Q&A: Clinical Challenges in Substance Use Disorders

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CONFERENCE REPORTER

Dr. Domingo is Assistant Professor at Baylor College of Medicine in Houston. Dr. Kosten is JH Waggoner Chair and Professor of Psychiatry, Neuroscience, Pharmacology, Immunology & Pathology and Co-Director, Dan Duncan Institute for Clinical and Translational Research at The Menninger Department of Psychiatry & Behavioral Sciences, Baylor College of Medicine.

Editor’s Note: We are pleased to present this brief summary based on the presentation, “Solving Clinical Challenges in Substance Use Disorders,” which took place on Monday, September 18 at the 2017 Psychiatric Congress. This was a cases/questions session that offered answers to a range of questions about diagnosis, treatment options, and management of adverse effects.

Diagnosis

Q: I have a lot of patients who smoke cannabis. Many say they use cannabis for what seems to be purely therapeutic reasons (eg, pain). Is it diagnostically important to differentiate substance use disorders attributable to an attempt to “self-treat” from other forms of substance use disorders?

A: As a treatment provider, the most prudent approach to addressing this issue is application of the DSM-5 diagnostic criteria for assessing substance use disorders (SUD). If a patient meets 4 or more of those criteria, they have objectively met requirements consistent with a diagnosis of a moderate SUD that could benefit from treatment. At the point of this determination, while the patient’s cannabis use as a form of “self-treatment” or a mitigation of some other disorder may provide value-added information, clinical treatment remains within prescribed guidelines. When considering mitigation of other pathological conditions like chronic pain, it is important to be aware of the cannabis source and the data supporting or refuting the mitigation.

Commercial sources such as state-sold cannabis products (eg, transdermal cannabis for pain) differ markedly from research cannabis or FDA-approved products. The efficacy, dose, routes of administration, or adverse effects of commonly used and commercially available cannabis products in the US are unknown.

Legal access to low THC/high-cannabidiol products for other “legal uses” in various states include PTSD, cancer, epilepsy, cachexia, glaucoma, HIV/AIDS, traumatic brain injury, Tourette syndrome, addiction, anxiety, depression, sleep disorders, and degenerative neurological conditions (eg, Alzheimer disease, amyotrophic lateral sclerosis, Huntington disease, Parkinson disease, vascular dementia). However, most all of these uses, although legally prescribed, are not supported by clinical trials data.

The few clinically demonstrated uses are pain, nausea, and vomiting, multiple sclerosis related spasticity, appetite stimulation in cachexia, and glaucoma. For all these conditions, the effects of cannabinoids are modest, and other FDA-approved treatments are more effective. Some uses such as for glaucoma are even harmful. Smoking cannabis significantly lowers intraocular pressure, but does not prevent nerve damage, while other glaucoma agents do prevent the nerve damage. Another particular controversy is using cannabidiol as an anticonvulsant in children refractory to other therapies. This effect was first noted in the 1940s, but no controlled clinical trials have tested it as an anticonvulsant.

Pharmacological treatments

Q: How do you decide in a patient with opiate addiction when to use an opiate antagonistic therapy (eg, naltrexone), when to use opiate partial agonist therapy (eg, buprenorphine), and when to use opiate agonist therapy (eg, methadone)?

A: A pharmacological maintenance regimen is widely accepted as the optimal strategy toward recovery from opioid use disorder (OUD). Compared with detoxification alone, these maintenance regimens are associated with much higher rates of treatment retention, reduction in illicit opiate use, decreased craving, and generally improved social functioning.

Current OUD pharmacotherapies for relapse prevention are methadone, naltrexone, and buprenorphine. Their mechanisms of action (MOA) differ in that methadone as a full µ-opioid receptor agonist, involves cross-tolerance at high doses, while naltrexone blocks the µ-opioid receptor and simply blocks euphoria. Buprenorphine has an interesting intermediate MOA as a partial opioid agonist that can provide cross-tolerance and withdrawal relief at low doses, while blocking euphoria at high doses like naltrexone.

In choosing among these medications for OUD here are some considerations. Methadone has a built-in structure of the program for better or for worse, but some patients will be well served by its structure. Methadone itself has a greater risk of diversion and overdose risk than buprenorphine, so “take-homes” of methadone are more restrictive. Naltrexone is difficult to start on because of the need for detoxification, but it is easy to stop without any withdrawal, which can make adherence difficult. Buprenorphine has two appealing attributes in that it is easy to start without requiring detoxification, but difficult to discontinue because of its agonist activity.

Overall, in choosing agonist versus antagonist therapy a key question is “What does the patient and family want?” The initial choice is a collaborative process among patient, family, employer, and sometimes other outside criminal justice negotiations.

The majority of patients with OUD prefer buprenorphine over the other 2 pharmacotherapies, and it has much to recommend it. Buprenorphine has reduced overdose potential and abuse liability and less severe withdrawal than methadone when stopped. It is comparable to methadone in treatment retention and reduced heroin abuse, and it can be given in the physician’s office leading to increased availability and reduced stigma.

While sublingual buprenorphine needs to be take daily, long-acting implanted buprenorphine can last several months. Compared with placebo it is significantly better in retention at 6 months (64% vs 26%) (n = 114 vs 54) and in attaining an illicit opioid-free state (64% vs “too many dropouts”). It is also comparable to 8-mg sublingual buprenorphine with 6 month retention (64% vs 64%; n = 114 vs 119) and rates of opioid-free urines (31% vs 33%).

The adverse effects of the implant include implant site pain, itching, and redness, as well as body symptoms of headache, depression, constipation, nausea, vomiting, and back pain. Further limitations are that it is equivalent to only 8-mg sublingual buprenorphine, when the average sublingual dose is 12 to 16 mg, and implanting and removal can be difficult for the average physician.

The major problem with buprenorphine is the insufficient number of physicians prescribing it for the 2.5 million treatment-seeking OUD patients. While most prescribers can be allowed up to 100 patients per prescriber and this number was recently increased to 275 patients, most prescribers provide for less than 10 OUD patients.

Management of adverse effects >

Management of adverse effects

Q: Which treatment for nicotine addiction has the most favorable adverse-effect profile and what are management strategies for these adverse effects? Specifically, what is the status on the psychiatric adverse effects associated with varenicline?

A: The adverse effects of nicotine pharmacotherapies vary among the FDA-approved medications, which include nicotine patch, gum, lozenge, inhaler, and spray. Varenicline is a partial nicotinic receptor agonist, and bupropion is an antidepressant that can be given alone and in combination with previously listed pharmacotherapies.

The adverse effects of these medications are clearly listed in the package inserts, but 3 deserve some emphasis for psychiatrists:

1. Post-smoking cessation depression

2. Post-smoking cessation weight gain

3. Psychiatric symptoms with varenicline

Depression is common with smoking cessation and inhibition of monoamine oxidase (MAO) improves depression. Tobacco smoke (not nicotine) inhibits MAO, and MAO decreases dopamine. Increasing dopamine by inhibiting MAO reduces depression after smoking cessation.

Selegiline is an MAO inhibitor that increases synaptic levels of dopamine, corrects this dopamine deficiency related to long-term smoking, and reduces post-cessation depression as well as relapse to smoking. While this is not specifically FDA approved, the selegiline transdermal patch at 6 to 12 mg/24 hours can be applied to the skin for treating this post-smoking cessation depression.

In a placebo controlled study, 50% of patients receiving selegiline attained smoking abstinence compared with 12% on placebo; 30% maintained their abstinence (60% of those initially becoming abstinent) at a month and 20% (40% of initial abstainers) at 6 months. The placebo group had 5% abstinence at one and 6 months.¹

Weight gain is frequent after smoking cessation: women can gain more than 10% over 12 months post-smoking cessation. Women taking 50-mg naltrexone daily post-smoking cessation reduced weight gain by 40%. The weight gain in a placebo controlled study was significantly lower for women treated with naltrexone versus placebo (6 months, 3.3 kg vs 5.5 kg; 12 months, 5.9 kg vs 7.4 kg, respectively).²

The FDA issued a warning about neuropsychiatric adverse events with varenicline in 2009, but it is important to recognize that the black box warning was removed in December 2016. While patients with depression, anxiety disorders, or schizophrenia should be observed for adverse effects on mood, behavior, or thinking, these psychiatric patients can greatly benefit from varenicline and it can be used with them.

A similar warning has been issued for suicidality with bupropion. One consideration for treating depression/negative symptoms after smoking cessation is to consider selegiline rather than bupropion in combination with varenicline for patients who develop depressive symptoms after cessation.

References:

1. George TP, Vessicchio JC, Termine A, et al. A preliminary placebo-controlled trial of selegiline hydrochloride for smoking cessation. Biol Psychiatry. 2003;53:136-143.

2. King AC, Cao D, Zhang L, O’Malley SS. Naltrexone reduction of long-term smoking cessation weight gain in women but not men: a randomized controlled trial. Biol Psychiatry. 2013;73:924-930.