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By Tricia Heitman, PharmD, PCCA Clinical Compounding Pharmacist, and Austin Tull, PharmD, BCPP, co-owner of Cherokee Custom Script Pharmacy
Substance use and mental health disorders can be treated successfully, but there are often many obstacles that patients and practitioners must overcome. Lack of awareness, social stigma, cost of treatment and limited options may prevent patients from seeking or receiving the care they need to meet these challenges.1,2 It might be a surprising statistic that the average delay in treatment of a mental disorder, from the first self-reported symptom to seeking help, is more than a decade.3
Pharmacists can be one of the most accessible points of care for these patients. Education on these conditions facilitate pharmacists’ recognition of mental health issues so that they can encourage patients to seek out help when possible. Pharmacists can also provide resources in a more private and professional environment by using one-on-one counselling and developing meaningful relationships with patients. Reduction in the inappropriate use of psychotropic medications, improved patient compliance and medication review services could greatly impact patients who need direction and accountability. Additionally, compounding pharmacists have a unique opportunity to customize medication delivery by using sublingual, suspension, suppository or permeation-enhancing topical dosage forms. By using compounding services, medication dosage strength can be customized by the prescriber as well, and innovative treatment options can be used.
Opioid use disorder (OUD) is one of the most difficult addictions to break due to the physical and psychological pain that is inevitable upon withdrawal of the drug. Opioid withdrawal is a severe condition leading most patients to relapse. It may include pain, muscle spasms, tremors, nausea, vomiting, diarrhea, abdominal cramps, anxiety, irritability and insomnia, among other symptoms. Both the half-life of the opioid and the duration of use determine the severity of a patient’s opioid withdrawal symptoms. Opioids with shorter half-lives — such as oxycodone, hydrocodone and heroin — have severe withdrawal symptoms that start within 12 hours of discontinuation and last up to 10 days. Withdrawal is less severe with longer-acting opioids, such as methadone, but may last more than two weeks. 4
Collaborating with physicians to assist patients with medication withdrawal can help patients feel a sense of accomplishment and reduce the financial burden of their medical care. Although medication dosages available may not meet every patient’s need, pharmacy compounding options can help fill the gap and have the potential to improve patient outcomes. Buprenorphine, a mixed opiate agonist and antagonist, is used to treat OUD because the danger of overdose and toxicity is less likely than when using full opioid agonists. Its long half-life also helps ease the withdrawal process for many patients battling OUD. Therefore, buprenorphine proves helpful as a temporary aid to relieve withdrawal symptoms for patients with OUD.
“Although medication dosages available may not meet every patient’s need, pharmacy compounding options can help fill the gap and have the potential to improve patient outcomes.”
Unfortunately, treatment with buprenorphine is indefinite for most patients because complete withdrawal from it is incredibly challenging. In fact, most patients will relapse. In a study measuring the outcomes of two taper lengths, a seven-day taper schedule and a 28-day taper schedule resulted in a relapse of 66% and 70%, respectively, at the one-month follow-up. Both groups were tapered to 2 mg Suboxone® (expressed as buprenorphine) as the final dosage. 5
The lowest strength of buprenorphine in a sublingual tablet is 2 mg, and some physicians are looking for lower strengths to further taper their patient's dose. A quick search of the internet reveals that websites exist to help patients perform a taper on their own, but dosages may not be exact.6 Most patients do not own instruments to weigh dosages accurately, leading to dosage variability and poor outcomes for the patient. Compounding pharmacists may assist physicians who are working with patients to achieve their treatment goal of successfully eliminating their dependance on buprenorphine. They could do this by compounding gradually tapered doses in forms that may help to deter abuse, such as sublingual troches. Tapering a small fraction of the dose over time allows a more gradual withdrawal with less psychological and physical stress to the patient.
“A quick search of the internet reveals that websites exist to help patients perform a taper on their own, but dosages may not be exact.”
Physicians can also consider buprenorphine sublingual troches for patients attempting to reduce dosages prior to a final taper. Reducing a patient from 8 mg to 4 mg may cause undue stress, but reducing the dosage more gradually can help reduce the severity of psychological or physical pain and discomfort.
In 2017, 2.6% of deaths in the United States (about 73,000) involved alcohol use. Chronic use of alcohol, or alcohol use disorder (AUD), accounted for more than half of these deaths.7 AUD leads to devastating medical consequences for patients. It may be surprising that alcohol, a simple molecule, can negatively affect almost every organ system in the body. High blood pressure, heart disease, liver disease, stroke, neuropathy, digestive issues and an increased risk of several cancer types are seen in patients who excessively consume alcohol.8
Alcohol withdrawal syndrome, which can occur in patients with AUD, can range from mild to life threatening. Mild symptoms such as anxiousness, irritability, depression, mood swings, nightmares, foggy thinking, vomiting and fatigue can be very unpleasant but relatively easy to treat and overcome. Patients who chronically consume larger quantities of alcohol may experience more severe withdrawal symptoms, however. The most severe symptoms of withdrawal are collectively called delirium tremens, which occurs in as many as 5-12% of AUD patients who withdraw. Delirium tremens is a life-threatening disorder and includes symptoms such as fever, seizures, extreme agitation and confusion, hallucinations, and high blood pressure.9
While disulfiram, naltrexone (oral and long-acting injectable formulations) and acamprosate are all FDA-approved drugs for the treatment of alcohol dependance in the United States, most patients receive only counseling to help free them from dependance. For the treatment of withdrawal symptoms, chlordiazepoxide, clorazepate, diazepam and oxazepam are FDA approved. 10,11 Practitioners also prescribe medications such as baclofen and topiramate off label for AUD.
“While disulfiram, naltrexone (oral and long-acting injectable formulations) and acamprosate are all FDA-approved drugs for the treatment of alcohol dependance in the United States, most patients receive only counseling to help free them from dependance.”
Baclofen may be a good choice for patients with AUD who are experiencing craving. Because it is 70-85% eliminated by the kidneys, it might be appropriate especially for patients suffering from alcohol-related liver disease.10,12 Studies show that baclofen helps reduce craving for alcohol and alcohol consumption in patients with AUD. According to a retrospective chart review of 113 patients treated with baclofen for alcohol dependence, 70% of the patients reported persistent and severe craving at baseline, while only 15% of the patients reported persistent craving after the use of baclofen at doses of 20-40 mg daily.13 In another study assessing 100 high-risk AUD patients, baclofen was prescribed in escalating dosages based on need. The average highest dosage taken was 147 mg per day. After two years, 63% of the patients were categorized as low risk.14
Baclofen can not only be used for prophylaxis, but also to treat the immediate needs of patients experiencing alcohol craving. Baclofen’s rapid resolution of agitation, anxiety and depression could be useful for patients as a rescue for such symptoms.14 Furthermore, a more rapid-release dosage form, such as a sublingual troche, could further reduce the time that it would take for baclofen to reduce craving. Given that commercially available baclofen products come in limited strengths and dosage forms, compounding pharmacists could work with prescribers to customize the dose and route of administration to meet each patient’s need.
“Baclofen can not only be used for prophylaxis, but also to treat the immediate needs of patients experiencing alcohol craving.”
Another promising option for patients with AUD is micro-dose ondansetron. In one randomized, controlled trial, a 4 mcg/kg dosage of ondansetron given twice daily combined with cognitive therapy reduced the number of drinks per day and increased the number of abstinent days. There were no serious adverse effects reported. The most common adverse events were headache (3.4%) and constipation (5%).15
Ondansetron selectively blocks serotonin 5-HT3 receptors. In the brain, 5-HT3 receptors trigger the release of dopamine in response to alcohol consumption. Blockade of the dopamine release therefore reduces the reward conception of alcohol consumption.15,16 Ondansetron seems to be most effective in patients with early onset alcoholism, which is defined as patients who begin their problematic drinking before the age of 25. 17 Like baclofen, though, ondansetron is only commercially available in limited dosage strengths, so compounders could work with physicians to create tailored options to meet the needs of these patients.
Ketamine has been used to successfully treat both major depression and post-traumatic stress disorder. As an example, dosages for racemic intranasal ketamine range from 25-100 mg and can be dosed as frequently as twice weekly in some patients with major depressive disorder. 18,19 Sublingual ketamine has also shown promise in the treatment of refractory depression.20
However, almost one third of patients with major depression also suffer from a substance abuse disorder, so treatment for these patients becomes challenging and complex.21 Addiction causes alterations in brain structure and function that produce a learned reward response to a substance or activity.22 These maladaptive reward memories could be one reason that many patients cannot break their addiction. A study was conducted of heavy drinkers to assess whether ketamine could help patients reduce the response to the memories by retrieving the maladaptive reward memory and then giving ketamine intravenously to the patients following the retrieval. The results show that ketamine following maladaptive reward memory retrieval showed significant reductions in general consumption. 23
“Addiction causes alterations in brain structure and function that produce a learned reward response to a substance or activity.”
Based on the data presented, ketamine may be an effective tool for patients suffering from both major depression and addiction. However, it is important to respect the potential for the abuse of ketamine nasal spray. Therefore, unless the patient is monitored in a facility, it may be best to prescribe a dosage form with lower abuse potential, such as a sublingual troche or tablet. The bioavailability of sublingual ketamine is approximately 30%.24 Some studies show that even at very low dosages of 10 mg, ketamine produces a rapid reduction in depressive symptoms that can last for days or longer. The length of effect was variable between patients.20
According to the CDC, approximately 13.2% of U.S. adults used antidepressant medications between 2015 and 2018.25 While antidepressant medication is extremely important for some patients, it is not without side effects, such as sexual problems and weight gain. Furthermore, many patients find it difficult to discontinue use of the medications even when they are ready.
Selective serotonin reuptake inhibitors are especially difficult to withdraw for most patients.26 One study found that 73.5% of patients studied reported withdrawal symptoms.27 Flu-like symptoms, insomnia, nausea, imbalance, shock-like sensations and hyperarousal are typical symptoms patients experience after antidepressant discontinuation. These withdrawal symptoms can even mimic the anxiety or depressive symptoms that they are prescribed for. This can lead practitioners to believe patients have had a relapse of their depression. 28,29 This condition is called antidepressant discontinuation syndrome and is caused by the sudden decrease in serotonin’s availability at the receptor site.
Antidepressant discontinuation syndrome symptoms can be mitigated by a slow taper of the medication. Giving the receptors time to adapt after medication reduction can take months rather than the usually prescribed two-week taper. Allowing this time can significantly reduce the symptoms associated with antidepressant withdrawal.26 Compounding pharmacies can create custom dosages to allow the patient to be slowly tapered in smaller increments than commercially available dosages allow. This can be accomplished in several ways. Capsule, lozenge, liquid and chewable options can be prescribed for the patients to ease their anxiety and symptoms of withdrawal.
“Giving the receptors time to adapt after medication reduction can take months rather than the usually prescribed two-week taper.”
As you can see, compounding pharmacies have a significant role to play in psychiatric medication delivery. Compounding has the potential to not only improve patient outcomes, but also to reduce symptoms in patients dealing with substance use disorders, depression and a multitude of other issues. Take the time to see how you can help the mental health community in your area.
Finally, it is important to remember that when compounding with controlled substances, pharmacists must follow state and federal guidelines regulating these substances. Always refer to the Prescription Monitoring Program guidelines of your state and the Drug Enforcement Administration’s Pharmacist’s Manual to ensure compliance.
Patricia Heitman, PharmD, 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 2000. She lectures frequently at PCCA International Seminars and symposiums. Her passions include pediatric compounding — especially for autistic patients — as well as women’s health, gastrointestinal health and pain management.
Austin Tull, PharmD, BCPP, is co-owner of Cherokee Custom Script Pharmacy in Canton, Georgia. He started his pharmacy career in a psychiatric hospital and independent retail setting where he recognized a gap in care that compounding could fill. Austin is board certified in psychiatric pharmacy and has been awarded the Distinguished Young Pharmacist Award from the Georgia Pharmacy Association.
A version of this article originally appeared in PCCA’s members-only magazine, the Apothagram.
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.