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Issue 75, Jul 2018
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Changes in Synthetic Opioid Involvement in Drug Overdose Deaths in the United States, 2010-2016

Jones CM et al. JAMA. 2018 May; 319(17):1819-1821. doi: 10.1001/jama.2018.2844. PMID: 29715347

Background

The opioid epidemic is escalating rapidly. Synthetic opioids are being increasingly implicated in overdose deaths in the United States.  Illicit drugs such as heroin, cocaine, methamphetamine, and counterfeit pills are commonly being mixed with synthetic opioids resulting in complex presentations of patients.  

Methods

This was a retrospective study in which data from the National Vital Statistics Systems multiple cause death file, based on review of death certificates submitted by the medical examiners and coroners, in the United States. Drug overdose deaths between 2010-2016 were assigned International Classification of disease (ICD-10) codes. The cause of death was classified as unintentional, suicide, homicide, and undetermined. Multiple drugs were implicated in the drug overdose deaths. The drugs were separated based on ICD-10 codes into natural/semi synthetic opioids and methadone; heroin; synthetic opioids excluding methadone, cocaine; psychostimulants; benzodiazepines; antidepressants; antipsychotics; barbiturates; other illicit drugs (cannabis, lysergic acid diethylamide and other hallucinogens); and alcohol. An assessment was made of the number of synthetic opioid deaths between 2010-2016. In addition, the number of overdose deaths in which synthetic opioids were implicated with another prescription drug, illicit drug or alcohol were assessed.   

Results

Synthetic opioid involvement increased alarmingly from 14.3% of opioid related deaths in 2010 to 45.9% in 2016.  There was an increase in synthetic opiate involvement in deaths involving prescription opioids, heroin, and all other psychotherapeutic and illicit drugs for the time frame studied. The data also suggest that amongst the synthetic opioid deaths, about 80% involve another drug or alcohol. The top three drugs in addition to the synthetic opioid were another opioid (48%), heroin (30%), and cocaine (21%). In 15% to 25% of death certificates the type of drug involved in the overdose was not specified suggesting that these data may be underestimates. Increased drug screening in recent times may also increase the estimate of opiate detection.

Conclusions

Synthetic opioids are the most common drug involved in overdose deaths in the United States eclipsing even the prescription opioids.  Lack of awareness of the synthetic opioid involvement, potency, as an adulterant with other drugs of abuse poses substantial risks to public health.

Clinical Commentary

This is a rapidly escalating problem in the mental health field and clinicians need to have increased awareness regarding the deadly potential of synthetic opioids. We need to educate patients regarding the risk of any drug they abuse (e.g. cannabis, cocaine, amphetamine, oxycontin) as synthetic opioids may be an adulterant and a deadly combination with psychiatric medications. We should be increasingly doing surprise urine drug screening as appearances are deceptive. Patients testing positive for drugs would benefit from enrollment in a dual diagnosis program where both substance abuse and mental health issues can be addressed.  I suggest that we think of addiction in terms of a disease model (diabetes mellitus) and aim for a comprehensive treatment plan.

Opioids are substances that act on opioid receptors to produce morphine like effects. The broad classification of opioids includes natural opioids (e.g. morphine and codeine); semisynthetic opioids created from natural opiates or morphine esters (e.g. hydrocodone, oxycodone, hydromorphone, and buprenorphine); fully synthetic opioids (e.g. fentanyl, methadone, tramadol, dextropropoxyphene, heroin sold on the streets); endogenous opioid peptides found naturally in the body (e.g. endorphins and enkephalins). 

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Prescription Opioid Use among Adults with Mental Health Disorders in the United States

Davis MA et al. Journal Am Board Fam Med. 2017 Jul-Aug; 30(4):407-417. doi: 10.3122/jabfm.2017.170112. PMID: 28720623

Background

In the last 15 years there is an epidemic of opioid abuse. Patients with psychiatric disorders are a vulnerable population. This study focused on prescription opiate use in individuals with mood and anxiety disorders.

Methods

This is a cross-sectional study of a nationally representative sample of outpatients from the Medical Expenditure Panel Survey. The relationship between mood and anxiety disorders and prescription opioid use was examined. Opioid use defined as a minimum of two prescriptions for opioid medication in a calendar year.

Results

There are 38.6 million Americans with mental health disorders of which 18.7% use prescription opioids. The adults with mood and anxiety disorders account for 51.4% of total opioid prescriptions in the United States. Compared with adults without mental health disorders, adults with mental health disorders were significantly more likely to use opioids (18.7% vs 5%; P < .001). Having a mental health disorder was associated with prescription opioid use (odds ratio, 2.08; 95% confidence interval, 1.83-2.35)

Conclusions

Americans with mental health disorders receive over half of all the opioid medications prescribed in the United States.

Clinical Commentary

I chose to review this paper because it was an eye opener for me. Many of us screen and select patients in our practices, who do not have drug and alcohol issues. In the real world we often do not have a complete updated list of current medications the patient is taking. As a mental health community, we all need to be aware of these issues particularly the high rate of opiate prescription (legal use) in our patients and pay attention to those with mood and anxiety disorders. I suggest looking into the Opiate Risk Tool (ORT) if suitable for the practice to identify those at risk for opiate abuse. This tool screens for risk factors for opiate abuse and is available online. Conversely primary care and pain management physicians should also be screening these patients for mood and anxiety disorders.

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A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients with Treatment-Resistant Depression.

Singh JB et al.  Am J Psychiatry 2016 August;173(8) 816-826. doi: 10.1176/appi.ajp.2016. 16010037. Epub 2016 Apr8.PMID: 27056608

Background

Patients with major depressive disorder (MDD) have a partial or nonresponse resulting in significant morbidity despite many available treatments. Ketamine a noncompetitive N-methyl-D-aspartate glutamate receptor antagonist, has demonstrated rapid onset of antidepressant effects in patients with treatment resistant depression. Antidepressant effects of intravenous ketamine were evaluated in twice -and thrice- weekly administration in patients with treatment resistant depression.

Methods

In this multicenter, double-blind placebo-controlled treatment resistant depression study using adult subjects (18-64 years), randomization was done to intravenous ketamine (0.5 mg/kg of body weight) or placebo administered over 40 minutes. The frequency was two or three times per week for up to 4 weeks. Patients discontinuing the double-blind phase at the end of two weeks due to lack of efficacy could participate in an optional 2-week open label phase to receive ketamine with the same frequency as in the double-blind phase. Change in the Montgomery-Asberg Depression rating scale (MADRS) was the primary outcome measure.

Results

68 patients were randomized into the four double-blind study arms out of 165 screened. Most of those who withdrew before day 29 were receiving placebo and the reason was lack of efficacy. In the twice weekly regimen mean change in MADRS was -18.4 (SD=12.0) for ketamine and -5.7 (SD=10.2) for placebo. In the thrice weekly group MADRS change was -17.7(SD=7.3) for ketamine and -3.1 (SD=5.7) for placebo. The open-label phase had similar results (twice weekly -12.2 (SD=12.8) on day 4; thrice weekly -14 (SD=12.5) on day 5. Both regimens were well tolerated. Headache, nausea, anxiety, dizziness, and dissociation were the most common side-effects. Dissociative symptoms were transient and attenuated with repeated dosing.

Conclusions

Twice and thrice weekly intravenous administration of ketamine (0.5 mg/kg) maintained similar antidepressant efficacy over 15 days.

Clinical Commentary

The role of intravenous ketamine is emerging as a rapidly efficacious modality for treatment resistant depression. Ketamine treatment is currently off-label (not FDA approved) but has robust data in support. This study suggests that twice or thrice a week administration appear to have similar efficacy. The key here is appropriate patient selection and administration of intravenous ketamine under strict controls. The patients should be under psychiatric care for diagnostic reasons and also for management of any side-effects. Safety of the patient is of utmost importance when using this treatment.

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Prolonged Grief and Cognitive Decline: A Prospective Population-Based Study in Middle-Aged and Older Persons

Pérez HCS et al. Am J Geriatr Psychiatry. 2018 April;26(4):451-460. doi:10.1016/jagp.2017.12.003. Epub 2017 Dec 12. PMID 29329723

Background

Middle aged and older adults often encounter the death of a loved one, and often the grief process is lengthy and complicated resulting in prolonged grief disorder (PGD). This process may affect cognitive functioning in an age group prone to cognitive decline. This study was precisely designed to assess PGD as a predictor of cognitive decline.

Methods

The sample comprised of the Rotterdam study participants (N=3126), mean age 64 were divided into three groups: no grief (N=2582), normal grief (N=418), and PGD (N=126). Each group had a seven year follow up. The participants underwent assessments with complicated grief inventory as well as cognitive tests (Mini-Mental State Examination [MMSE] Letter-Digit Substitution Test, Stroop, Word fluency task, Word learning task). Participants with major depression were excluded. The analyses were done adjusting for baseline cognition and depressive symptoms.

Results

The participants with PGD had a decrease in global cognitive function, MMSE scores, and Word learning test (immediate and delayed) over time. Those with normal grief did not show a stronger decline than the reference group.

Conclusions

Participants with PGD showed a stronger cognitive decline over the seven year follow-up compared to the reference group. This suggests that PGD is a risk factor for cognitive decline. This study was not designed to detect the psychobiological mechanisms underlying this longitudinal association.

Clinical Commentary

This longitudinal study has important clinical relevance. Middle-aged patients as well as older adults are at risk of losing loved ones, and cognitive decline also begins as part of the aging process. Our patients who have lost a loved one should be monitored for prolonged grief (symptoms > 6 months, bitterness, functional impairment etc.) due to it being a risk factor for cognitive decline. Early aggressive intervention with therapy such as cognitive behavioral therapy (CBT) is suggested to treat prolonged grief disorder. If complicated by major depression it should be treated with antidepressant therapies.

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Lithium and suicide in mood disorders: Updated meta-review of the scientific literature

Smith KA et al. Bipolar Discord. 2017 Nov; 19:575-586. doi: 10. 1111/bdi.12543. Epub 2017 Sep 12 PMID:28895269

Background

Mood disorders are associated with increased risk of suicide and suicidal behavior. There is an ongoing effort to develop evidenced based therapies that reduce suicide risk and behavior. Observational studies and small randomized controlled clinical trials (RCT) support the notion of lithium associated reduction in these rates. This manuscript reviewed the updated evidence of lithium associated reduction in suicide and self-harm.

Methods

The search included PubMed, PsychINFO, and the Cochrane Library for systematic reviews and meta-analyses of RCTs of lithium and suicide and self-harm published between January 1980 and June 2017 (period of 37 years). The most recent and most comprehensive reviews were considered.

Results

16 publications were systematic reviews as identified. Of these, three systematic reviews of only Lithium and suicide rates and only of lithium and self-harm confined only to RCTs were identified. Despite some methodological concerns of heterogeneity in terms of participants, diagnoses, duration and phase of illness the evidence is overwhelmingly in favor of lithium as an anti-suicidal agent.

The rate of self-harm in patients prescribed mood stabilizer medication for bipolar disorder was 340 (95%CI 313-370) per 10 000-person years at risk (PYAR). The self- harm rates were reduced in patients taking lithium compared with those taking valproate, olanzapine, or quetiapine. The rates of unintentional injury were 616 (95% CI 579-656) in people taking lithium compared with those taking valproate, olanzapine, quetiapine but not olanzapine. The rate of suicide deaths was 14(95% CI 9-21) numbers too low to show any difference between drugs.

Conclusions

The anti-suicidal effects of lithium have been consistently reported over the last 40 years. The most robust evidence comes from RCTs, however it is hard to conduct high quality studies in this area. This updated review also confirms anti-suicidal effects of lithium.

These findings are important because in addition to death by suicide individuals with bipolar disorder have an increased risk of death by accidental injury six times higher than the general population. Lithium should be used preferentially in bipolar disorder not only because it reduces the suicide rate but also death from all cause mortality. Lithium has the potential to impact outcomes substantially in the treatment of bipolar illness.

Clinical Commentary

This study once again reiterates the anti-suicidal effects of lithium which is underutilized in clinical practice. The need for serum lithium levels and a narrow therapeutic index has resulted in the increased use of atypical antipsychotics. We as clinicians should revisit using lithium due to its anti-suicidal effects. Other drugs with similar effects include clozapine and ketamine. Clozapine, another underutilized drug, has been found to have anti-suicidal effects in schizophrenia and schizoaffective disorder especially in treatment resistant patients. Ketamine administered intravenously has recently been shown to have rapid acute efficacy for suicidal ideation independent of diagnosis, although further studies are needed. Stay tuned as the ketamine story is unfolding.

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Sanjay Gupta, MD
Clinical Professor of Psychiatry, SUNY Buffalo

GME Research Review is a monthly newsletter edited by Sanjay Gupta, MD, Clinical Professor of Psychiatry, SUNY Buffalo. Dr. Gupta selects, summarizes, and provides a clinical commentary on the latest published research in psychiatry. 

We are always carefully evaluating which research papers to discuss in GME Research Review. Have come across a research paper published in the last 6 months that you thought is clinically relevant? Do you want me to analyze it for you and for the benefit of others? Please email Dr. Gupta the citation at [email protected]

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