Samantha A. Gnanasegaram, MD

Several years ago, I was approached by a pharmaceutical representative who wanted to tell me about a “new” agent, brexpiprazole. Sure, I was familiar with it having learned about it in training-the serotonin 1A and dopamine D2 receptors partial agonist and serotonin 2A and noradrenaline alpha receptors antagonist that was FDA-approved for schizophrenia and as adjunctive therapy to antidepressant for major depressive disorder (MDD).

 But there is no way I would use it; after all it was likely just another "pharma" push of a drug that would not work, right?

At least in academia we have been groomed to see such advancements as an advertisement or a marketing scheme, and it is taboo to engage in discussions, let alone prescribe, a marketed drug. Looking back now, it is way too often that we take on a narrow view and regard pharmaceutical companies as enemies rather than allies in providing the best treatments for our patients.

We have all had patients with refractory or partially responsive MDD, despite antidepressant treatment, patients who continue to suffer and have their lives turned upside down. According to the STAR*D study, only 30% achieve a level of symptom resolution that would be considered close to remission range.

 Augmentation with atypical antipsychotics, among other agents, has been proven to be effective. However, the adverse effect profiles are often intolerable, particularly from a sedation and metabolic standpoint.

After that sales representative visited, I happened to encounter a patient presenting to me as a new evaluation for a second opinion.

A woman in her mid to late 20s reported a multitude of neurovegetative depressive symptoms and complaints of anxiety. She was quite tearful and described feeling hopeless and nothing would help her feel “normal” again. She discussed having had a series of medication trials including most SSRIs, and SNRIs which either did not work or produced undesirable effects.

The patient even tried augmentation with lithium and other second-generation antipsychotics, the latter which were fairly intolerable due to either activation, sedation, or development of compulsions and various worries. Despite asking for help, she was rather hesitant to be thought of as a “guinea pig.”

Brexpiprazole was fresh in my mind at the time. It differs from other antipsychotics in its pharmacological profile. I presented her with several options, including brexpiprazole, in an attempt to empower her in her care, discussing the modes of actions, potential benefits, the risks. She agreed on a trial of the drug in addition to the antidepressant she was currently taking. At two-week follow-up, she reported feeling more at ease, now being able to not feel on edge during the day, having less irritability in her work and home life, and no longer becoming tearful in public.

She continued to experience an improvement in her mood at the next follow-up. She felt she had more energy and motivation to engage in activities she enjoyed, and she even started enjoying social interactions with friends and family.

Brexiprazole (Rexulti) has been on the market since 2015, hence it is relatively new. In recent years, meta-analyses of studies have attempted to generate post-marketing data and, indeed found evidence of efficacy as an adjunct in those with MDD with a relatively safe adverse effect profile.

 examined four phase-3 studies in adult patients with MDD who had inadequate response to antidepressants in which brexpiprazole was used. Here they pooled analysis of data from these six week-long randomized double-blind placebo controlled treatment phases of four studies, encompassing a total of 1853 patients using brexpiprazole (1 mg to 3 mg daily).

They evaluated efficacy using the Montgomery-Asberg Depression Rating Scale (MADRS) and safety by treatment-emergent adverse effects (TEAEs). From baseline to week six, treatment with antidepressant plus brexpiprazole 2 mg to 3mg per day showed significantly improved MADRS scores compared with antidepressant plus placebo. In terms of TEAEs, in the treatment arm several were identified such as akathisia (8 versus 2.6% for placebo); headache (5.8 versus 6% for placebo); and weight gain (5.8 versus 1.6% for placebo).

It is important to keep an open mind and be able to craft personalized treatment regimens for patients with depression. In medicine, one size does not fit all. We need to be familiar with all agents currently available to us and be able to implement such treatment modalities to best help patients who are suffering.

The above case is presented for instructional purposes only and does not represent any one individual. -Ed

is Assistant Professor of Psychiatry at Dartmouth’s Geisel School of Medicine and Director of Addiction Services at New Hampshire Hospital, Concord, NH.

is Instructor in Psychiatry at Dartmouth’s Geisel School of Medicine and Attending Psychiatrist at New Hampshire Hospital, Concord, NH.

The authors report no conflicts of interest concerning the subject matter of this article.

1. Maeda K, Sugino H, Akazawa H, et al. Brexpiprazole I: 

 characterization of a novel serotonin–dopamine activity modulator. 

2. Sinyor M, Schaffer A, Levitt A. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Trial: A Review. 

3. Spielmans GI, Berman MI, Linardatos E, et al. Adjunctive atypical antipsychotic treatment for major depressive disorder: a meta-analysis of depression, quality of life, and safety outcomes. 

4. Antoun Reyad A, Girgis E, Mishriky R. Efficacy and safety of brexpiprazole in acute management of psychiatric disorders: a meta-analysis of randomized controlled trials. 

https://www.ncbi.nlm.nih.gov/pubmed/32141908

5. Thase ME, Youakim JM, Skuban A, et al. Efficacy and safety of adjunctive brexpiprazole 2 mg in major depressive disorder: a Phase 3, randomized, placebo-controlled study in patients with inadequate response to antidepressants. 

https://www.tandfonline.com/doi/full/10.1080/14656566.2019.1638913

Articles

A patient with refractory MDD continued to suffer and feel as though her life was turned upside down, despite treatment. Learn the outcome of the case.

Augmentation Strategies for Depression

Based on the currently available data, those over the age of 65, and of all ages with underlying medical comorbidities, are considered to be at higher risk for severe illness from coronavirus.

This is a new challenge all across medicine, and most institutions do not have set policies as of yet, so we can always learn from each other and learn from the institutions that have taken the lead. Remember that many of the people making the policies for our organizations are not medically trained, so don't be afraid to share your knowledge to keep yourself and others in your situation safe.

In this video, Samantha Gnanasegaram, MD, a psychiatrist New Hampshire Hospital, Concord, NH, talks about the challengers of being a clinician in the days of the coronavirus pandemic.

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This activity offers CE credits for:
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	2. Other

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

The goal of this activity is to provide a comprehensive understanding of the opioid-like effects of loperamide and kratom and raise awareness of potential dangers associated with use.

At the end of this CE activity, participants should be able to:

• Explain the evolutionary paths of loperamide and kratom

• Discuss the mechanisms for the opioid-like effects of loperamide and kratom

• Identify the pharmacodynamic/toxicodynamic effects of loperamide and kratom

This continuing medical education activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

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Of Americans 12 and older, 2 million have a substance use disorder (SUD) that involves prescription pain relievers and 591,000 have a SUD involving heroin.

 Withdrawal from opioids is extremely unpleasant and individuals often return to substance use to ameliorate symptoms. The individual may be interested in stopping opioid use altogether but has no access to FDA-approved treatment or wishes to pursue a more “natural” alternative.

In recent years, two agents have gained popularity as off-label opioid alternatives-loperamide and kratom. These are readily available at low costs and for these reasons they have at times been referred to as “the poor man’s methadone” and “poor man’s buprenorphine,” respectively. On drug-use websites and online forums, high doses of these agents have been promoted as options for opioid withdrawal management and, less often, for psychoactive effects.

Loperamide has been approved by the FDA for medical use since 1976. It is part of the World Health Organization’s List of Essential Medicine and is widely available as an inexpensive and over-the-counter (OTC) remedy used in managing diarrhea. Loperamide is marketed OTC under the brand name Imodium A-D but is also available as store brands and generic versions. As a piperidine opioid in nature, it was once a schedule V drug. At therapeutic doses, its actions are restricted to the gastrointestinal tissue by poor absorption and active efflux from the CNS by membrane transporter P-glycoprotein. The maximum daily dose is 8 mg for adults as OTC use and 16 mg by prescription.

When larger than recommended doses are taken, CNS penetration occurs. This practice of ingestion of large doses (in excess of 70 mg daily) has been gaining popularity among users of opioids to manage withdrawal symptoms and, less frequently, to achieve psychoactive opioid-like effects.

Early studies showed no abuse potential for loperamide; however, by 2013, reports of recreational use of 70 to 100 mg doses started surfacing.

 Subsequently, from 2011 to 2014 a 71% increase in loperamide-related presentations was noted by poison control agencies. In recent years, reports of extremely high doses have emerged.

 Users report using primarily to ease withdrawal symptoms but also, less often, as a substitute for opioids.

 Most users have a history of opioid use with no reports of loperamide as an initial, gateway drug.

 Unfortunately, national surveys do not track use, and the Drug Abuse Warning Network (DAWN) does not monitor loperamide use.

A dose-dependent effect is seen with loperamide that determines the anatomical system it acts on. Within the recommended dose of up to 16 mg daily, Î¼-opioid receptors are agonized at the large intestinal myenteric and submucosal plexi, stimulating secretion of inhibitory neurotransmitters to increase non-propulsive contractions thereby decreasing peristalsis and allowing for fluid and electrolyte absorption. CNS effects are avoided as transporter P-glycoprotein actively pumps it out at the blood brain barrier.

Above recommended doses, P-glycoprotein systems become saturated, and CNS entry occurs. Several agents (including loperamide) such as antineoplastic drugs, steroids, ketoconazole, and quinidine, can block the P-glycoprotein system, facilitating CNS entry. (Some users may supplement with these.) CYP 3A4 inhibitors allow loperamide to circumvent first pass effect.

Loperamide’s onset of action is 1-hour post-ingestion and reaches peak plasma levels between 3 to 5 hours, with a half-life between 7 to 19 hours. Users typically have to dose every 8 to 12 hours; however, sustained benefit of up to 2 days has also been reported by some. Doses range from 70 to 400 mg daily. Although use is with the intent of amelioration of withdrawal, in this range there is also potential for euphoric effects that tend to not be as pleasurable as with opioids.

 CNS effects do not include any analgesic benefits.

There have been several reports of the development of tolerance after weeks to months of use, resulting in the need to increase the dose by 25% to 50% increments.

 Withdrawal symptoms are also mentioned, which are similar to opioid withdrawal but milder and less prolonged. Most users report successfully being able to taper with limited symptoms.

 Unlike buprenorphine or methadone tapers, once loperamide is discontinued, cravings for opiates subside.

At therapeutic doses, there may be constipation, dizziness, nausea, and abdominal cramps. More serious yet rare adverse effects of long-term use include toxic megacolon, paralytic ileus, angioedema, and Stevens-Johnsons Syndrome.

 When administered in supra-therapeutic doses, cardiac life-threatening adverse effects include QTc prolongation, QRS widening, ventricular dysrhythmias, syncope, and sudden deaths.

 The FDA has responded by adding a warning to the drug label in 2016 and also has been working with manufacturers to limit the number of doses per package of OTC medication.

Routine drug screens do not pick up loperamide use; hence, a high degree of suspicion is required to detect abuse. Opioid users often present with respiratory depression, whereas those using supra-therapeutic loperamide doses will present with arrhythmias (ie, long QT, wide QRS) and may be awake and alert. Patients typically have histories of opioid use with recent discontinuation and will present with unexplained syncope and the electrocardiogram abnormalities. Identification of misuse should open discussion regarding the underlying reason for use, promoting treatment.

, is a deciduous tree related to the coffee family indigenous to Southeast Asia. Historically, its leaves were chewed or brewed as a tea (less commonly smoked) to help cope with the physical demands of laborers by improving endurance and reducing fatigue. In traditional medicine, kratom has also been used as an opium substitute. When used in small amounts (< 5 g), stimulant properties emerge such as increased alertness and stamina; however, in larger doses (>5 g) opioid-like sedative, euphoric, and anti-nociceptive properties are seen. Kratom leaves contain at least 40 identified alkaloids and various other organic molecules. The active constituents are mitragyine and 7-hydroxymitragynine; each leaf contains varied concentrations and proportions.

In recent years, because of its unique properties and “harmless” perception, kratom has been gaining popularity in parts of the Western world. It is available in headshops, health stores, and is sometimes grown locally or available over the Internet. Products are available as crushed or powdered leaves; sometimes as extracts or combined with other agents in tinctures or capsules for very low costs.

Although commercially available products show a recommended dose, the amount of actual active ingredient present is not certain. Kratom was legal to grow and purchase in all 50 states until 2015 when the Drug Enforcement Administration identified kratom as a substance of concern. As of June 2018, kratom is illegal to buy, sell, and use in Wisconsin, Rhode Island, Vermont, Indiana, Arkansas, Alabama, Washington, DC, as well as in some specific counties. Outside of the US, use and sale of kratom is illegal in Thailand and has been banned in Australia, Poland, Denmark, Sweden, Malaysia, and Vietnam.

A recent survey suggested that kratom was one of the most widely sold “legal highs,” offered in 44% of online shops. The 

National Survey of Drug Use and Monitoring the Future

 survey do not track kratom use and few data exist on the prevalence of kratom use. It is estimated by advocacy organizations that between 3 and 5 million Americans are regular users.

An anonymous online survey of 10,000 current users located through the American Kratom Association and search of social media in October 2016 had 8094 responses.

The majority of users were male (57%), nonhispanic white (82%), aged between 21 and 50 years; 40% disclosed their use to their medical provider; 55% were married; 57% were fully employed; and 82% had a college education. The most common use was as a dissolved powder (49%) taken with a beverage; 37% used capsules, and 13% used kratom as a prepared tea. The primary reason for use was self-treatment of chronic pain. A similar percentage reported using to relieve depressed or anxious mood. Adverse effects were reported by only 51 users.

It is estimated that 55% of regular users become dependent on kratom.

 Between 2011 and 2017 the number of calls to Poison Control Centers related to kratom exposures increased from one a month to two daily.

Isolation and chemical characterization of its components has been of interest since the 1960s with over 40 different alkaloids having been isolated to date, only two of which are active (mitragynine, 7-hydroxymitragynine). The composition of the plant varies significantly depending on the environment in which it is grown, breeding and harvesting techniques, and age of the plant. For example, a plant from Thailand has on average 66% mitragynine alkaloid content whereas one from Malaysia has approximately 12%; younger plants tend to have greater mitragynine content. The various different alkaloids found in the plant have unique properties: anti-nociceptive, anti-inflammatory, anti-depressant, or muscle relaxant.

Its two active constituents display opioid-like properties in vivo and in vitro. The potency at the opioid receptor has been found to exceed that of morphine. Competitive binding studies further examined affinity at the various opioid receptor subtypes and found a preference for the Îº receptors (antagonism) followed by Î¼ (partial agonism) and lastly Î´, which is a similar profile to buprenorphine.

 The highest potency of 7-hydroxymitragynine is at the Î¼ receptor.

 Mitragynine also plays a role in noradrenergic and serotonergic pathways where it stimulates postsynaptic Î±2 adrenergic receptors and inhibits 5-H2A receptors.

These properties explain how kratom counteracts withdrawal in opioid dependent individuals.

Mitragynine has a relatively short half-life as well as a large volume of distribution. Individuals using it to counteract opioid withdrawal require dosing as frequent as every 6 to 12 hours with withdrawal symptoms emerging 12 hours after last use and lasting up to 4 days.

When it comes to interactions of its multiple constituents with the CYP 450 system, one study found kratom may inhibit 2C9, 2D6, 3A4 isoenzymes and to some extent 1A2.

 This raises concern over the impact kratom use can have on clinical populations prescribed pharmacological agents.

Case reports document effects such as weight loss, insomnia, constipation and dehydration, skin hyperpigmentation, and fatigue occurring in chronic use of kratom.

 Some acute effects include seizures, delusions and hallucinations, respiratory depression, hepatotoxicity, coma, and death. In recent years emergency departments as well as poison call centers across the country have seen an increasing number of presentations related to kratom use. According to the State Unintentional Drug Overdose Reporting System, between July 2016 and June 2017, in 8 of the states reporting to the system a total of 25 deaths involved kratom co-ingestion.

 This number could be an underestimate since kratom testing and assessment for it is not uniform.

In one published report, a male patient addicted to hydromorphone attempted to use kratom to prevent withdrawal. He was admitted to the hospital after mixing kratom and modafinil and sustaining a generalized tonic-clonic seizure. It was deemed unclear whether the seizure resulted from the kratom or the drug combination.

Most reported cases involve mixing kratom with other agents or ingesting contaminated kratom products (eg, Krypton). In a case series from Sweden, researchers reported 9 cases of Krypton intoxication and death. The product known as “Krypton” is an herbal preparation of dried, crushed kratom leaves mixed primarily with another Î¼-opioid receptor agonist, O-desmethyltramadol which is known to cause seizures.

Abrupt discontinuation of high dose, long-term use of kratom mimics opioid withdrawal: chills, body aches, loose bowels, insomnia, restlessness and irritability, fatigue, anxiety and mood disturbances, among others. Symptoms begin 12 hours from last use and can last upwards of 4 days. Symptoms are positively correlated to the amount and duration of use; they are uncomfortable both physiologically and psychologically, which prompts return to use. Cravings are also present. In managing withdrawal, the best approach involves symptomatic management of a hyperadrenergic state. Use of regulated agents such as methadone and buprenorphine has been hindered from a medico-legal perspective and very few reports exist.

Kratom use during pregnancy can lead to neonatal abstinence syndrome in the neonate. Nothing is known about the extent of placental crossing of kratom’s active alkaloids. In two case reports, symptoms such as jitteriness, irritability, feeding intolerance, and vomiting emerged around day 2 postpartum requiring neonatal intensive care unit admission and standard opioid protocol with intravenous morphine subsequently tapered with oral formulation over 5 days.

Screening for kratom has its challenges. Since it is not detected through the standard urine toxicology screen, special confirmatory testing is necessary. Detection of breakdown products of mitragynine can be detected through gas chromatography coupled with mass spectrometry, liquid chromatography with linear ion trap mass spectrometry, or through electrospray tandem mass spectrometry.

Loperamide and kratom are growing in popularity because of their opioid-like effects. Motives include opioid withdrawal suppression or to taper off opioids as well as, less frequently, psychoactive effects. With loperamide, this practice requires above label doses, placing users at risk for cardiotoxicity among other effects. Kratom is concerning because of its variability in alkaloid composition and preparations that contain dangerous additives, as well as its potential for dependence and withdrawal on discontinuation. Clinicians need to be aware of such substitutional behaviors in those with a history of opioid use to provide proper diagnosis, management, and patient education.

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Dr Stanciu is Assistant Professor, Dartmouth Geisel School of Medicine, Hanover, NH, and Director of Addiction Services, New Hampshire Hospital, Concord, NH; Dr Gnanasegaram is Clinical Instructor, Dartmouth Geisel School of Medicine and Attending Psychiatrist, New Hampshire Hospital; Dr Penders is Affiliate Professor, East Carolina University Brody School of Medicine and Attending Psychiatrist, Walter B. Jones Drug and Alcohol Treatment Center, Greenville, NC.

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https://www.samhsa.gov/data/sites/default/files/NSDUH-FFR1-2015/NSDUH-FFR1-2015/NSDUH-FFR1-2015.htm

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 MacDonald R, Heiner J, Villarreal J. Loperamide dependence and abuse. BMJ Case Repor. 2015. 

https://casereports.bmj.com/content/2015/bcr-2015-209705

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http://www.fda.gov/Drugs/DrugSafety/ucm504617.htm

 Eggleston W, Marraffa JM, Stork CM, et al. Notes from the field: cardiac dysrhythmias after loperamide abuse. 

 Marraffa JM, Holland MG, Sullivan RW, et al. Cardiac conduction disturbance after loperamide abuse. 

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 Stanciu C, Gnanasegaram S, Ahmed S, Penders T.Kratom withdrawal: a systematic review with case series. 

 Suhaimi FW, Yusoff NHM, Hassan R, et al. Neurobiology of kratom and its main alkaloid mitragynine. 

 Prozialeck WC, Jivan JK, Andurkar SV. Pharmacology of kratom: an emerging botanical agent with stimulant, analgesic and opioid-like effects. 

 Hanapi NA, Ismail S, Mansor SM. Inhibitory effect of mitragynine on human cytochrome P450 enzyme activities. 

 Hughes RL. Fatal combination of mitrgynine and quetiapine: a case report with discussion of a potential herb-drug interaction. 

 Saingam D, Sawitri A, Geater AF, Lerkiatbundit S. Factor analytical investigation of krathom (Mitragyna speciosa Korth.) withdrawal syndrome in Thailand. 

 Vicknasingam B, Narayanan S, Goh TB, Mansor SM. The informal use of ketum (Mitragyna speciosa) for opioid withdrawal in the northern states of peninsular Malaysia and implications for drug substitution therapy. 

This CME discusses the opioid-like effects of loperamide and kratom and raises awareness of potential dangers associated with use.

Author | Samantha A. Gnanasegaram, MD

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