Saeed Ahmed, MD

*A note from the authors: When we first presented our study at the APA annual meeting, we only had preliminary results. Now that our investigation is complete, the results are presented in this article.

Buprenorphine, along with methadone and extended-release naltrexone, is 1 of 3 medications currently approved by the US Food and Drug Administration (FDA) to treat opioid use disorder (OUD). Buprenorphine is considered the “gold standard” treatment for OUD and has been proven to reduce mortality and to improve treatment retention and remission. Buprenorphine has an advantage over methadone in that it has a lower overdose risk due to its ceiling effect and is less likely to cause QTc prolongation.

Opioid receptors have been extensively studied for the treatment of opioid addiction, but recent research has shifted to investigating opioid receptors in the treatment of psychiatric conditions. A significant proportion of patients with an OUD also have cooccurring psychiatric conditions. There is growing evidence from neurobiological research that the endogenous opioid system is involved in mood regulation and that disturbance of this system may lead to depression and anxiety, making it a potential therapeutic target for the treatment of these ailments.

Our study’s goal was to analyze clinical studies in order to determine the efficacy of buprenorphine in treating psychiatric conditions, in particular depression and suicidality (

 Buprenorphine and Its Therapeutic Potentials in Psychiatric Disorders, Presented at the American Psychiatric Association 2022 Annual Meeting

We conducted a literature search in 5 major databases, including PubMed, using inclusion and exclusion criteria. Of the 1347 identified studies, 6 clinical trials were included in this meta-analysis pooling in 417 adult participants. First, HAM-D inter-group assessment favored buprenorphine use compared to control (Cohen’s d=-0.34, 95% CI=-0.66, -0.02, P=0.04). Second, MADRS scores found endline (mean score changes compared to baseline) shifts of depression scores were in favor of buprenorphine (Cohen’s d=-0.31, 95% CI=-0.61, -0.01, P=0.04). Third, BSSI favored the use of buprenorphine (Cohen’s d=-1.4, 95% CI=-0.61, -0.01), and in the intra-group analysis, a single dose (64 mg) of sublingual buprenorphine was superior to 96 mg (Cohen’s d=0.19) and 32 mg (Cohen’s d=-0.22) single doses.

Several hypotheses have been proposed as to the mechanism of action of buprenorphine in the treatment of psychiatric disorders. The review of study shows that buprenorphine has an antidepressant effect at doses ranging from 2 to 8 mg/day, as well as an antisuicidal effect at relatively low doses (0.1 mg to 0.44 mg). According to several studies, buprenorphine's antisuicidal effect may be due to a partial agonist effect on the μ-opioid receptor and an antagonist effect on the delta and κ-opioid receptor. One plausible explanation for buprenorphine's antisuicidal effect is its potential to reduce the psychological or physical pain processing. Also, because of its agonism of nociceptive receptors, it may have anti-anxiety properties, too, and anxiety is an independent risk for suicidality.

A growing body of literature indicates that buprenorphine has therapeutic potential in treating psychiatric conditions, mainly via the endogenous opioid system. The findings of this study show that buprenorphine has a promising role in reducing depression and suicidality. Lower dosages appear to be more effective in producing favorable psychiatric outcomes in terms of decreasing suicidality.

Despite growing evidence in favor of buprenorphine in the treatment of psychiatric conditions, there are issues to consider before prescribing such as diversion and the potential for abuse. Larger and more rigorous studies are required to establish the efficacy of buprenorphine in psychiatric conditions or to widely use it in clinical practice.

 is an addiction psychiatrist; diplomate of the American Board of Psychiatry and Neurology; and medical director of the West Ridge Center for Addiction Recovery at Rutland Regional Medical Center in Rutland, Vermont. 

 is the chief resident at the St. Elizabeth Boston psychiatry residency program and a co-investigator for this study.

Articles

Researchers discuss new research on buprenorphine, the “gold standard” treatment for opioid use disorder at the APA Annual Meeting.

Buprenorphine and Its Therapeutic Potential in Psychiatric Disorders

This is a time of heightened anxiety for all of us. Patients and frontline health care workers are dying from 

, while some of the latter are also dying from its mental toll, case in point, the suicide of Dr Lorna Breen, a veteran emergency department (ED) physician. The frontline residents and fellows that I am personally in touch with or those whom I follow on social media often complain of “being forced to work harder than I can handle,” “being pushed to my limits,” “no availability of PPEs,” etc. The onslaught of stress and bad news has become a co-virus of challenged mental health. Much of that frontline mental health support is coming from 

 (IMGs) such as I am, who constitute almost 30% of the total physician work force in the US.

My experience as an IMG during the COVID-19 crisis has entailed working as an addiction psychiatry fellow at the 

 and VA Boston Healthcare system. This experience has proved very empowering. Why? Because my patient population, those who likely already struggle with their mental health and addiction, and the frontliners who care for them, need those like me more than ever. Those of us on the frontlines of the pandemic are seeing increased anxiety, stress, depression, and substance abuse. We also foresee a second-wave pandemic of mental health issues caused by COVID-19 and its effects. The sad fact is that there are more patient hospitalizations, suicides, and overdose deaths to come.

The existing stress has been compounded not only by isolation but also by the pressure of follow-up sessions and appointments over the phone or video, although some patients have neither. We are learning the new best outreach practices on our feet.

IMGs as a workforce: a critical component of health care


	COVID-19 has infected more than 1.3 million US citizens and the health care system is struggling to supply critical care to these patients. Some states have called in retired health care professionals, volunteers, medical students-including those from out of state. The US already had a shortage of physicians before the pandemic, and it has now been seriously exacerbated by COVID-19. The question I have is, why not to enlist the many IMGs already present? IMGs have historically worked in underserved areas, serving socioeconomically disadvantaged, minority, and aging populations, the same populations now suffering the worst ravages of COVID-19.

It would be beneficial and reasonable to allow at least 65,000 of the unmatched IMGs who have passed their US exams to join this battle via the path of supervised training or by creating programs like Missouri’s physician assistant program for those immigrant doctors who didn’t match into US residencies.

 The COVID-19 crisis has created a potential grand match for these IMGs. The top-10 hardest hit states-not only New York, but states like Massachusetts and Ohio-ought to immediately consider this model.

Temporarily waiving the geographical restrictions on IMG physicians with H-1B and J-1 visas, allowing them to serve outside the employer of sponsorship can alleviate the shortage in hot-spot areas or field hospitals. Currently many of these physicians are underused because they are unable to go to another facility such as epicenter hospitals in, for example, New York City. I applaud the efforts by the APA and AMA for IMGs, and we are encouraged by the outcomes of their advocacy, such as the resumption of visa processing at US consulates for non-US citizen IMGs.


	Regardless of our origins or background, we are all subject to the physical and mental ravages of COVID-19. We are all in this together-doctors, nurses, patients, and other essential workers. Many professionals with the right mix of skills, credentials, and drive are currently being recruited to join this fight. So should IMGs!

 is an Addiction Psychiatry Fellow, Boston Medical Center/VA Boston Healthcare System, Boston, MA. He reports no conflicts of interest concerning the subject matter of this article.

99th General Assembly of the State of Missouri. House Bill No. 330. 2020

Frontline residents and fellows complain of “being forced to work harder than I can handle,” “being pushed to my limits,” “no availability of PPEs,” etc.

Should I Stay or Should I Go: IMGs and the US Health Care System During COVID-19

is Resident Physician, Department of Psychiatry and Behavioral Sciences, Nassau University Medical Center, East Meadow, NY;

is Addiction Psychiatry Fellow, Dartmouth-Hitchcock Medical Center, Lebanon, NH; and 

is Clinical Associate Professor, Department of Psychiatry and Behavioral Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, and Medical Director, Consultation-Liaison Psychiatry, Cape Cod Healthcare, Hyannis, MA.

Opioid-related overdoses are now the leading cause of death in Americans aged younger than 50 years, with a resultant 2.5 months of life expectancy lost.

 While this includes deaths from pain pills and illicit heroin, the overwhelming initial source of addiction is prescribed opioids; 83% of heroin users started off abusing prescription opioids. More than 6 out of 10 deaths involve prescribed opioids.

 in the number of prescriptions written as well as dosages per prescription.

 yearly to supply every American with an average of 36 pills. In addition, in 2016, overprescribing of postsurgical opioids resulted in 3.3 billion unused pills flooding into communities, making these available for diversion and misuse.

Use of naloxone, an opioid receptor antagonist, has been shown to reverse opioid-induced respiratory suppression. Current evidence suggests that bystanders can and will use naloxone to reverse opioid overdoses when appropriately trained. This training is possible through community-based opioid overdose prevention programs. There is a movement to increase public awareness and training on the use of naloxone, with laws being passed that require students as young as elementary school age to receive training.

Despite this, there has been only a modest increase in naloxone prescribing between 2009 and 2015, from 2.8 million to 3.2 million.

 The relatively slow adoption of naloxone is in part due to stigmatization and absence of familiarity with the treatment among clinicians and opioid users. Most physicians do not receive formal training on the use of naloxone and its various methods of delivery. There is a need to increase prescribing and to improve clinicians’ training to effectively help ameliorate overdose response and deaths (

Because of the effects of the overdose epidemic, states passed legislation designed to enhance layman access to naloxone and give legal immunity to medical professionals who prescribe or dispense naloxone as well as to those who administer naloxone. Individuals such as emergency medical services personnel, police officers, and firefighters as well as those authorized to administer naloxone are required to undergo training and education in recognition of signs and symptoms of overdose, techniques for administration of naloxone, and referral to emergency medical services. Residents and fellows are the exception. They undergo training in clinical skills such as advanced cardiac life support, pediatric advanced life support, and basic life support; however, they do not receive naloxone and opioid reversal training. Training is relatively simple in part because of the absence of complicated administration requirements or serious adverse reactions (

Naloxone competitively antagonizes the delta (Î´), mu (Î¼), and kappa(Îº) receptors with a 10-fold higher affinity for Î¼ than Îº. Given its ability to displace receptor-bound opioid molecules, its main use is intended for reversal of opioid-induced respiratory 

 Evidence of efficacy is noted within 30 seconds of intravenous administration; however, the most common route is nasally with a spray. This allows for convenient administration to patients by their relatives at home. The recommendation is to create an “overdose plan” to share with friends, partners, and/or caregivers. Such a plan contains information on the signs of overdose and how to administer naloxone or otherwise provide emergency care.

A medical provider must have a high suspicion and low threshold for use of naloxone, since overdose patients are usually found unresponsive or sedated. This is particularly true in cases where getting a collaborative history from a relative or close companion is difficult.

Currently, there are 4 naloxone delivery systems (

The onset of action of naltrexone and the duration depend on the route of administration. When used intravenously, it has the quickest onset of action (1-2 min) compared with subcutaneously (5 min), intramuscular (6 min), and nebulized (5 min).

 recommend initial doses of 0.4 to 2 mg via intramuscular or intravenous routes, followed by repeated doses up to 10 mg.

 Dosing is empirically determined; however, many factors need to be considered including morphine equivalence in the system, naloxone administration route, concurrent medications in the system such as benzodiazepines, and overall opioid tolerance.

Typical administration begins with a low dose to avoid precipitating withdrawal. Considerably higher doses of naloxone are required for potent opioids such as fentanyl.

 This should be a consideration in an individual who does not respond to the initial dose. Because of the increased prevalence of fentanyl and other powerful synthetic opioids, the naloxone requirements are on the rise. Given the potency of fentanyl, even multiple doses are sometimes unsuccessful.

Naloxone’s safety profile is extremely high especially when used in low doses and titrated to effect. When administered to nonopioid-dependent and nonopioid-intoxicated healthy volunteers, it produces no clinical effects even at high doses. Even in tolerant patients, rapid opioid withdrawal-although unpleasant-is not always life-threatening.

The duration of action of some opioids exceeds that of naloxone and can result in recurrence of CNS and respiratory system depression. It is important to be prepared for additional administrations and to be able to facilitate ICU admission for monitoring after reversal. It is also pertinent to consider the limitation of naloxone when dealing with mixed agonists/antagonists and partial agonists because of the low efficacy of the drug.

When used in cases of opioid overdoses, the abrupt reversal can sometimes result in vomiting, sweating, increased blood pressure, tremulousness, and tachycardia. Naloxone can also cause acute withdrawal symptoms in opioid-dependent individuals. Agitation, yawning, diaphoresis, rhinorrhea, lacrimation, nausea, vomiting, and diarrhea are not life-threatening.

 At the same time, in rare cases, it is possible to encounter 

 such as pulmonary edema, acute respiratory distress syndrome, seizures, and cardiac arrhythmias.

 Because of the short half-life of naloxone, withdrawal symptoms have a tendency to dissipate in approximately 30 minutes to 1 hour. In the case of an overdose, the risk of the symptoms listed above are balanced against the risk of death. (It is important to note that most overdoses typically involve co-administrations of benzodiazepines and opioids; hence, it is important to consider and be able to manage both.)

There has been criticism from some emergency department physicians who view naloxone prescription as perpetuating drug abuse. Some argue that users are not afraid to indulge in drug use because they know that there is a potent antidote. As users indulge more and more in this practice, they develop tolerance to the effects of the opioid drugs. An increased tolerance results in a continuous and upsurge use of 

 and leads to emergency department presentations.

 Emergency department physicians frequently face serious ethical dilemmas of either medically helping patients recover or playing a part in propagating their drug use.

An increasing number of individuals refuse naloxone treatment because they fear that it will precipitate withdrawal symptoms. This can be prevented through appropriate dosing, and patients can be reassured on arrival to the hospital that if withdrawal symptoms are noted, supportive treatment will be initiated. Some patients who experience these unpleasant symptoms will ask for early discharge with the hope of going back to using opioids to control their symptoms. Thus, there is a need for close collaboration between all the stakeholders concerned with the care of these patients.

Instead of discharge, best outcomes are achieved when patients are referred to drug rehabilitation centers for further management and law enforcement authorities notified to ensure that the patient is compliant with rehabilitation.

 This is even more effective when medication-assisted therapy with buprenorphine-naloxone is initiated before hospital discharge.

Individuals who have DNR statuses and are found comatose should still receive naloxone resuscitation as part of correct medical ethics conduct. If upon reversal, when they awaken, they continue to maintain a DNR stance, subsequent dosing should still be administered if needed, provided it is part of the overdose sequela while collaborating with the institution’s medical ethics council.

There is reassurance that prescribing naloxone to manage opioid overdose is consistent with the drug’s FDA indication, which results in no increased liability as long as the prescriber adheres to general rules of professional conduct. State laws and regulations generally 

 from prescribing to a third party, such as a caregiver. Illinois, Massachusetts, New York, and Washington State are the exceptions to this general principle.

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

 Dowell D, Arias E, Kochanek K, et al. Contribution of opioid-involved poisoning to the change in life expectancy in the United States, 2000-2015. 

 Centers for Disease Control and Prevention. Wide-ranging online data for epidemiologic research (WONDER). 2016. https://www.healthdata.gov/dataset/wide-ranging-online-data-epidemiologic-research-wonder. Accessed November 16, 2017.

 New Research: Overprescribing of Postsurgical Opioids Poses a Serious Threat to Patients and Their Communities. 2017. https://finance.yahoo.com/news/research-overprescribing-postsurgical-opioids-poses-120000057.html?.tsrc=rss. Accessed November 16, 2017.

 Gupta R, Shah ND, Ross JS. The rising price of naloxone: risks to efforts to stem overdose deaths. 

 Walley AY, Sorensen-Alawad A, Dwyer K, et al. Nasal naloxone rescue kits in an emergency department overdose education program. 

 Kim HK, Nelson LS. Reducing the harm of opioid overdose with the safe use of naloxone: a pharmacologic review. 

 FDA Advisory Committee on the Most Appropriate Dose or Doses of Naloxone to Reverse the Effects of Life-threatening Opioid Overdose in the Community Settings. 2016. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndAnalgesicDrugProductsAdvisoryCommittee/UCM522688.pdf. Accessed November 16, 2017.

 Clark AK, Wilder CM, Winstanley EL. A systematic review of community opioid overdose prevention and naloxone distribution programs. 

 Greene S, Dargan PI, Jones AL. Acute poisoning: understanding 90% of cases in a nutshell. 

 Rudd-Barnard G, Pangarkar S, Moaleji N, Glassman P. Epidemiology of naloxone use for opioid overdose in a tertiary care medical center. 

 Lin RJ, Reid MC, Chused AE, Evans AT. Quality assessment of acute inpatient pain management in an academic health center. 

 Jones JD, Roux P, Stancliff S, et al. Brief overdose education can significantly increase accurate recognition of opioid overdose among heroin users. 

 The Network for Public Health Law. Using Law to Support Pharmacy Naloxone Distribution. https://www.networkforphl.org/_asset/qdkn97/Pharmacy-Naloxone-Distributions.pdf. Accessed November 16, 2017.

 Guidelines for Opioid Overdose Education and Naloxone Distribution. 2015. http://www.ct.gov/dph/lib/dph/aids_and_chronic/prevention/pdf/open_access_ct_guidelines.pdf. Accessed November 16, 2017.

More than 6 out of 10 deaths involve prescribed opioids. The authors address guidelines for who should (and who should not) receive a naloxone prescription.

Saeed Ahmed, MD

Articles

Buprenorphine and Its Therapeutic Potential in Psychiatric Disorders

Should I Stay or Should I Go: IMGs and the US Health Care System During COVID-19

Opioid Overdoses and Naloxone: What Everyone Needs to Know