Overdose risk increases five-fold with concurrent opioid and benzodiazepine use

In continuation of my update on benzodiazepine

In the first 90 days of concurrent opioid and benzodiazepine use, the risk of opioid-related overdose increases five-fold compared to opioid-only use among Medicare recipients, according to a new study from the University of Pittsburgh School of Pharmacy, published today in JAMA Network Open.

The U.S. Centers for Disease Control and Prevention recommends against concurrent use of opioids and benzodiazepines, but nearly a quarter of Medicare recipients who are prescribed opioids also fill prescriptions for benzodiazepines. Both drugs have sedative effects.

"Patients who must be prescribed both an opioid and a benzodiazepine should be closely monitored by health care professionals due to an increased risk for overdose, particularly in the early days of this medication regimen," said Inmaculada Hernandez, Pharm.D., Ph.D., assistant professor at Pitt's School of Pharmacy and the study's lead author. "Moving forward, policy interventions should focus on preventing concurrent exposure instead of simply reducing the length of time patients use both drugs."

Hernandez and her team used 2013-2014 Medicare Part D data to assess how the duration of simultaneous exposure to the two types of drugs impacts the risk of overdose. Beneficiaries not being treated for cancer who filled at least one opioid prescription during that year were included in the analysis, which ultimately looked at more than 71,000 beneficiaries who averaged 66.5 years of age.

Patients were divided into two groups, those with a supply of only opioids the day before an overdose, and those with an opioid and benzodiazepine supply. The second group was then divided into four subgroups based on the cumulative number of days with overlapping opioid and benzodiazepine supplies.

For patients who did not have an overdose event in the first 90 days of concurrent use, overdose risk in the next 90 days decreased from five-fold to less than double, which is still elevated compared to opioid-only use. After 180 days of concurrent use, the risk of overdose was no higher than the risk for opioid-only use.

Results were adjusted to account for patient demographics, health insurance factors, clinical characteristics, and the number of unique clinicians who prescribed opioids or benzodiazepines to the patients.

Hernandez and her team also found that a beneficiary's risk of concurrent opioid and benzodiazepine use and of overdose increased with the numbers of opioid and benzodiazepine prescribers. In other words, the more clinicians prescribing medications to a beneficiary, the higher the risk of that beneficiary overdosing.

"These findings demonstrate that fragmented care plays a role in the inappropriate use of opioids, and having multiple prescribers who are not in communication increases the risk for overdose," said Yuting Zhang, Ph.D., director, Pharmaceutical Economics Research Group, Health Policy and Management, Pitt Graduate School of Public Health, and the study's senior author. "Prescription monitoring programs and policy interventions can help curb this problem and reduce risk for patients."

Overdose risk increases five-fold with concurrent opioid and benzodiazepine use

Some drug combinations may be more effective than others for schizophrenic patients

  Patients with schizophrenia are often treated with more than one type of psychiatric medication, but a new study suggests that some combinations may be more effective than others.

The findings were published in JAMA Psychiatry.

Antipsychotic drugs are usually the first line of treatment for individuals with schizophrenia. But because these drugs often fail to control symptoms adequately on their own, doctors often prescribe additional psychiatric medications, such as another antipsychotic, an antidepressant, a benzodiazepine, or a mood stabilizer.

"Antipsychotic medications are used to treat psychotic symptoms such as delusions and hallucinations but there is little guidance on what to do for other types of symptoms like depression, anxiety or excitement. Additional medications are often prescribed, but we know little about how different psychiatric drug combinations affect people with schizophrenia," says T. Scott Stroup, MD, MPH, professor of psychiatry at Columbia University Vagelos College of Physicians and Surgeons and lead author of the paper. "Until now we have known virtually nothing about how these strategies compare to each other."

To find out, the researchers conducted a comparative effectiveness study using Medicaid records of 81,921 adults with schizophrenia who had been taking only an antipsychotic drug for at least 3 months before starting either an antidepressant, benzodiazepine, mood stabilizer, or another antipsychotic drug.

The researchers found that individuals with schizophrenia who added an antidepressant were less likely to land in the emergency room or hospital for a mental health issue than those who started another antipsychotic or a benzodiazepine. Antidepressants reduced the risk of hospitalization by 16% compared to antipsychotics and by 22% compared to benzodiazepines. For emergency room visits, antidepressants reduced the risk by 8% compared to antipsychotics and by 18% compared to benzodiazepines.

"Our study adds more evidence that benzodiazepine use should be limited and that combining antidepressants with antipsychotic drugs for individuals with schizophrenia may have benefits," says Stroup. "We still need to know more about when to use antidepressants, which may be useful for conditions other than depression."

Combining medications is often referred to as polypharmacy. "The results of our study should promote rational polypharmacy," added Stroup. He thinks that clinicians will find the results believable and hopes that they will lead to practice changes and improved patient outcomes.

The study is titled, "Comparative Effectiveness of Adjunctive Psychotropic Medications in Patients with Schizophrenia."

https://www.cuimc.columbia.edu/

Some drug combinations may be more effective than others for schizophrenic patients

Benzodiazepines linked to increased risk of death among Alzheimer’s disease patients

Benzodiazepine and related drug use is associated with a 40 per cent increase in mortality among persons with Alzheimer's disease, according to a new study from the University of Eastern Finland. The findings were published in the International Journal of Geriatric Psychiatry.

The study found that the risk of death was increased right from the initiation of benzodiazepine and related drug use. The increased risk of death may result from the adverse events of these drugs, including fall-related injuries, such as hip fractures, as well as pneumonia and stroke.

The study was based on the register-based MEDALZ (Medication Use and Alzheimer's Disease) cohort, which includes all persons diagnosed with Alzheimer's disease in Finland during 2005-2011. Persons who had used benzodiazepines and related drugs previously were excluded from this study, and therefore, the study population consisted of 10,380 new users of these drugs. They were compared with 20,760 persons who did not use these drugs.

Although several treatment guidelines state that non-pharmacological options are the first-line treatment of anxiety, agitation and insomnia in persons with dementia, benzodiazepines and related drugs are frequently used in the treatment of these symptoms. If benzodiazepine and related drug use is necessary, these drugs are recommended for short-term use only. These new results encourage more consideration for benzodiazepine and related drug use in persons with dementia.

Ref : https://www.uef.fi/en/-/bentsodiatsepiinit-lisaavat-kuolleisuutta-alzheimerin-tautia-sairastavilla

Benzodiazepines linked to increased risk of death among Alzheimer’s disease patients

Benzodiazepines linked to increased risk of death among Alzheimer’s disease patients

Benzodiazepine and related drug use is associated with a 40 per cent increase in mortality among persons with Alzheimer's disease, according to a new study from the University of Eastern Finland. The findings were published in the International Journal of Geriatric Psychiatry.

The study found that the risk of death was increased right from the initiation of benzodiazepine and related drug use. The increased risk of death may result from the adverse events of these drugs, including fall-related injuries, such as hip fractures, as well as pneumonia and stroke.

The study was based on the register-based MEDALZ (Medication Use and Alzheimer's Disease) cohort, which includes all persons diagnosed with Alzheimer's disease in Finland during 2005-2011. Persons who had used benzodiazepines and related drugs previously were excluded from this study, and therefore, the study population consisted of 10,380 new users of these drugs. They were compared with 20,760 persons who did not use these drugs.

Although several treatment guidelines state that non-pharmacological options are the first-line treatment of anxiety, agitation and insomnia in persons with dementia, benzodiazepines and related drugs are frequently used in the treatment of these symptoms. If benzodiazepine and related drug use is necessary, these drugs are recommended for short-term use only. These new results encourage more consideration for benzodiazepine and related drug use in persons with dementia.

Ref : https://www.uef.fi/en/-/bentsodiatsepiinit-lisaavat-kuolleisuutta-alzheimerin-tautia-sairastavilla

Benzodiazepines linked to increased risk of death among Alzheimer’s disease patients

Flumazenil reverses stress-triggered anxiety in methamphetamine dependant rats

We know that, Flumazenil (also known as flumazepil, code name Ro 15-1788, trade names Anexate, Lanexat, Mazicon, Romazicon) is abenzodiazepine receptor antagonist primarily available by injection only, and the only benzodiazepine receptor antagonist on the market today.

It was first introduced in 1987 by Hoffmann-La Roche under the trade name Anexate, but only approved by the FDA on December 20, 1991. Some years ago an oral preparation was under development,  though it had low bio-availability and was thus abandoned.

Flumazenil reverses stress-triggered anxiety in methamphetamine dependant rats

FDA Approves Nayzilam (midazolam) Nasal Spray to Treat Seizure Clusters

  

UCB announced   that the U.S. Food and Drug Administration (FDA) has approved a New Drug Application for the company’s newest anti-epileptic drug (AED) Nayzilam (midazolam) nasal spray CIV, a benzodiazepine indicated for the acute treatment of intermittent, stereotypic episodes of  frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy 12 years of age and older. Nayzilam now provides patients and caregivers with the first and only FDA-approved nasal option for treating seizure clusters.  

It is estimated that more than 150,000 people in the U.S. with uncontrolled epilepsy also experience seizure clusters.2 Rescue treatment of seizure clusters is critical because when left untreated, seizure clusters can increase the risk of physical injury, neurological damage, prolonged seizures, and status epilepticus. Despite the impact of seizure clusters, many diagnosed patients may go untreated because currently available treatment options are not preferred.

Nayzilam is a short-term treatment for seizure clusters in patients with epilepsy. The nasal spray is designed as a single-use treatment that can be carried with a patient. Nayzilam allows for administration by a non-healthcare professional in patients actively seizing when and where a seizure cluster occurs. Nayzilam can provide value to patients who are experiencing these disruptive seizures.

“As global leaders in epilepsy, the approval of Nayzilam complements our already strong epilepsy portfolio, improving our ability to provide value to people living with poorly controlled seizures, and builds on our passion and expertise in this field. We are pleased to expand and diversify the solutions we can offer to the epilepsy community, providing an innovative and differentiated solution to help support management of seizure clusters,” said Jean-Christophe Tellier, Chief Executive Officer, UCB.

Nayzilam is the first new medication approved to treat seizure clusters in more than 20 years in the U.S. Its nasal delivery could provide significant value to patients who currently have limited treatment options.

“When a patient experiences seizure clusters, there is often significant impact on their overall quality of life, in addition to posing greater risks for increased emergency department related hospitalizations and more serious seizure emergencies,” said Dr. Steven S. Chung, MD, Executive Director and Program Chair of the Neuroscience Institute and Director of the Epilepsy Program at Banner – University Medical Center. “Further, as a neurologist specializing in epilepsy, treating seizure clusters today presents a challenging barrier for many patients. The availability of a new treatment option, such as Nayzilam, has potential to help improve the lives of patients and their families by providing another option for rescue care.”

https://www.drugbank.ca/drugs/DB00683

New class of sleeping pill preserves ability to wake in response to danger signals

https://chem.nlm.nih.gov/chemidplus/rn/1088991-95-0

In a trial of one of the main class of prescription sleeping pills, half the participants slept through a fire alarm as loud as someone vacuuming next to their bed. But a newer alternative preserves the ability to wake in response to danger signals, according to a new research.

Published this week in Frontiers in Behavioral Neuroscience, the study showed that mice given the experimental hypnotic drug DORA-22 wake as quickly when threatened as drug-free sleepers - and then fall back asleep as quickly as ones given standard sleeping pills, once the threat is gone.

Common sleeping pills muffle your sleeping brain's 'intruder alert'

Even during sleep the brain continuously processes sensory information, waking us if it detects a threat. But the most widely prescribed class of sleeping pills, known as benzodiazepines, makes us less likely to rouse in response to sensory input.

"Benzodiazepines stimulate the widespread brain receptor GABA-A, which makes us sleepy but also suppresses off-target brain areas - including the 'gatekeeper' that decides which sensory inputs to process," explains study senior author Professor Tomoyuki Kuwaki of Kagoshima University, Japan.

Over the last decade, researchers have been developing a new class of hypnotic drugs called dual orexin receptor antagonists (DORAs). DORAs more selectively target the brain's sleep/wake pathways, which gives them safety advantages over benzodiazepines. These include a reduced 'hangover effect', with DORAs less likely to affect driving ability the day after use.

Kuwaki and colleagues hypothesized that the selectivity of DORAs could make them a safer alternative during sleep as well - by allowing the brain's sensory gatekeeper to stay vigilant to threats.

DORA-22 allows mice to wake to a threat, but still helps them sleep

The group tested their theory in mice.

The mice were dosed and tested after dark, when they are normally most active. One group was administered DORA-22, another a benzodiazepine called triazolam - and a third group was given placebo as a control.

"DORA-22 and triazolam had similar sleep promoting effects, extending the duration of deep sleep by 30-40% compared to placebo," reports Kuwaki.

One to four hours after dosing, the deep-sleeping mice were presented with a threatening stimulus: the smell of a fox, a high-pitched noise like a dog whistle, or trembling of their cage. The trembling frequency was designed to match that of an earthquake - a serious threat in Kuwaki's native Japan and many other parts of the word.

"As expected, arousal in response to these threatening stimuli was delayed significantly in the triazolam treatment, but not in the DORA-22 treatment, compared to placebo.

Even more promising, the sleep-promoting effect of DORA-22 remained after the rude awakening.

"Even though the DORA-22-treated mice were quickly woken by a threat, they subsequently fell back asleep as quickly as with triazolam, and significantly faster than with placebo."

To help demonstrate that the delay in waking to a threat during triazolam treatment was due specifically to inhibition of sensory gating in the brain, the researchers also tested the sleeping mice with a non-sensory stimulus.

"The three groups woke equally quickly when we suddenly reduced the amount of oxygen in their cage. This suggests that the delay in rousing to threatening stimuli caused by triazolam was not caused by a general inhibition of waking systems in the brain."

Human studies are needed to confirm DORA safety and efficacy

"Although it remains to be seen whether DORAs have the same properties when used in humans, our study provides important and promising insight into the safety of these hypnotics."

Since 2014, another DORA called surovexant has gained regulatory approval in Japan, the USA and Australia. So far, the high cost and limited clinical testing of surovexant have limited its use, amid concerns that doses high enough to significantly improve sleep lead to drowsiness the following day. New DORAs currently in development could overcome this hangover effect if they are cleared more quickly from the body than suvorexant, so that their effects are less likely to last beyond bedtime. Keep your eyes peeled.

Olanzapine as long-acting injection (LAI) for acute and maintenance treatment of schizophrenia.?

Olanzapine (2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine) is one of the most commonly used drugs for atypical antipsychotics. Olanzapine has been approved by the FDA for the treatment of schizophrenia, acute mania in bipolar disorder, agitation associated with schizophrenia and bipolar disorder, and as maintenance treatment in bipolar disorder and psychotic depression. Zyprexa is Lilly’s top-selling drug, with sales of $4.2 billion last year.

Olanzapine's antipsychotic activity is mediated primarily by antagonism (blocking or inhibition) at dopamine receptors.

FDA required the manufacturers of all atypical antipsychotics to include a warning about the risk of hyperglycemia and diabetes with atypical antipsychotics.

Lilly is continuing to work with the agency on the new drug application (NDA). I think Lilly, has a come with a smart move like NDA, becoz., the FDA does not require any additional clinical trials for the continued review of the NDA. Per the agency's request, Lilly is preparing a proposed Risk Evaluation and Mitigation Strategy (REMS), which will be submitted in the near future. Hope this drug will not have the said side effects. A ray of hope for schizophrenia patients ? time will tell the story, best of luck Lilly....

Talampanel has potential to slow the muscle weakening that comes with amyotrophic lateral sclerosis (ALS)...

Talampanel (strutcure, source:ChemSpider), (8R)-7-Acetyl-5-  (4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine  is a drug used to treat epilepsy. Now researchers from Johns Hopkins and Indiana University, have found interesting activity of the same anticonvulsant drug, i.e., the drug has potential to slow the muscle weakening that comes with amyotrophic lateral sclerosis (ALS)  . The researchers after completing a Phase II clinical trial-an early, small-scale test to show if the drug works and continues to be safe. As per the claim by the researchers,  the drug talampanel showed some ability to slow the loss of major daily life activities such as speaking, walking and dressing that typically slip away as the disease progresses. Interestingly the drug  has the anti-anxiety and  muscle relaxing activity too (work in the brain and spinal cord).

The trial in 59 volunteers with ALS - also called Lou Gehrig's disease - showed that talampanel can be safe for patients with the disease and that any recorded side effects are tolerable.  Phase II trials are designed to show on a small scale if a drug is safe and if it works. So the present trial included ways to measure the drug's benefits, which came across as clear, if not statistically significant. The research demonstrates that talampanel appears able to slow the progression of disabling ALS symptoms. Though the effect isn't overwhelming at the dosage of medicine used in this early, very small trial and the researchers claims that  having promising human data is reason enough to keep it in the drug pipeline where they can really find out where it stands for patient.

With the exception of riluzole, the single FDA-approved drug for the disease, there's no other treatment to slow or stop it. Riluzole can extend life only modestly and hasn't been shown to slow ALS symptoms. so the need for better therapy is real. Hope in the days to come people with ALS symptoms will have a better drug...

Ref : http://www.hopkinsmedicine.org/Press_releases/2010/01_04a_10.html

Successful Completion Of Proof-of-concept Clinical Trial Of Levotofisopam For The Treatment Of Gout

Pharmos Corporation,  announced that it has successfully completed a proof-of-concept clinical trial using its compound levotofisopam (5S)-1-(3,4-dimethoxyphenyl)-5-ethyl-7,8-dimethoxy-4-methyl-5H-2,3-benzodiazepine, S-tofisopam see structure below) to treat patients with hyperuricemia and gout. This phase 2a trial was conducted at the Duke Clinical Research Unit of Duke University and the principal investigator was John Sundy, MD, PhD, an expert and key opinion leader in the treatment of gout. The trial was designed to assess the safety and efficacy of levotofisopam as a uric acid-lowering agent in patients with gout.

The trial enrolled 13 patients in an open label study with patients confined in the Duke facility.  The study enrolled patients with screening serum urate between 8 and 12 mg/dL. Subjects received a single dose of 50 mg on days 1 and 7 and 50 mg TID on days 2 through 6.  Levotofisopam was well tolerated. The mean reduction in serum urate was over 45%. All 13 patients were responders, and demonstrated a serum urate level of less than 6 mg/dL on day 7. Seven subjects achieved a serum urate level less than 4 mg/dL on day 7. Additionally there was an increase in the fractional excretion of urate, confirming the compound's mechanism of action as a uricosuric agent that enhances urate excretion by the kidneys. 

Commenting on the results of this Phase 2a trial, the principal investigator Dr. John Sundy said, "monotherapy with levotofisopam was well tolerated and induced clinically important reductions in serum urate levels in all patients studied. These results support further development of levotofisopam for treating hyperuricemia in patients with gout."

In continuation of my update on usefulness of benzodiazepine derivatives

Lundbeck Inc. presented interim data from its long-term, open-label extension study evaluating ONFI™ (clobazam see structure below) CIV for the adjunctive treatment of drop seizures associated with Lennox-Gastaut syndrome (LGS). Company claims that, these interim results support the reductions in drop seizure rates associated with ONFI when used as add-on therapy for adult and pediatric patients, two years of age or older, with a current or previous diagnosis of LGS. ....

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