Opioid Antagonists: Will they Solve all of the Problems Associated with Opioid Agonists?

Physicians employed in operating and emergency rooms have utilized opioid antagonist for almost half a century for the treatment of opioid overdose. The prototype antagonist remains naloxone hydrochloride, which actually received FDA approval back in 1971. Why after so many years on the market is this medication now being formulated in the form of an easy to use “auto-injector” that was designed for non-medical professionals to be able to utilize at a moment\u27s notice? Could this wonder product, being hailed as the best possible safety tool available for life threatening opioid emergencies actual make heroes out of lay people? [1]. Will marketing and providing to the family and caregivers of chronic pain patients prevent the epidemic of opioid medication related deaths of people in our country? What else can be done by physicians and the U.S. Food and Drug Administration (FDA) to reduce the unbelievable statistic of a death every 36 minutes from an opioid overdose in the United States? With upwards of 17,000 Americans dying yearly from prescription opioid overdose, accidently or intentionally via suicide& deliberate misuse, and constantly consuming more and more of these powerful painkillers-the million dollar question remaining to be answered is: will a new drug formulation device in the hands of laypeople really make a dent in this crisis that in recent years has actually surpassed car accidents as the leading cause of accidental death? [2]

Combination Olanzapine and Samidorphan for the Management of Schizophrenia and Bipolar 1 Disorder in Adults: A Narrative Review

Schizophrenia is a debilitating psychotic disorder characterized by positive symptoms such as delusions, hallucinations, and disorganized thoughts, and negative symptoms like lack of effect or motivation. Bipolar 1 disorder (B1D) is a psychiatric illness characterized by recurrent manic episodes in alternation with depressive episodes and interspersed periods of euthymia, ultimately resulting in psychological distress and impairment of daily functioning. Effective treatments are needed for both schizophrenia and B1D to reach the treatment goals of reducing the debilitating symptomology, improving social functioning and quality of life, and increasing the chances of recovery and more favorable long-term outcomes. To date, olanzapine is one of the most efficacious atypical antipsychotics (AAPs) for the treatment of both schizophrenia and B1D and is associated with fewer extrapyramidal effects compared to other treatments. However, compared to other AAPs, olanzapine is associated with a greater chance of metabolic syndrome, limiting its clinical use and affecting treatment compliance. Samidorphan mitigates the weight gain side effects of olanzapine by antagonizing μ-, κ-, and δ-opioid receptors. The use of combination drugs to treat psychiatric conditions is an emerging field with the goal of increasing therapeutic efficacy and decreasing undesirable side effects. Clinical trials have demonstrated combination on olanzapine and samidorphan (OLZ/SAM) treatment resulted in significantly less weight gain than olanzapine monotherapy. Clinical trial patients reported improvements in symptoms of psychosis, reduced weight gain, and overall satisfaction with their treatment. OLZ/SAM has been as shown to be a safe and effective pharmaceutical option for the clinical management of schizophrenia and B1D

Deutetrabenazine for the treatment of chorea associated with Huntington’s disease

This is a comprehensive review of the literature regarding the use of Deutetrabenazine in treating chorea associated with Huntington’s disease. Unfortunately, treatment has been limited for many aspects of this neurodegenerative disease. The present investigation presents the background, evidence, and indications for the use Deutetrabenazine in the setting of Huntington’s disease. Huntington’s disease is characterized by a variety of motor, psychiatric, and cognitive symptoms with chorea being one of the more notable ones. Chorea is a movement disorder present in multiple neurologic diseases that causes involuntary and irregular muscle movements theorized to be stemming from high dopamine levels. Deutetrabenazine is thought to function as an inhibitor of the VMAT2 vesicular monoamine transporter resulting in decreased monoamine release, including dopamine, in the synaptic cleft which has a therapeutic effect in management of chorea. This drug was approved by the FDA in 2017 with a specific indication for tardive dyskinesia and choreiform movement in Huntington’s disease. Currently, there is no definitive treatment for Huntington’s disease. Thus, management is primarily focused on symptom management with the use of a variety of pharmaceutical agents. Chorea is one of the many manifestations that significantly alter the quality of life of many patients. Deutetrabenazine is a promising new option for the treatment of chorea in the setting of Huntington’s disease. Although studies so far have displayed mixed results, further research, including head-to-head studies, is necessary to elucidate the true potential of this drug

pitolisant, a novel histamine-3 receptor competitive antagonist, and inverse agonist, in the treatment of excessive daytime sleepiness in adult patients with narcolepsy

Narcolepsy is a debilitating sleep disorder that presents with excessive daytime sleepiness (EDS) and cataplexy, which is a sudden paralysis of muscle tone triggered by strong emotions such as laughing. It is also associated with many other disorders, including psychiatric disorders, neurologic illnesses, and medication side effects. Common causes of delayed and incorrect diagnoses of these conditions include lack of physician familiarity with narcolepsy symptoms and comorbidities which mask narcolepsy signs and symptoms. Current pharmacologic therapies include Modafinil and Armodafinil for EDS and sodium oxybate for cataplexy. This review discusses the epidemiology, pathophysiology, risk factors, presentation, treatment of narcolepsy, and the role of a novel drug, Pitolisant, in the treatment of EDS in adults with narcolepsy. Pitolisant is a histamine-3 receptor (H3R), competitive antagonist, and inverse agonist, acting through the histamine system to regulate wakefulness. It is a novel drug approved in August 2019 by the FDA, is not classified as a controlled substance, and is approved for use in Europe and the United States to treat EDS and cataplexy in narcolepsy. Recent phase II and III trials have shown that Pitolisant helps reduce the ESS score and cataplexy. In summary, based on comparative studies, recent evidence has shown that Pitolisant is non-inferior to Modafinil in the treatment of EDS but superior to Modafinil in reducing cataplexy

Chronic pain treatment strategies in Parkinson’s disease

Neurological disorders, including Parkinson’s disease (PD), have increased in prevalence and are expected to further increase in the coming decades. In this regard, PD affects around 3% of the population by age 65 and up to 5% of people over the age of 85. PD is a widely described, physically and mentally disabling neurodegenerative disorder. One symptom often poorly recognized and under-treated by health care providers despite being reported as the most common non-motor symptom is the finding of chronic pain. Compared to the general population of similar age, PD patients suffer from a significantly higher level and prevalence of pain. The most common form of pain reported by Parkinson’s patients is of musculoskeletal origin. One of the most used combination drugs for PD is Levodopa-Carbidopa, a dopamine precursor that is converted to dopamine by the action of a naturally occurring enzyme called DOPA decarboxylase. Pramipexole, a D2 dopamine agonist, and apomorphine, a dopamine agonist, and Rotigotine, a dopamine receptor agonist, have showed efficacy on PD-associated pain. Other treatments that have shown efficacy in treating pain of diverse etiologies are acetaminophen, Nonsteroidal anti-inflammatory drugs (NSAIDs), and cyclooxygenase-2 (COX-2) inhibitors. Opioids and opioid-like medications such as oxycodone, morphine, tramadol, and codeine are also commonly employed in treatment of chronic pain in PD. Other opioid related medications such as Tapentadol, a central-acting oral analgesic with combined opioid and noradrenergic properties, and Targinact, a combination of the opioid agonist oxycodone and the opioid antagonist naloxone have shown improvement in pain. Anticonvulsants such as gabapentin, pregabalin, lamotrigine, carbamazepine and tricyclic antidepressants (TCAs) can be trialed when attempting to manage chronic pain in PD. The selective serotonin and noradrenaline reuptake inhibitors (SNRIs) also possess pain relieving and antidepressant properties, but carry less of the risk of anticholinergic side effects seen in TCAs. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been shown in multiple studies to be effective against various types of PD associated pain symptoms. Massage therapy (MT) is one of the most common forms of complementary and alternative medicine. Studies have shown that pressure applied during MT may stimulate vagal activity, promoting reduced anxiety and pain, as well as increasing levels of serotonin. In a survey study of PD patients, rehabilitative therapy and physical therapy were rated as the most effective for pain reduction, though with only temporary relief but these studies were uncontrolled. Yoga has been studied for patients with a wide array of neurological disorders. In summary, PD pathology is thought to have a modulating effect on pain sensation, which could amplify pain. This could help explain a portion of the higher incidence of chronic pain felt by PD patients. A treatment plan can be devised that may include dopaminergic agents, acetaminophen, NSAIDs, opioids, antidepressants, physical therapies, DBS and other options discussed in this review. A thorough assessment of patient history and physical examination should be made in patients with PD so chronic pain may be managed effectively

Chronic pain treatment strategies in Parkinson’s disease

Neurological disorders, including Parkinson’s disease (PD), have increased in prevalence and are expected to further increase in the coming decades. In this regard, PD affects around 3% of the population by age 65 and up to 5% of people over the age of 85. PD is a widely described, physically and mentally disabling neurodegenerative disorder. One symptom often poorly recognized and under-treated by health care providers despite being reported as the most common non-motor symptom is the finding of chronic pain. Compared to the general population of similar age, PD patients suffer from a significantly higher level and prevalence of pain. The most common form of pain reported by Parkinson’s patients is of musculoskeletal origin. One of the most used combination drugs for PD is Levodopa-Carbidopa, a dopamine precursor that is converted to dopamine by the action of a naturally occurring enzyme called DOPA decarboxylase. Pramipexole, a D2 dopamine agonist, and apomorphine, a dopamine agonist, and Rotigotine, a dopamine receptor agonist, have showed efficacy on PD-associated pain. Other treatments that have shown efficacy in treating pain of diverse etiologies are acetaminophen, Nonsteroidal anti-inflammatory drugs (NSAIDs), and cyclooxygenase-2 (COX-2) inhibitors. Opioids and opioid-like medications such as oxycodone, morphine, tramadol, and codeine are also commonly employed in treatment of chronic pain in PD. Other opioid related medications such as Tapentadol, a central-acting oral analgesic with combined opioid and noradrenergic properties, and Targinact, a combination of the opioid agonist oxycodone and the opioid antagonist naloxone have shown improvement in pain. Anticonvulsants such as gabapentin, pregabalin, lamotrigine, carbamazepine and tricyclic antidepressants (TCAs) can be trialed when attempting to manage chronic pain in PD. The selective serotonin and noradrenaline reuptake inhibitors (SNRIs) also possess pain relieving and antidepressant properties, but carry less of the risk of anticholinergic side effects seen in TCAs. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been shown in multiple studies to be effective against various types of PD associated pain symptoms. Massage therapy (MT) is one of the most common forms of complementary and alternative medicine. Studies have shown that pressure applied during MT may stimulate vagal activity, promoting reduced anxiety and pain, as well as increasing levels of serotonin. In a survey study of PD patients, rehabilitative therapy and physical therapy were rated as the most effective for pain reduction, though with only temporary relief but these studies were uncontrolled. Yoga has been studied for patients with a wide array of neurological disorders. In summary, PD pathology is thought to have a modulating effect on pain sensation, which could amplify pain. This could help explain a portion of the higher incidence of chronic pain felt by PD patients. A treatment plan can be devised that may include dopaminergic agents, acetaminophen, NSAIDs, opioids, antidepressants, physical therapies, DBS and other options discussed in this review. A thorough assessment of patient history and physical examination should be made in patients with PD so chronic pain may be managed effectively

Bremelanotide for Treatment of Female Hypoactive Sexual Desire

Hypoactive sexual desire disorder (HSDD) is a persistent deficiency or absence of sexual fantasies and desire resulting in significant distress or interpersonal difficulty. Women with this disorder may display a lack of motivation for sexual activity, reduced responsiveness to erotic cues, a loss of interest during sexual activity, and avoidance of situations that could lead to sexual activity. The pathophysiology of HSDD is thought to be centered around inhibitory and excitatory hormones, neurotransmitters, and specific brain anatomy. Due to the multifactorial nature of HSDD, treatment can be complex and must attempt to target the biological and psychosocial aspects of the disorder. Bremelanotide is a melanocortin receptor agonist and has been recently approved by the FDA to treat HSDD. Bremelanotide is administered intranasally or as a subcutaneous injection. The recommended dosage of bremelanotide is 1.75 mg injected subcutaneously in the abdomen or thigh at least 45 min before sexual activity. Studies showed improvements in desire, arousal, and orgasm scores when 1.75 mg of bremelanotide was administered before sexual activity compared to a placebo. Bremelanotide is a promising way to treat HSDD

Pharmacological Advances in Opioid Therapy: A Review of the Role of Oliceridine in Pain Management

Problems with the treatment of acute pain may arise when a patient is opioid-tolerant, such as those on chronic therapy with opioids or opiate replacement therapy, those who misuse opioids, and those who are in recovery. While some of the adverse effects of opioid medications are well known, it is also important to recognize the roles of tolerance and hyperalgesia. Oliceridine can target and modulate a novel μ-receptor pathway. The G protein-biased agonism of oliceridine allows for effective re-sensitization and desensitization of the mu-opioid receptor, which decreases the formation of opioid tolerance in patients. Oliceridine has been demonstrated to be an effective and relatively safe intravenous analgesic for the treatment of postoperative pain and is generally well tolerated with a favorable side effect profile when compared to morphine. As the prevalence of pain increases, it is becoming increasingly important to find safe and effective analgesics

Antipsychotic Polypharmacy-Related Cardiovascular Morbidity and Mortality: A Comprehensive Review

Schizophrenia is a psychotic disorder that exists at the more extreme end of a spectrum of diseases, and significantly affects daily functioning. Cardiovascular adverse effects of antipsychotic medications are well known, and include changes in blood pressure and arrhythmias. Sudden cardiac death is the leading cause of death worldwide, and antipsychotic medications are associated with numerous cardiac side effects. A possible link exists between antipsychotic medications and sudden cardiac death. Common prescribing patterns that may influence cardiovascular events include the use of multiple antipsychotics and/or additional drugs commonly prescribed to patients on antipsychotics. The results of this review reflect an association between antipsychotic drugs and increased risk of ventricular arrhythmias and sudden cardiac death by iatrogenic prolongation of the QTc interval. QTc prolongation and sudden cardiac death exist in patients taking antipsychotic monotherapy. The risk increases for the concomitant use of specific drugs that prolong the QTc interval, such as opioids, antibiotics, and illicit drugs. However, evidence suggests that QTc intervals may not adequately predict sudden cardiac death. In considering the findings of this narrative review, we conclude that it is unclear whether there is a precise association between antipsychotic polypharmacy and sudden cardiac death with QTc interval changes. The present narrative review warrants further research on this important potential association

Ozanimod to treat relapsing forms of multiple sclerosis: A comprehensive review of disease, drug efficacy and side effects

Multiple sclerosis (MS) is a prevalent and debilitating neurologic condition characterized by widespread neurodegeneration and the formation of focal demyelinating plaques in the central nervous system. Current therapeutic options are complex and attempt to manage acute relapse, modify disease, and manage symptoms. Such therapies often prove insufficient alone and highlight the need for more targeted MS treatments with reduced systemic side effect profiles. Ozanimod is a novel S1P (sphingosine-1-phosphate) receptor modulator used for the treatment of clinically isolated syndrome, relapsing–remitting, and secondary progressive forms of multiple sclerosis. It selectively modulates S1P1 and S1P5 receptors to prevent autoreactive lymphocytes from entering the CNS where they can promote nerve damage and inflammation. Ozanimod was approved by the US Food and Drug Administration (US FDA) for the management of multiple sclerosis in March 2020 and has been proved to be both effective and well tolerated. Of note, ozanimod is associated with the following complications: increased risk of infections, liver injury, fetal risk, increased blood pressure, respiratory effects, macular edema, and posterior reversible encephalopathy syndrome, among others. Further investigation including head-to-head clinical trials is warranted to evaluate the efficacy of ozanimod compared with other S1P1 receptor modulators