodynia. Journal of Lower Genital Tract Disease, 16(4), 394–397. https://doi.org/10.1097/LGT.0b013e3182449bd6

30. Goldstein, A. T., Pukall, C. F., Brown, C., Bergeron, S., Stein, A., & Kellogg-Spadt, S. (2016). Vulvodynia: Assessment and treatment. The Journal of Sexual Medicine, 13(4), 572–590. https://doi.org/10.1016/j.jsxm.2016.01.020

31. Faubion, S. S., Shuster, L. T., & Bharucha, A. E. (2012). Recognition and management of nonrelaxing pelvic floor dysfunction. Mayo Clinic Proceedings, 87(2), 187–193. https://doi.org/10.1016/j.mayocp.2011.09.004

32. Rogalski, M. J., Kellogg-Spadt, S., Hoffmann, A. R., Fariello, J. Y., & Whitmore, K. E. (2010). Retrospective chart review of vaginal diazepam suppository use in high-tone pelvic floor dysfunction. International Urogynecology Journal, 21(7), 895–899. https://doi.org/10.1007/s00192-009-1075-7

33. Larish, A. M., Dickson, R. R., Kudgus, R. A., McGovern, R. M., Reid, J. M., Hooten, W. M., Nicholson, W. T., Vaughan, L. E., Burnett, T. L., Laughlin-Tommaso, S. K., Faubion, S. S., & Green, I. C. (2019). Vaginal diazepam for nonrelaxing pelvic floor dysfunction: The pharmacokinetic profile. The Journal of Sexual Medicine, 16(6), 763–766. https://doi.org/10.1016/j.jsxm.2019.03.003

Permeation-Enhanced Topical Pain Therapy: A Literature Review

Wed, 13 May 2020 13:04:05 GMT

By Nat Jones, RPh, FAPC, PCCA Clinical Compounding Pharmacist

Topical preparations made of animal, mineral or plant extracts were in common use in ancient Egyptian and Babylonian medicine by 3000 BCE.¹ Humans have known for a very long time that products may be applied to the skin for either local or systemic effects, and as our understanding of the anatomy and physiology of the skin has improved, science has brought about the development of technologies to effectively and quantitatively deliver substances across this barrier to specific target sites in the skin and systemically in the body.² This brings us to modern health care, including pharmacy compounding.

Permeation Enhancement in Compounding

Compounding pharmacists have brought a variety of topical treatment options forward within the last 25 years in the field of pain therapy. Permeation-enhanced topical pain therapy (PETPT) has been commonly called transdermal pain therapy for a long time in our industry. More recently in the pharmaceutical industry, though, the word “transdermal” has primarily referred to manufactured patches (e.g., fentanyl) and not compounded creams or gels. With that being the case, the term “permeation-enhanced” seems appropriate.

In the practice of compounding, permeation enhancement can come from certain chemicals, some of which have dual function in formulating for topical applications. These agents can both increase penetration through the stratum corneum (permeation enhancers), and they can also improve incorporation of the active pharmaceutical ingredient (API) into the delivery base (wetting agents). Common examples would include propylene glycol, ethoxy diglycol or ethylene glycol monoethyl ether.³ It is also important when compounding to select a wetting agent that is compatible with the base, of course.

Over the years, compounding bases have become more advanced, with some having intrinsic permeation-enhancing properties. Compounders made the use of pluronic lecithin organogels (PLO gels) popular in the 1990s and early 2000s, but with the invention of Lipoderm^® in the early 2000s, the landscape of delivering small to medium-sized molecules through the stratum corneum changed. Lipoderm was the first proprietary permeation-enhancing vehicle in the compounding industry, and it showed increased delivery of ketoprofen versus a PLO gel with Franz finite permeation testing.⁴ Other APIs were successfully tested for permeation through the skin, including a four-drug study of both Lipoderm and Lipoderm ActiveMax^®proving delivery of ketamine, gabapentin, baclofen and clonidine simultaneously from the same permeation-enhancing topical base.⁵ More recently, PermE8^® Anhydrous Gel shows promise as another option. Initial in vitro testing revealed that it delivered ketoprofen into and through human skin tissue comparably to Lipoderm.⁶ This leads to a discussion of the evidence we have for PETPT.

Levels of Evidence in Medicine

Clinical data about the efficacy of PETPT has presented various levels of evidence that is useful in helping our medical colleagues to treat patients experiencing pain. Evidence-based medicine is the hierarchical system of classifying evidence in order to be able to make more logical clinical decisions. There are many different levels of evidence that can be used. At one extreme, there are systematic reviews of multiple clinical trials with homogeneity. At the other end, there is expert opinion without explicit critical appraisal or that is based on physiology bench research or fundamental information (“first principles”).⁷ Table 1 explains this range of evidence.

Table 1. Levels of Evidence for Studies⁷
Level	Type of Evidence
1A	Systematic review (with homogeneity) of randomized, controlled trials (RCTs)
1B	Individual RCT (with narrow confidence intervals)
1C	All-or-none study
2A	Systematic review (with homogeneity) of cohort studies
2B	Individual cohort study (including low quality RCT, e.g., <80% follow-up)
2C	“Outcomes” research; ecological studies
3A	Systematic review (with homogeneity) of case-control studies
3B	Individual case-control study
4	Case series (and poor-quality cohort and case-control study)
5	Expert opinion without explicit critical appraisal or based on physiology bench research or first principles

In the practice of medicine, there is not always a systematic review of homogeneous, randomized clinical trials available for us to use when making every clinical decision. In fact, in the compounding world, that level of evidence is essentially nonexistent. It has been stated many times that we are attempting the practice of medicine and not the exact science of medicine, and that on many occasions the only level of evidence we have is an expert opinion without explicit critical appraisal, or we must base our decision on physiology bench research or first principles. This does not mean we are not practicing evidence-based medicine. We are, but just not with the highest level of evidence that could exist in an ideal world. The practice of medicine is still far from being perfected, and we still make great use of the information we have.

Literature Review of PETPT

Last year, we at PCCA undertook a literature review of PETPT, totaling 168 single-API studies and 48 multi-API studies. We looked at the design and outcomes of these studies published from around the world. Their size and quality varied from single-patient case studies to larger randomized, placebo-controlled clinical trials. Most of them showed an effective outcome for the patients treated (153 out of 168 single-API studies, or 91%, and 38 out of the 48 multi-API studies, or 79%). The researchers used a variety of APIs in these studies, such as amitriptyline, baclofen, capsaicin, clonidine, diclofenac, doxepin, gabapentin, ibuprofen, ketamine, ketoprofen, lidocaine and piroxicam, along with others. Navigating this bulk of literature and deciding which articles to share with prescribers to help make clinical decisions can be difficult and time consuming. A brief summary of some selected studies from our review (Table 2 and Table 3) can serve as a reference guide for pharmacists and prescribers in choosing an effective API for incorporation into their PETPT for various types of patients. We hope it will make the selection process a little easier and, ultimately, help you to serve your patients.

Table 2. Single-API PETPT Studies
Clinical Use	Size	Ingredient	Outcomes	Citation
Central neuropathic pain	1	Amitriptyline	EFFECTIVE: Patient noted that in the week of using the active cream, no allodynia was present, with a carryover effect of one day. She did not need to use the escape medication in the week of using the active cream, though she frequently used the escape medication in the placebo weeks.	Kopsky, D. J., Liebregts, R., Keppel Hesselink, J. M. (2012). Central neuropathic pain in a patient with multiple sclerosis treated successfully with topical amitriptyline. Case Reports in Medicine, 2012. https://doi.org/10.1155/2012/471835
Chemotherapy-induced neuropathies	44	Amitriptyline	EFFECTIVE: The median VAS pain score decreased from 7 (4–9) at baseline to 2 (0–4) after 4-week topical treatment.	Rossignol, J., Cozzi, B., Liebaert, F., Hatton, S., Viallard, M.-L., Hermine, O., & Greco, C. (2019). High concentration of topical amitriptyline for treating chemotherapy-induced neuropathies. Supportive Care in Cancer, 27(8), 3053–3059. https://doi.org/10.1007/s00520-018-4618-y
Hemorrhoid post-op pain	66	Baclofen	EFFECTIVE: Baclofen group has significantly lower pain score on week 1 and week 2 than placebo. Baclofen group consumed significantly less analgesic agents on week 1 and week 2.	Ala, S., Alvandipour, M., Saeedi, M., Mansourifar, M., Monajati, M., & Shiva, A. (2020). Effect of topical baclofen 5% on post-hemorrhoidectomy pain: Randomized double blind placebo-controlled clinical trial. Journal of Gastrointestinal Surgery, 24, 405–410. https://doi.org/10.1007/s11605-019-04147-7
Diabetic Neuropathy	102	Amitriptyline vs. Capsaicin	EFFECTIVE: Both drugs significantly relieved pain in 12 weeks compared with baseline values. Treatment responders were similar in both groups (P = 0.545).	Kiani, J., Nasrollahi, S. A., Esna-Ashari, F., Fallah, P., & Sajedi, F. (2015). Amitriptyline 2% cream vs. capsaicin 0.75% cream in the treatment of painful diabetic neuropathy (Double blind, randomized clinical trial of efficacy and safety).Iranian Journal of Pharmaceutical Research, 14(4), 1263–1268.
Diabetic neuropathy	139	Clonidine, capsaicin	EFFECTIVE: Both drugs significantly relieved pain at 12 weeks, but no significant difference in the efficacy between the 2 treatments was observed.	Kiani, J., Sajedi, F., Nasrollahi, S. A., & Esna-Ashari, F. (2015). A randomized clinical trial of efficacy and safety of the topical clonidine and capsaicin in the treatment of painful diabetic neuropathy.Journal of Research in Medical Sciences, 20(4), 359–363.
Osteoarthritis of the knees	216	Diclofenac	EFFECTIVE: This topical diclofenac solution demonstrated relief of the symptoms of primary osteoarthritis of the knee at 6 weeks.	Baer, P. A., Thomas, L. M., & Shainhouse, Z. (2005). Treatment of osteoarthritis of the knee with a topical diclofenac solution: A randomised controlled, 6-week trial [ISRCTN53366886]. BMC Musculoskeletal Disorders, 6. https://dx.doi.org/10.1186%2F1471-2474-6-44
Central neuropathic pain	33	Ketamine	EFFECTIVE: Daily 75 mg S(+)-ketamine showed significant improvements on the Pain Disability Index, on the EQ-5D, and on the SF-36. Daily 50 mg was not effective.	Vranken, J. H., Dijkgraaf M. G. W., Kruis, M. R., van Dasselaar, N. T., & van der Vegt, M. H. (2005). Iontophoretic administration of S(+)-ketamine in patients with intractable central pain: A placebo-controlled trial. Pain, 118(1–2), 224–231. https://doi.org/10.1016/j.pain.2005.08.020
Complex regional pain syndrome, type 1 (CRPS I)	5	Ketamine	EFFECTIVE: Improvement of the report of pain intensity, measured by the visual analog scale, in 4 patients with acute early dystrophic stage of CRPS I. Swelling of the affected limbs subsided as well. No apparent changes were noticed in 1 patient with chronic atrophic stage of CRPS I and in both patients with CRPS II.	Ushida, T., Tani, T., Kanbara, T., Zinchuk, V. S., Kawasaki, M., Yamamoto, H. (2002). Analgesic effects of ketamine ointment in patients with complex regional pain syndrome type 1.Regional Anesthesia & Pain Medicine, 27(5), 524–528. https://doi.org/10.1053/rapm.2002.35517
Post herpetic neuralgia and neuropathic pain syndromes	23	Gabapentin	EFFECTIVE: Collectively, 20 of the 23 patients benefited from topical gabapentin, with a reduction in mean pain scores after 1 month, and 11 achieved a clinically meaningful 30% reduction in pain.	Hiom, S., Patel, G. K., Newcombe, R. G., Khot, S., & Martin, C. (2015). Severe postherpetic neuralgia and other neuropathic pain syndromes alleviated by topical gabapentin. British Journal of Dermatology, 173(1), 300–302. https://doi.org/10.1111/bjd.13624
Refractory, focal peripheral neuropathic pain	23	Gabapentin 6% in Lipoderm	EFFECTIVE: Topical gabapentin resulted in rapid improvement of symptoms (<1 month) when compared to the gradual titration required with oral administration (<8 weeks), with the associated patient and institution benefits. Results support anecdotal evidence that topical gabapentin is safe and efficacious for use in refractory focal peripheral neuropathic pain.	Hiom, S., Khot, S., Mogford, S., Hart, C., Patel, G., Roberts, G., Martin, C., & Newcombe, R. (2015). Topical delivery of gabapentin (GabaGel^™) for neuropathic pain: A ‘proof of concept’ study.International Journal of Pharmacy Practice, 23(Suppl. S2), 23–106. https://doi.org/10.1111/ijpp.12213

Table 3. Multi-API PETPT Studies
Clinical Use	Size	Ingredients	Outcomes	Citation
Radicular pain	Case series	Diclofenac, ibuprofen, baclofen, cyclobenzaprine, bupivacaine, gabapentin, pentoxifylline	EFFECTIVE: The topical formulation addresses both neuropathic and inflammatory components of radicular pain. It was found to be well tolerated, reduce radicular pain, and improve function and sleep in this case series of 3 patients who had failed other conservative or surgical treatment.	Safaeian, P., Mattie, R., Hahn, M., Plastaras, C. T., & McCormick, Z. L. (2016). Novel treatment of radicular pain with a multi-mechanistic combination topical agent: A case series and literature review. Anesthesiology and Pain Medicine, 6(2). http://dx.doi.org/10.5812/aapm.33322
Diabetic neuropathy and other chronic pain conditions	283	Ketamine, baclofen, gabapentin, amitriptyline, bupivacaine, clonidine, also a + nifedipine arm	EFFECTIVE: Both creams significantly decreased pain score. Also effective in all secondary outcomes.	Somberg, J. C., & Molnar, J. (2015). Retrospective study on the analgesic activity of a topical (TT-CTAC) cream in patients with diabetic neuropathy and other chronic pain conditions. American Journal of Therapeutics, 22(3), 214–221. https://doi.org/10.1097/mjt.0000000000000253
Chronic neuropathic pain	200	Doxepin, capsaicin, combination of doxepin and capsaicin	EFFECTIVE: Topical application of doxepin, capsaicin and doxepin/capsaicin produced analgesia of similar magnitude. However, the combination produced more rapid analgesia.	McCleane, G. (2000). Topical application of doxepin hydrochloride, capsaicin and a combination of both produces analgesia in chronic human neuropathic pain: A randomized, double-blind, placebo-controlled study.British Journal of Clinical Pharmacology, 49(6), 574–579. https://doi.org/10.1046/j.1365-2125.2000.00200.x
Neuropathic pain	16	Amitriptyline, ketamine, lidocaine	EFFECTIVE: The APIs significantly reduced (p<0.05) pain intensity, sharpness, burning, sensitivity, itchiness, unpleasantness and depth of pain levels on a short-term basis (i.e., between pre-treatment and 30 min post-treatment). They significantly reduced (p<0.05) burning levels on a long-term basis (i.e., between pretreatment and 2 weeks post-treatment).	Uzaraga, I., Gerbis, B., Holwerda, E., Gillis, D., & Wai, E. (2012). Topical amitriptyline, ketamine, and lidocaine in neuropathic pain caused by radiation skin reaction: A pilot study. Supportive Care in Cancer , 20(7), 1515–1524. https://doi.org/10.1007/s00520-011-1240-7

Nat Jones, RPh, FAPC, graduated from the Virginia Commonwealth University, Medical College of Virginia’s School of Pharmacy in 1979. In 2014, after 20 years of owning a compounding pharmacy, he joined PCCA’s staff. Nat has given continuing education lectures at medical professional seminars and webinars on numerous topics, including general compounding, wound care, pain management, nutrition, otolaryngology, women’s health, sexual dysfunction, insulin resistance, hormone replacement therapy, neurotransmitter imbalance and dermatology. He has published many articles and case studies in magazines and professional journals along with an open-access ebook titled Advances in Psoriasis with Avid Science. Since 2016, Nat has served on the Texas State Palliative Care Interdisciplinary Advisory Council.

A version of this article originally appeared in PCCA’s members-only magazine, the Apothagram.

References

1. Geller, M. J. (2010). Ancient Babylonian medicine. Malden, MA: Wiley-Blackwell.

2. Benson, H. A. E., Grice, J. E., Mohammed, Y., Namjoshi, S., & Roberts, M. S. (2019). Topical and transdermal drug delivery: From simple potions to smart technologies. Current Drug Delivery, 16 (5), 444–460. https://doi.org/10.2174/1567201816666190201143457

3. Osborne, D. W. (2011). Diethylene glycol monoethyl ether: An emerging solvent in topical dermatology products. Journal of Cosmetic Dermatology, 10(4), 324–329. https://doi.org/10.1111/j.1473-2165.2011.00590.x

4. Bassani, A. S., Banov, D., & Phan, H. (2016). Characterization of the percutaneous absorption of ketoprofen using the Franz skin finite dose model. Postgraduate Medicine, 128(2), 262–267. https://doi.org/10.1080/00325481.2016.1144448

5. Bassani, A. S., & Banov, D. (2015). Evaluation of the percutaneous absorption of ketamine HCl, gabapentin, clonidine HCl, and baclofen, in compounded transdermal pain formulations, using the Franz finite dose model. Pain Medicine, 17(2), 230–238. https://doi.org/10.1111/pme.12899

6. PCCA Science. (2019). Evaluation of the in vitro human skin percutaneous absorption of ketoprofen in PCCA PermE8 Anhydrous Gel vs. PCCA Lipoderm [PCCA Document #99732]. http://beta.pccarx.com/pdf_files/PCCA%20Science/Technical%20Reports/99732_TR_Ketoprof-PermE8-Lipoderm.pdf

7. Burns, P. B., Rohrich, R. J., & Chung, K. C. (2011). The levels of evidence and their role in evidence-based medicine. Plastic and Reconstructive Surgery, 128(1), 305–310. https://dx.doi.org/10.1097%2FPRS.0b013e318219c171

Compounding Opportunity with Isometheptene Mucate USP

Mon, 10 Jun 2019 16:18:00 GMT

The article was updated May 27, 2021.

Over 10% of people worldwide experience migraines, including about 12% of Americans.^1,2 Women tend to have them more than men, and people with a family history of migraines or those who are experiencing hormonal changes have a higher risk as well.^1,2,3 Migraines can be disabling and, by some estimates, have accounted for billions of dollars in lost productivity in the U.S.⁴

Many people who experience chronic migraines have been prescribed products containing isometheptene mucate along with dichloralphenazone and acetaminophen, commonly known by the brand name Midrin^™. However, the manufacturer discontinued Midrin several years ago. Recently, the FDA ordered manufacturers of all other isometheptene mucate-containing products to stop distributing them as well.⁵ Drug products approved by the FDA between 1938 and 1962 were only required to be proven safe. Isometheptene mucate was approved prior to 1962 and fell into this group of drugs only tested for safety. The 1962 Amendments to the Federal Food, Drug and Cosmetic (FD&C) Act established that a manufacturer had to prove both the safety of its product and the drug’s efficacy for its intended purpose.⁶ Because it was already on the market and deemed safe, isometheptene mucate was exempted from the efficacy requirement until the FDA’s recent order that stopped all distribution.

This presents a challenge for prescribers and the patients previously helped by medications that are no longer available. Commercially manufactured products containing isometheptene mucate now need to go through the FDA’s new drug approval process before they can be distributed. Fortunately, isometheptene mucate and acetaminophen have drug substance monographs in the United States Pharmacopeia and National Formulary (USP-NF). Therefore, compounding pharmacies can still compound with these ingredients in compliance with section 503A of the FD&C Act.⁷ (For more information about this, read our blog post about compounding with bulk drug substances .) Though dichloralphenazone is no longer available for pharmacy compounding, we have a blog post about two potential alternatives to dichloralphenazone where pharmacists can learn about some options.

To support compounding pharmacies in meeting the needs of practitioners and patients, PCCA offers isometheptene mucate and acetaminophen that are USP grade, and that meet The PCCA Standard ^™ above and beyond industry requirements.

As always, compounders should consult with the prescriber and the patient to find a solution tailored to the patient’s unique needs. If PCCA member pharmacies with Clinical Services support have questions about compounding for these patients, they can contact our clinical compounding pharmacists for more information at 800.331.2498.

References

1. National Institute of Neurological Disorders and Stroke. (2019). Migraine information page. Retrieved from https://www.ninds.nih.gov/Disorders/All-Disorders/Migraine-Information-Page

2. U.S. National Library of Medicine. (2019). Migraine. Retrieved from https://medlineplus.gov/migraine.html

3. Mayo Clinic. (2018). Migraine. Retrieved from https://www.mayoclinic.org/diseases-conditions/migraine-headache/symptoms-causes/syc-20360201

4. Burton, W. N., Landy, S. H., Downs, K. E., & Runken, M. C. (2009). The impact of migraine and the effect of migraine treatment on workplace productivity in the United States and suggestions for future research. Mayo Clinic Proceedings, 84(5), 436–445. https://dx.doi.org/10.1016%2FS0025-6196(11)60562-4

5. U.S. Food & Drug Administration. (2018). FDA notification regarding isometheptene-containing drug products. Retrieved from https://www.fda.gov/drugs/unapproved-prescription-drugs-drugs-marketed-united-states-do-not-have-required-fda-approval/fda-notification-regarding-isometheptene-containing-drug-products

6. U.S. Food & Drug Administration. (2012). Kefauver-Harris Amendments revolutionized drug development. Retrieved from https://www.fda.gov/consumers/consumer-updates/kefauver-harris-amendments-revolutionized-drug-development

7. U.S. Food & Drug Administration. (2018). Section 503A of the Federal Food, Drug, And Cosmetic Act. Retreived from https://www.fda.gov/drugs/human-drug-compounding/section-503a-federal-food-drug-and-cosmetic-act

These statements are provided for educational purposes only. They have not been evaluated by the Food and Drug Administration, and are not to be interpreted as a promise, guarantee or claim of therapeutic efficacy or safety. The references cited did not necessarily evaluate PCCA products or formulas included in these statements. The information contained herein is not intended to replace or substitute for conventional medical care, or encourage its abandonment.

Lipoderm®: Still the Standard in Topical Pain Management Compounding

Mon, 18 Mar 2019 16:38:10 GMT

This article was updated October, 29, 2020

In 2018, we introduced the pharmacy compounding world to PermE8^® Anhydrous Gel, a new permeation-enhancing topical base that holds a lot of potential for compounding pharmacies and their patients. While PermE8 delivers active pharmaceutical ingredients very well, and provides prolonged beyond-use dates by default, the experts in our Clinical Services and Formulation Development departments still recommend Lipoderm as a first choice for customized permeation-enhancing medications. Here’s why.

Incomparable Support

Lipoderm has provided important options for many patients over the years as the premier base used in deep-penetrating topical compounds for local absorption or systemic absorption. It is scientifically proven to deliver active ingredients through the skin, even up to four at one time. It is also supported by a significant portfolio of peer-reviewed publications. In fact, it has been included in over 30 journal articles. Most recently, the United States Pharmacopeial Convention included Lipoderm in an official USP compounded preparation monograph, “Ondansetron Compounded Topical Gel (20 mg/mL).”

Don’t Forget the Pets

Many compounders are familiar with Lipoderm for human use, but some don’t know that it has also been third-party tested for feline use , and that it is safe for topical use in dogs, cats and horses as well as certain exotic species. This means it provides options that can be easier for a pet owner to apply to the patient than administering pills or liquids.

Numerous Formulas

We have developed over 150 formulas with Lipoderm, including many for veterinary use. We have studied over 20 of those in our FormulaPlus ^™ program, and they have extended beyond-use dates backed by stability-indicating methods. Four of those are bracketed studies, offering compounders extended beyond-use dates in a range of active pharmaceutical ingredient concentrations. These FormulaPlus beyond-use date studies can save compounders thousands of dollars in stability testing because we’ve already taken care of it. PCCA members with Clinical Services access can find all of our Lipoderm formulas , including those with extended beyond-use dates, in the PCCA formula database.

Meet the Family

The technology at the core of Lipoderm has been so powerful that we have used it to develop a line of bases to give compounding pharmacies even more options:

Lipoderm ActiveMax^® is appropriate when compounding with ingredients in salt form at high concentrations
Lipoderm HMW^™ can accommodate ingredients with high molecular weight
Anhydrous Lipoderm is useful when working with ingredients that are unstable in aqueous environments, similar to our newer base, PermE8 Anhydrous Gel

If PCCA members have questions about Lipoderm , they can contact us at 800.331.2498. Not a member? Learn more about all that comes with PCCA membership, including access to Lipoderm and other exclusive compounding bases.

Pictured in the banner: David, a patient who has benefited from compounded permeation-enhancing medication. Watch David’s story .

A New Choice in Customized Medication for Pain Management

Mon, 07 Jan 2019 16:17:18 GMT

A New Choice in Customized Medication for Pain Management

This article was updated 10/19/2020

At our International Seminar in 2018, we were excited to debut PermE8^® Anhydrous Gel, a compounding base that holds a lot of potential for compounding pharmacies and their patients.

PermE8 is an anhydrous gel that can hold multiple active pharmaceutical ingredients and deliver them through the skin comparably to Lipoderm ^®, the industry standard for permeation-enhancing bases. PermE8 is ideal for compounded medication related to pain management, sports medicine, oncology and many other specialties.

We developed PermE8 because we wanted to help compounders to extend default beyond-use dates (BUDs) for their penetration-enhancing topical preparations without having to spend thousands of dollars on stability testing. This makes customized medications more efficient for compounders and more convenient for their patients.

At the same time, we wanted to improve on older anhydrous bases to invent something that delivers active pharmaceutical ingredients very well, has a silky texture that isn’t greasy and spreads easily on the skin.

Below is some additional information about this base. We have developed and tested over 45 formulas with PermE8 that PCCA members with Clinical Services access can find in our formula database, and we will continue to create more.

Benefits for Compounders

Lower Operating Costs
PermE8 is anhydrous, allowing for prolonged default BUDs without having to spend thousands of dollars on stability testing, and increasing operational efficiency for compounders making anticipatory batches
Higher Performance
In vitro testing shows that PermE8 significantly outperformed Anhydrous Lipoderm in delivering ketoprofen through human skin tissue (Figures 1 and 2)
Broader Application
It is a stable base that can accommodate multiple drugs in one preparation, including those in salt forms and those not stable in aqueous environments

Benefits for Patients

Convenience
It is anhydrous, which allows for longer BUDs and less-frequent prescription refills
Pleasant Application
PermE8 isn’t tacky or oily, and spreads on the skin more easily than some other anhydrous bases, such as Anhydrous Lipoderm

Delivery Performance

We tested PermE8 to compare it to two of our other transdermal bases: the industry-leading Lipoderm, as well as Anhydrous Lipoderm, our first-generation anhydrous base for permeation-enhancing topical compounds.

The in vitro testing showed that PermE8 performed comparably to Lipoderm and significantly outperformed Anhydrous Lipoderm. (Figures 1 and 2.)

Figure 1: Amount of Ketoprofen Special Micronized USP 10% (μg) Delivered into and through ex Vivo Human Abdomen Skin over 40 Hours from a Single Application

Figure 2: Mean Flux (μg/cm2/hr) Results: Percutaneous Absorption of Ketoprofen Special Micronized USP 10% through ex Vivo Human Abdomen Skin over 40 Hours from a Single Application

Note

We still recommend that compounders use Lipoderm for their permeation-enhancing topical compounds, and we have numerous Lipoderm-based formulas with extended BUDs that have been studied using stability-indicating methods. But for compounders who need prolonged BUDs for formulas that do not have stability studies behind them, we recommend using PermE8.

Pharmacy Compounding & the U.S. Opioid Epidemic

Tue, 30 Oct 2018 19:48:00 GMT

By A.J. Day, PharmD, RPh, PCCA Director of Clinical Services, and Maria Carvalho, PharmD, MRPharmS, PhD, Manager of PCCA Science

This article was updated October 2, 2020

Pain affects more Americans than diabetes, heart disease and cancer combined. It represents an important public health issue that is associated with a wide range of injury and disease.¹ As a result, an estimated 20% of patients with chronic pain receive an opioid prescription when visiting physician offices, and rates of opioid prescribing have grown significantly, in particular for family practice, general practice and internal medicine.²

The Epidemic

This has in turn contributed to further problems. Over two million people had an opioid-use disorder in 2016, translating to an economic burden of $504 million. On average, 116 Americans died every day from an opioid-related drug overdose.³Today, the addictive properties and the potentially fatal risks of opioids have led to a nationwide public health emergency, as declared by the Acting Secretary of Health and Human Services on October 26, 2017.⁴

Prevention, assessment and treatment of pain can be challenging not only to patients and caregivers, but also to health care providers. The Centers for Disease Control and Prevention recommend nonopioid pharmacological treatments and nonpharmacological treatments as preferred for chronic pain (outside of active cancer, palliative, or end-of-life care).⁵

How Pharmacy Compounding Can Help

Local compounding pharmacies are an integral part of their communities and are readily accessible to patients and physicians. For decades, compounding pharmacists have been helping patients with chronic pain by dispensing customized topical pain medications using permeation-enhancing bases. While avoiding the use of addictive drugs, these medications may be customized to include different types of drugs, in various dosage strengths, that are delivered simultaneously in one application.

However, there are still many patients and health care providers who are unaware of this nonopioid treatment. Compounding pharmacists are in a unique position to help combat the opioid epidemic by suggesting permeation-enhancing topical pain medications to their patients and physicians. PCCA members in particular have access to a wide array of pain formulas with plenty of supporting literature on our PCCA Science page under Journal Articles > Lipoderm. Furthermore, PCCA members have access to a broad range of in-person and web-based compounding training and specialized support in pain management.

More recently, we co-authored an article published in the Journal of Opioid Management, titled “ The Role of Transdermal Compounding in Opioid Safety .” It discusses the current U.S. opioid epidemic and explains how topical compounding with penetration-enhancing bases can be a safe and effective therapeutic option for specific patients who need help with pain management.⁶ This article may be a useful scientific resource for patients and health care providers who are not yet familiar with the benefits of permeation-enhancing topical pain medications. PCCA members who are interested in sharing this article can contact us at pccascience@pccarx.com to access the full text of the journal article.

A version of this article was originally published in the Apothagram, PCCA’s members-only magazine.

References

1. American Academy of Pain Medicine. (n.d.). AAPM facts and figures on pain. Retrieved from http://www.painmed.org/patientcenter/facts-on-pain/

2. Centers for Disease Control and Prevention. (2016). CDC guideline for prescribing opioids for chronic pain — United States, 2016. Morbidity and Mortality Weekly Report: Recommendations and Reports , 65(1). Retrieved from https://www.cdc.gov/mmwr/volumes/65/rr/pdfs/rr6501e1.pdf

3. U.S. Department of Health and Human Services. (2018). The opioid epidemic by the numbers in 2016 …. Retrieved from https://www.hhs.gov/opioids/sites/default/files/2018-01/opioids-infographic.pdf

4. Hargan, E. D. (2017). Determination that a public health emergency exists. Retrieved from https://www.hhs.gov/sites/default/files/opioid%20PHE%20Declaration-no-sig.pdf

5. Centers for Disease Control and Prevention. (n.d.). CDC guideline for prescribing opioids for chronic pain. Retrieved from https://www.cdc.gov/drugoverdose/pdf/guidelines_at-a-glance-a.pdf

6. Bucher, C. V., Day, A. J., & Carvalho, M. (2018). The role of transdermal compounding in opioid safety. Journal of Opioid Management, 14(1), 17-22. http://dx.doi.org/10.5055/jom.2018.0425