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Trazodone and Mirtazapine: A possible opioid involvement in their use (at low dose) for sleep?
Abstract
The efficacy of each antidepressant available has been found equal to that of amitriptyline in double-blind studies. However, a few of them are being prescribed (at under-therapeutic doses) for sleep, in non-depressed persons, when there are relative contraindications for sedative-hypnotics. Following previous studies regarding the antinociceptive mechanisms of various antidepressants, we suggest that the involvement of the opioid system in some of the antidepressants' mechanism of action may contribute to these medications' use for the induction and maintenance of sleep. The mostly prescribed antidepressants for sleep are trazodone (a weak, but specific inhibitor of the synaptosomal uptake of serotonin, that also binds to alpha-1 and alpha-2 adrenoreceptor sites) and mirtazapine (a postsynaptic drug which enhances noradrenergic and 5-HT1A-mediated serotonergic neurotransmission via antagonism of central alpha-2-auto- and hetero-adrenoreceptors). In our previous studies when ICR mice were tested with a hotplate analgesia meter, both trazodone and mirtazapine induced, a naloxone-reversible antinociceptive effect following i.p administration. Summing up the various interactions of trazodone and mirtazapine with opioid, noradrenergic and serotonergic agonists and antagonists, we found that the antinociceptive effect of trazodone is influenced by the opioid receptor subtypes mu and delta (and a clear 5-HT mechanism of antinociception), while the antinociceptive effect of mirtazapine is mainly influenced by kappa and mu opioid receptor subtype (combined with both serotonergic and noradrenergic receptors). This opioid profile of the two drugs may be one of the explanations to their efficacy in the treatment of insomnia, when sedatives (either benzodiazepines or the non-benzodiazepine "Z-compounds") cannot be prescribed.
... The drugs were prepared immediately before testing, and the requisite doses were given at a volume of 10 mL/kg. All agonists and antagonists were chosen according to our previous studies [67]. ...
... Mice were tested with the hotplate analgesic meter Model 35D (IITC Inc., Woodland Hills, CA, USA), as previously described [67]. The device basically consists of a metal plate (40 × 35 cm) heated to a constant temperature, on which a plastic cylinder was placed. ...
... As described in the original studies published [66][67][68][69][70][71][72][73][74], the results of the antidepressant drugs were divided into antidepressants with opioid interaction and antidepressants with no opioid interaction. For each drug, the study was conducted over three experiments. ...
About 30% of major depression disorder patients fail to achieve remission, hence being diagnosed with treatment-resistant major depression (TRD). Opium had been largely used effectively to treat depression for centuries, but when other medications were introduced, its use was discounted due to addiction and other hazards. In a series of previous studies, we evaluated the antinociceptive effects of eight antidepressant medications and their interaction with the opioid system. Mice were tested with a hotplate or tail-flick after being injected with different doses of mianserin, mirtazapine, trazodone, venlafaxine, reboxetine, moclobemide, fluoxetine, or fluvoxamine to determine the effect of each drug in eliciting antinociception. When naloxone inhibited the antinociceptive effect, we further examined the effect of the specific opioid antagonists of each antidepressant drug. Mianserin and mirtazapine (separately) induced dose-dependent antinociception, each one yielding a biphasic dose-response curve, and they were antagonized by naloxone. Trazodone and venlafaxine (separately) induced a dose-dependent antinociceptive effect, antagonized by naloxone. Reboxetine induced a weak antinociceptive effect with no significant opioid involvement, while moclobemide, fluoxetine, and fluvoxamine had no opioid-involved antinociceptive effects. Controlled clinical studies are needed to establish the efficacy of the augmentation of opiate antidepressants in persons with treatment-resistant depression and the optimal dosage of drugs prescribed.
... Trazodone has been demonstrated to exert antinociceptive effects even at low dosages, possibility via a µ-opioid receptors-mediated mechanism [123,124]. These properties may be helpful in manage the altered pain interoception of BPD patients-their "mental pain"-, as well as in treating their susceptibility to automedication with analgesics or substances. ...
Personality disorders (PD) are described as enduring patterns of markedly deviant and pervasive inner experiences and behaviors, with onset in adolescence, which lead to severe distress or impairment. Patients suffering from major depressive disorder (MDD) display higher rates of comorbidity with personality disorders, often complicating the treatment, and worsening the outcomes. Borderline personality disorder (BPD) is the most common of PD and is frequently associated with MDD, with which shares several features. The most part of research agrees on the fact that comorbid BPD in MDD patients quite doubles the poor response to treatments. Moreover, no treatment strategy stands out currently to emerge as more effective in these cases, thus urging the call for the need of new approaches. Herein, we revise the current literature on BPD, its neurobiology and comorbidity with MDD, as well as the more recent treatment strategies used. Then, based on its pharmacology, we propose a possible role of trazodone as a valuable tool to approach comorbid BPD-MDD.
... Trazodone has been demonstrated to exert antinociceptive effects even at low dosages, possibility via a µ-opioid receptors-mediated mechanism [118,119]. These properties may be helpful in manage the altered pain interoception of BPD patients-their "mental pain"-, as well as in treating their susceptibility to auto-medication with analgesics or substances. ...
Personality disorders (PD) are described as enduring patterns of markedly deviant and pervasive inner experiences and behaviors, with onset in adolescence, which lead to severe distress or impairment. Patients suffering with major depressive disorder (MDD) display higher rates of comorbidity with personality disorders, often complicating the treatment, and worsening the outcome. Borderline personality disorder (BPD) is the most common of PD and is frequently associated with MDD, with which shares several features. The most part of research agrees on the fact that comorbid BPD in MDD patients quite double the poor response to treatments. Moreover, no treatment strategy stands out currently to emerge as more effective in these cases, thus urging the call for the need of a new approach. Herein, we revise the current literature on BPD, its neurobiology and comorbidity with MDD, as well as the more recent treatment strategies used. Then, based on its pharmacology, we propose a possible role of trazodone as a valuable tool to approach underlying BPD in MDD
... Atypical antidepressants (mirtazapine, trazodone, bupropion and vortioxetine). Mirtazapine and trazodone are two atypical antidepressants that work on the serotonergic system [77,78]. Compared to all other antidepressants, mirtazapine seems to be associated with the highest incidence of weight gain (RR 1.5; 95% CI [1.45-1.56]) ...
Background
Depression and chronic pain are two major chronic non-communicable diseases (CNCD). Considering the bidirectional relationship between obesity and CNCD, it is of the utmost importance to understand the effect of medications utilized to treat these diseases on body weight.
Methods
This is a clinical review on the effect of medications for depression and chronic pain on body weight. We searched PubMed, Scopus, MEDLINE, and Google Scholar databases for studies on the topic from January 1, 1950 to April 1, 2022 in English language. Additionally, we present expert opinions in the fields of obesity, depression and chronic pain, providing a weight-centric approach to treat depression and chronic pain.
Results
Several antidepressant and chronic pain medications are associated with weight gain. Selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidases, mirtazapine and trazodone are common antidepressants that can increase body weight while bupropion is significantly associated with weight loss. Gabapentin and pregabalin are common chronic pain medications that are linked to weight gain. On the other hand, topiramate is associated with significant weight loss. Obesity, depression and chronic pain experts recommend avoiding medications that can increase body weight if another effective alternative is available.
Conclusion
By shifting prescribing practices toward a weight-conscious approach (i.e., switching from weight gain medications to weight loss/neutral), it is possible to mitigate the incidence of drug-induced weight gain.
... Cannabis mainly acts through CB 1 receptors [26]. While there is basic science support to the use of trazodone in opioid withdrawal syndrome [27], and a possible involvement of opioid receptors has been hypothesized in its hypnotic action [28], no interference with cannabinoid mechanisms has been described heretofore for trazodone; hence, we are unable to explain the anti-cannabinoid craving effect it showed in all three cases we here reported. However, a variety of drugs used to treat psychiatric disorders comorbid with substance use disorders have shown anti-craving effects [29][30][31], the mechanism of which is unknown. ...
(1) Background: During the SARS-CoV-2 (COVID-19) pandemic, cannabis use increased relative to pre-pandemic levels, while forced home confinement frequently caused sleep/wake cycle disruptions, psychological distress, and maladaptive coping strategies with the consequent appearance of anxiety symptoms and their potential impact on substance use problems. (2) Aim: Long-acting trazodone (150 mg or 300 mg daily) has a potential benefit as monotherapy in patients with cannabis use disorder. The present work aims to investigate the effectiveness of trazodone in optimizing the condition of people with cannabis dependence under pandemic conditions. (3) Methods: All cases with cannabis use disorder were uniformly treated with long-acting trazodone 150 mg or 300 mg/day; their craving and clinical status were monitored through appropriate psychometric scales. Side effects were recorded as they were reported by patients. We described the cases of three young patients—one man and two women—who were affected by chronic cannabis use disorder and who experienced lockdown-related psychological distress and sought psychiatric help. (4) Results: The described cases highlight that the once-a-day formulation of trazodone seems to have a therapeutic role in patients with cannabis use disorder and to guarantee tolerability and efficacy over time. No significant side effects emerged. (5) Conclusions: The use of long-acting trazodone (150 mg or 300 mg daily) has a potential benefit as monotherapy in patients with cannabis use disorder. Trazodone deserves to be studied in terms of its efficacy for cannabis use disorder.
... Atypical antidepressants (mirtazapine, trazodone, bupropion and vortioxetine). Mirtazapine and trazodone are two atypical antidepressants that work on the serotonergic system [77,78]. Compared to all other antidepressants, mirtazapine seems to be associated with the highest incidence of weight gain (RR 1.5; 95% CI [1.45-1.56]) ...
Background
This study aimed to describe the incidence and clinical presentation of fully vaccinated and unvaccinated patients who tested positive for COVID-19 in the first year after Madina Women’s Hospital in Alexandria, Egypt, resumed bariatric surgery procedures. (The clinic was closed between March 2020 and reopened in mid-October 2020)
Methods
This prospective cohort study was conducted between November 2020 till the end of December 2021. We identified patients undergoing bariatric surgery infected with COVID-19 with and without vaccination. COVID-19 severity was assessed based on the Egypt Ministry of Health guidelines. Some patients were isolated at home, whereas others were hospitalised.
Results
During the one year after the restart of bariatric surgery procedures, 606 patients underwent bariatric procedures (n = 280 fully vaccinated, n = 320 unvaccinated). During follow-up, that period, the incidence of COVID-19 in the vaccinated group was 1.07% (n = 3) versus 14.1% (n = 46) in the unvaccinated group.
Three patients had mild symptoms in the vaccinated group, and no hospital admission was necessary. In the unvaccinated group, 27 patients (60%) were classified as mild, eight (17.8%) as moderate, eight (17.8%) as moderate with risk, and two (4.4%) as severe; the mortality rate was 0%. Of these, 16 (88.9%) were hospitalised, of which six (33.3%) were admitted to the intensive care unit in the moderate to severe groups.
Conclusion
Patients with obesity are at increased risk for COVID-19 infection and adverse consequences. Our findings showed a higher incidence of COVID-19 among those unvaccinated versus vaccinated. Therefore, at least during times and locations of a COVID-19 pandemic, vaccinations may be beneficial for patients against COVID-19 prior to bariatric surgery.
... Особенность противоболевого эффекта миртазапина продемонстрирована в исследованиях Schreiber S, et al. Доказано воздействие миртазапина на опиоидную систему через μ-и κ-рецепторы [59,81]. В работах других авторов данные эффекты подтверждены блокадой антиноцицептивных эффектов миртазапина при применении налоксона [82,83]. ...
The article attempts to generalize the currently known pathogenetic mechanisms of antinociceptive effects of the most widely used antidepressants and to forecast their effectiveness in certain comorbid pathologies
Le nombre de patients douloureux chroniques avec des troubles du sommeil est élevé. Les données de la littérature suggèrent que les troubles du sommeil et la douleur sont liés. Cependant, des questions subsistent quant à la direction de la causalité de leur association, ainsi que les mécanismes qui peuvent expliquer cette association. Pour comprendre cette interrelation, il est primordial de prendre en compte le schéma dit biopsychosocial : trois dimensions fondamentales dans l’analyse des processus complexes et multidisciplinaires que sont la douleur et le sommeil. Cet article cite les résultats et observations des études scientifiques des dernières années sur ce thème ouvrant la réflexion d’une prise en charge multimodale inévitable chez ces patients comorbides.
Sleep deficiency is now considered an emerging global epidemic associated with many serious health problems, and a major cause of financial and social burdens. Sleep and mental health are closely connected, further exacerbating the negative impact of sleep deficiency on overall health and well-being. A major drawback of conventional treatments is the wide range of undesirable side-effects typically associated with benzodiazepines and antidepressants, which can be more debilitating than the initial disorder. It is therefore valuable to explore the efficiency of other remedies for complementarity and synergism with existing conventional treatments, leading to possible reduction in undesirable side-effects. This review explores the relevance of microalgae bioactives as a sustainable source of valuable phytochemicals that can contribute positively to mood and sleep disorders. Microalgae species producing these compounds are also catalogued, thus creating a useful reference of the state of the art for further exploration of this proposed approach. While we highlight possibilities awaiting investigation, we also identify the associated issues, including minimum dose for therapeutic effect, bioavailability, possible interactions with conventional treatments and the ability to cross the blood brain barrier. We conclude that physical and biological functionalization of microalgae bioactives can have potential in overcoming some of these challenges.
Niet-medicamenteuze interventies zijn bij slaapstoornissen van groot belang en vaak de primaire behandelstap. Toch wordt om diverse redenen frequent gekozen voor inzet van medicatie; bijvoorbeeld door onvoldoende effect van de gekozen interventies of de noodzaak zo snel mogelijk slaapverbetering te induceren. Dan is kennis over de werking van en evidentie voor het gebruiken van diverse middelen voor het verbeteren van slaap noodzakelijk. Geregistreerde slaapmiddelen, zoals benzodiazepinen, zijn effectief op de korte termijn, maar kennen aanzienlijke nadelen. Off-labelgebruik van diverse psychofarmaca, met als doel slaapverbetering, is voor een aantal middelen goed verdedigbaar gezien de effecten op de slaaparchitectuur, maar ook deze hebben alle hun eigen (bijwerkingen)profiel. De invloed op de rijvaardigheid moet standaard besproken worden. Indien langdurig gebruikte slaapmiddelen afgebouwd moeten worden, zijn belangrijke uitgangspunten dit langzaam te doen en intensief te begeleiden. De voorschrijver van psychiatrische medicatie dient zich verder bewust te zijn van slaapverstorende bijwerkingen van diverse psychofarmaca.
Abstract
Background
Although originally marketed as safe alternatives to the habit-forming benzodiazepines, growing numbers of zaleplon, zolpidem, and zopiclone (‘Z-drugs’) clinical concerns relating to their potential of abuse, dependence and withdrawal have been reported overtime. We aimed here at assessing these issues analysing datasets of Adverse Drug Reactions (ADR) provided by the European Medicines Agency (EMA) through the EudraVigilance (EV) system.
Methods
Analysing the ADR databases of each Z-drug, descriptive analyses have been performed on cases, and Proportional Reporting Ratios (PRRs) computed.
Results
An overall number of 33,240 (e.g. 23,420 zolpidem; 9,283 zopiclone; and 537 zaleplon) misuse/abuse/dependence/withdrawal-related ADRs, corresponding to some 6,246 unique patients given Z-drugs, were here identified. Cases were studied and described, including demographic characteristics and clinical data, such as concomitant drugs, doses, routes of administration, and outcomes of the reactions, being fatalities recorded. Considering PRR values, and in comparison with zopiclone, zolpidem was more frequently involved in both misuse/abuse and withdrawal issues. Zolpidem and zopiclone presented with the same dependence risk, but zopiclone was the most involved in overdose ADRs. If compared with zaleplon, zopiclone presented higher dependence and overdose-related issues, but slightly lower misuse/abuse and withdrawal PRR values.
Conclusion
Current data may only represent a gross underestimate of the Z-drugs’ misusing issues’ real prevalence. Caution should be exercised when prescribing those molecules, especially for patients with psychiatric illnesses and/or history of drug abuse. We recommend the need to invest in proactive pharmacovigilance activities to better and promptly detect, understand and prevent any possible misusing potential of prescribed medications.
Background:
Insomnia disorder is a subjective condition of unsatisfactory sleep (e.g. sleep onset, maintenance, early waking, impairment of daytime functioning). Insomnia disorder impairs quality of life and is associated with an increased risk of physical and mental health problems including anxiety, depression, drug and alcohol abuse, and increased health service use. hypnotic medications (e.g. benzodiazepines and 'Z' drugs) are licensed for sleep promotion, but can induce tolerance and dependence, although many people remain on long-term treatment. Antidepressant use for insomnia is widespread, but none is licensed for insomnia and the evidence for their efficacy is unclear. This use of unlicensed medications may be driven by concern over longer-term use of hypnotics and the limited availability of psychological treatments.
Objectives:
To assess the effectiveness, safety and tolerability of antidepressants for insomnia in adults.
Search methods:
This review incorporated the results of searches to July 2015 conducted on electronic bibliographic databases: the Cochrane Central Register of Controlled Trials (CENTRAL, 2015, Issue 6), MEDLINE (1950 to 2015), Embase (1980 to 2015) and PsycINFO (1806 to 2015). We updated the searches to December 2017, but these results have not yet been incorporated into the review.
Selection criteria:
Randomised controlled trials (RCTs) of adults (aged 18 years or older) with a primary diagnosis of insomnia and all participant types including people with comorbidities. Any antidepressant as monotherapy at any dose whether compared with placebo, other medications for insomnia (e.g. benzodiazepines and 'Z' drugs), a different antidepressant, waiting list control or treatment as usual.
Data collection and analysis:
Two review authors independently assessed trials for eligibility and extracted data using a data extraction form. A third review author resolved disagreements on inclusion or data extraction.
Main results:
The search identified 23 RCTs (2806 participants).Selective serotonin reuptake inhibitors (SSRIs) compared with placebo: three studies (135 participants) compared SSRIs with placebo. Combining results was not possible. Two paroxetine studies showed significant improvements in subjective sleep measures at six (60 participants, P = 0.03) and 12 weeks (27 participants, P < 0.001). There was no difference in the fluoxetine study (low quality evidence).There were either no adverse events or they were not reported (very low quality evidence).Tricyclic antidepressants (TCA) compared with placebo: six studies (812 participants) compared TCA with placebo; five used doxepin and one used trimipramine. We found no studies of amitriptyline. Four studies (518 participants) could be pooled, showing a moderate improvement in subjective sleep quality over placebo (standardised mean difference (SMD) -0.39, 95% confidence interval (CI) -0.56 to -0.21) (moderate quality evidence). Moderate quality evidence suggested that TCAs possibly improved sleep efficiency (mean difference (MD) 6.29 percentage points, 95% CI 3.17 to 9.41; 4 studies; 510 participants) and increased sleep time (MD 22.88 minutes, 95% CI 13.17 to 32.59; 4 studies; 510 participants). There may have been little or no impact on sleep latency (MD -4.27 minutes, 95% CI -9.01 to 0.48; 4 studies; 510 participants).There may have been little or no difference in adverse events between TCAs and placebo (risk ratio (RR) 1.02, 95% CI 0.86 to 1.21; 6 studies; 812 participants) (low quality evidence).'Other' antidepressants with placebo: eight studies compared other antidepressants with placebo (one used mianserin and seven used trazodone). Three studies (370 participants) of trazodone could be pooled, indicating a moderate improvement in subjective sleep outcomes over placebo (SMD -0.34, 95% CI -0.66 to -0.02). Two studies of trazodone measured polysomnography and found little or no difference in sleep efficiency (MD 1.38 percentage points, 95% CI -2.87 to 5.63; 169 participants) (low quality evidence).There was low quality evidence from two studies of more adverse effects with trazodone than placebo (i.e. morning grogginess, increased dry mouth and thirst).
Authors' conclusions:
We identified relatively few, mostly small studies with short-term follow-up and design limitations. The effects of SSRIs compared with placebo are uncertain with too few studies to draw clear conclusions. There may be a small improvement in sleep quality with short-term use of low-dose doxepin and trazodone compared with placebo. The tolerability and safety of antidepressants for insomnia is uncertain due to limited reporting of adverse events. There was no evidence for amitriptyline (despite common use in clinical practice) or for long-term antidepressant use for insomnia. High-quality trials of antidepressants for insomnia are needed.
Although the GABAergic benzodiazepines (BZDs) and Z-drugs (zolpidem, zopiclone, and zaleplon) are FDA-approved for insomnia disorders with a strong evidence base, they have many side effects, including cognitive impairment, tolerance, rebound insomnia upon discontinuation, car accidents/falls, abuse, and dependence liability. Consequently, the clinical use of off-label drugs and novel drugs that do not target the GABAergic system is increasing. The purpose of this review is to analyze the neurobiological and clinical evidence of pharmacological treatments of insomnia, excluding the BZDs and Z-drugs. We analyzed the melatonergic agonist drugs, agomelatine, prolongedrelease melatonin, ramelteon, and tasimelteon; the dual orexin receptor antagonist suvorexant; the modulators of the a2d subunit of voltage-sensitive calcium channels, gabapentin and pregabalin; the H1 antagonist, low-dose doxepin; and the histamine and serotonin receptor antagonists, amitriptyline, mirtazapine, trazodone, olanzapine, and quetiapine. The pharmacology and mechanism of action of these treatments and the evidence-base for the use of these drugs in clinical practice is outlined alongwith novel pipelines. There is evidence to recommend suvorexant and low-dose doxepin for sleep maintenance insomnia; there is also sufficient evidence to recommend ramelteon for sleep onset insomnia. Although there is limited evidence for the use of the quetiapine, trazodone, mirtazapine, amitriptyline, pregabalin, gabapentin, agomelatine, and olanzapine as treatments for insomnia disorder, these drugs may improve sleep while successfully treating comorbid disorders, with a different side effect profile than the BZDs and Z-drugs. The unique mechanism of action of each drug allows for a more personalized and targeted medical management of insomnia. © 2018 by The American Society for Pharmacology and Experimental Therapeutics.
Objective:
zolpidem, zopiclone, eszopiclone and zaleplon, also known as 'Z-drugs', are commonly used as alternatives to benzodiazepines (BZDs) to treat insomnia. Z-drugs are often perceived as safer than BZDs. We conducted a systematic review and meta-analysis evaluating the association between Z-drugs and fracutres, falls and injuries.
Methods:
a systematic review was performed using MEDLINE, EMBASE and ClinicalTials.gov. Pooled effect-sizes were calculated comparing Z-drugs users with non-users, using fixed and random-effect models with corresponding 95% confidence of intervals (CI).
Results:
we identified 14 eligible studies reporting on the association between Z-drugs and outcomes of interest. Z-Drugs were associated with a statistically significant increased risk for fractures, with evidence of considerable heterogeneity (OR = 1.63; 95% CI: 1.42-1.87; I2 = 90%; n = 830,877). Likewise, there was a trend suggesting a 2-fold increase in the odds for falls, however, this result was not statistically significant and there was evidence of considerable heterogeneity (OR = 2.40; 95% CI: 0.92-6.27; I2 = 95%; n = 19,505). In an analysis assessing the risk for injuries following exposure to zolpidem we found a statistically significant increased risk of injuries, with no evidence of heterogeneity (OR = 2.05; CI 95%: 1.95-2.15; I2 = 0; n = 160,502). Results were similar in sensitivity analyses, including analyses restricted to studies of high-quality, studies with control groups suffering from insomnia, and with specific Z-drugs.
Conclusion:
our results indicate that Z-drugs are associated with an increased risk for fractures, and suggest a possible increased risk for falls and injuries as well. However, studies included were observational and susceptible to confounding. Physicians should consider these potential risks before prescribing these medications in older adults.
The authors conducted a study in order to evaluate the antinociceptive effects of the serotonin-selective reuptake inhibitor (SSRI) antidepressant fluvoxamine and its interaction with various opioid receptor subtypes. Male ICR mice were tested with a hotplate analgesia meter. Fluvoxamine elicited antinociceptive effect in a dose-dependent manner following i.p., i.t. and i.c.v. injection. Naloxone 10 mg/kg s.c. did not abolish the fluvoxamine antinociceptive effect. At the next stage fluvoxamine was administered together with various agonists of opioid receptors. When administered together with opiates, fluvoxamine significantly potentiated analgesia at the Kj-opioid receptor subtype (P<.005) and to a lesser extent, at the μ-, δ-, and K1-opioid receptors. We conclude that fluvoxamine alone induces an antinociceptive effect. This effect is mediated by a non-opioid mechanism of action. These results suggest a potential role for fluvoxamine in the management of pain when co-administered with opioids at low doses.
Sleep disorders are common in the general population and even more so in clinical practice, yet are relatively poorly understood by doctors and other health care practitioners. These British Association for Psychopharmacology guidelines are designed to address this problem by providing an accessible up-to-date and evidence-based outline of the major issues, especially those relating to reliable diagnosis and appropriate treatment. A consensus meeting was held in London in May 2009. Those invited to attend included BAP members, representative clinicians with a strong interest in sleep disorders and recognized experts and advocates in the field, including a representative from mainland Europe and the USA. Presenters were asked to provide a review of the literature and identification of the standard of evidence in their area, with an emphasis on meta-analyses, systematic reviews and randomized controlled trials where available, plus updates on current clinical practice. Each presentation was followed by discussion, aimed to reach consensus where the evidence and/or clinical experience was considered adequate or otherwise to flag the area as a direction for future research. A draft of the proceedings was then circulated to all participants for comment. Key subsequent publications were added by the writer and speakers at draft stage. All comments were incorporated as far as possible in the final document, which represents the views of all participants although the authors take final responsibility for the document.
The antinociceptive effects of the selective noradrenaline reuptake inhibitor antidepressant reboxetine and its interaction with various opioid and noradrenaline receptor subtypes were evaluated. Reboxetine (i.p.) induced a weak dose-dependent antinociceptive effect in acute pain, using the hotplate model. The reboxetine-induced antinociception was significantly inhibited by the opioid receptor antagonists naloxone, nor-BNI, naltrindole and b-FNA, implying a non-selective role for the opioid receptors in the reboxetine's antinociceptive effect. The adrenergic antagonists yohimbine and phentolamine attenuated to some extent the reboxetine-induced antinociception, implying a minor adrenergic mechanism of antinociception. The addition of opioid or alpha2 agonists, did not potentiate the antinociception effect of reboxetine. Thus, it seems that reboxetine possesses a weak antinociceptive effect, mediated by non-selective opioid receptors and influenced somewhat by noradrenaline alpha2 receptors. These results suggest that reboxetine as monotherapy does not have sufficient efficacy in the management of acute pain. However, further research is needed in order to establish its possible use alone or in combination with other antidepressants or analgesics in the amelioration of chronic pain disorders.
To assess the association of insomnia with health-related quality of life (HRQOL), work productivity, and activity impairment.
Data were obtained from the 2005 US National Health and Wellness Survey. Subjects were assigned to the insomnia group (diagnosed insomnia experienced at least a few times a month) or the noninsomnia group (no insomnia or sleep symptoms). HRQOL was assessed using the short form 8 (SF-8) (mental and physical scores). The work productivity and activity impairment questionnaire (WPAI) assessed absenteeism (work time missed), presenteeism (impairment at work), work productivity loss (overall work impairment), and activity impairment. Linear regression models were used to control for potential confounders.
A total of 19,711 adults were evaluated (5,161 insomnia, 14,550 noninsomnia). Subjects in the insomnia group had significantly lower SF-8 physical (-5.40) and mental (-4.39) scores and greater activity impairment scores (+18.04) than subjects in the noninsomnia group (P < 0.01 for all). Employed subjects in the insomnia group had greater absenteeism (+6.27), presenteeism (+13.20), and work productivity loss (+10.33) scores than those in the noninsomnia group (P < 0.01 for all).
Insomnia is significantly associated with poorer physical and mental quality of life and work productivity loss and activity impairment.
The antinociceptive effects of the tetracyclic antidepressant mianserin and its interaction with various opioid receptor subtypes was evaluated. Mice were tested with a hotplate analgesia meter. Mianserin elicited an antinociceptive effect in a dose-dependent manner following doses from 1-25 mg/kg. As the mianserin dose increased beyond 30 mg/kg, latencies returned to baseline, yielding a biphasic effect. This effect of mianserin was antagonized by naloxone (P<0.005), implying a possible opioid mechanism of action involved in the mianserin induced antinociceptive effect. When administered with various opioid antagonists, the sensitivity of mianserin to selective opioid antagonists was found significant for mu and kappa1 opioid receptor subtypes (P<0.005), but not for delta-receptor. At the next stage mianserin was administered together with various agonists of opioid receptors. When administered together with opiates, mianserin significantly potentiates analgesia at the mu, kappa1 and kappa3 opioid receptor subtype (P<0.005) and to a lesser extent, at the delta opioid receptors. These results suggest a potential use of mianserin in the management of some pain syndromes. However, further research is needed in order to establish both the exact clinical indications and the effective doses of mianserin when prescribed for pain.
The antinociceptive effects of the novel phentylethylamine antidepressant drug venlafaxine and its interaction with various opioid, noradrenaline and serotonin receptor subtypes were evaluated. When mice were tested with a hotplate analgesia meter, venlafaxine induced a dose-dependent antinociceptive effect following i.p. administration with an ED50 of 46.7 mg/kg (20.5; 146.5; 95% CL). Opioid, adrenergic and serotoninergic receptor antagonists were tested for their ability to block venlafaxine antinociception. Venlafaxine-induced antinociception was significantly inhibited by naloxone, nor-BNI and naltrindole but not by beta-FNA or naloxonazine, implying involvement of kappa1- and delta-opioid mechanisms. When adrenergic and serotoninergic antagonists were used, yohimbine (P < 0.005) but not phentolamine or metergoline, decreased antinociception elicited by venlafaxine, implying a clear alpha2- and a minor alpha1-adrenergic mechanism of antinociception. When venlafaxine was administered together with various agonists of the opioid and alpha2- receptor subtypes, it significantly potentiated antinociception mediated by kappa1- kappa3- and delta-opioid receptor subtypes. The alpha2-adrenergic agonist clonidine significantly potentiated venlafaxine-mediated antinociception. Summing up these results, we conclude that the antinociceptive effect of venlafaxine is mainly influenced by the kappa- and delta-opioid receptor subtypes combined with the alpha2-adrenergic receptor. These results suggest a potential use of venlafaxine in the management of some pain syndromes. However, further research is needed in order to establish both the exact clinical indications and the effective doses of venlafaxine when prescribed for pain.
The antinociceptive effects of the noradrenergic and specific serotonergic antidepressant (NaSSA) drug mirtazapine and its interaction with various opioid receptor subtypes were evaluated in mice with a hotplate analgesicmeter. Mirtazapine elicited an antinociceptive effect in a dose-dependent manner following doses from 1 to 7.5mg/kg. As the mirtazapine dose increased beyond 10mg/kg latencies returned to baseline, yielding a biphasic dose-response curve. The effect of opioid, adrenergic, and serotonergic receptor antagonists was examined as to their ability to block mirtazapine antinociception. Mirtazapine (at 10mg/kg)-induced antinociception was significantly inhibited by naloxone, nor-BNI, and naltrindole, but neither by beta-FNA nor by naloxonazine, implying the involvement of kappa(1)- and delta-opioid mechanisms. When adrenergic and serotonergic antagonists were used, both metergoline and yohimbine, decreased antinociception elicited by mirtazapine, implying a combined serotonergic and noradrenergic mechanism of antinociception. When mirtazapine was administered together with various agonists of the opioid receptor subtypes, it significantly potentiated antinociception mediated only by kappa(3)-opioid receptor subtypes. Summing up these results we conclude that the antinociceptive effect of mirtazapine is mainly influenced by the kappa(3)-opioid receptor subtype combined with both serotonergic and noradrenergic receptors. These results suggest a potential use of mirtazapine in the management of some pain syndromes, and raise questions regarding a possible indirect opioid-dependence induced by mirtazapine. However, further research is needed in order to establish both the exact clinical indications and the effective doses of mirtazapine when prescribed for pain.
Zolpidem and zopiclone are two of a newer hypno-sedative class of drugs, the "Z compounds". Their use for the treatment of short-term insomnia has been expanding constantly during the last two decades. The "Z compounds" are considered to cause less significant rebound insomnia or tolerance than the conventional hypnotic benzodiazepines. Their possible antinociceptive effect and interaction with the opioid system has not been studied yet. Our results demonstrate a significant difference between the antinociceptive properties of zopiclone and zolpidem when injected s.c. in the hotplate analgesic assay in mice. Zopiclone induced a weak, dose-dependent antinociceptive effect, antagonized only by the alpha2-adrenergic receptor antagonist yohimbine. Zolpidem induced a weak, biphasic dose-dependent antinociceptive effect, antagonized primarily by the non-selective opioid antagonist naloxone and by yohimbine. The weak antinociceptive effect of both drugs, evident only at very high doses (far beyond those used clinically to induce sleep), implies no clinical use for zopiclone or zolpidem in the management of pain. However, the possible interaction of zolpidem with the opioid system should be further investigated (in behavioral models, which do not overlap with the acute-pain antinociception model we used), both for possible side effects in special populations (i.e. elderly) and for possible drug-drug interactions, in order to minimize possible hazards and maximize clinical beneficial effects of its use for sleep.
This article introduces a special issue of Current Pharmaceutical Design focusing on the various side effects of benzodiazepine medications. We argue that an increased awareness of the risk of dependence, withdrawal symptoms upon discontinuation, and cognitive side effects of the benzodiazepines has likely contributed to the decline in their prescription rate over the last two decades, as has increased availability of alternative pharmacologic and non-pharmacologic treatments for anxiety and insomnia. The present special issue consists of series of five papers covering current issues in the area of benzodiazepine side effects. These reviews cover a wide range of topics pertaining to adverse, unintended consequences of this class of pharmacologic agents including their potential for tolerance and withdrawal, their profile of associated cognitive impairments, as well as current understanding of means for minimizing these unintended effects. The reviews also cover a variety of methodologies and disciplines from laboratory-based research findings with animals, to laboratory-based studies with healthy human volunteers, to findings obtained in the clinic with anxious patients. All reviews are timely contributions, covering highly relevant topics for consideration of benzodiazepine side effects at present. The papers presented herein should serve to stimulate future research that may ultimately help improve the quality of life of those patients living with debilitating anxiety-related conditions.
Background: Benzodiazepine misuse is a growing public health problem, with increases in benzodiazepine-related overdose deaths and emergency room visits in recent years. However, relatively little attention has been paid to this emergent problem. We systematically reviewed epidemiological studies on benzodiazepine misuse to identify key findings, limitations, and future directions for research.
Methods: PubMed and PsychINFO databases were searched through February 2019 for peer-reviewed publications on benzodiazepine misuse (e.g., use without a prescription; at a higher frequency or dose than prescribed). Eligibility criteria included human studies that focused on the prevalence, trends, correlates, motives, patterns, sources, and consequences of benzodiazepine misuse.
Results: The search identified 1,970 publications, and 351 articles were eligible for data extraction and inclusion. In 2017, benzodiazepines and other tranquilizers were the third most commonly used illicit or prescription drug in the U.S. (approximately 2.2% of the population). Worldwide rates of misuse appear to be similar to those reported in the U.S. Factors associated with misuse include other substance use, receipt of a benzodiazepine prescription, and psychiatric symptoms and disorders. Benzodiazepine misuse encompasses heterogeneous presentations of motives, patterns, and sources. Moreover, misuse is associated with myriad poor outcomes, including mortality, HIV/HCV risk behaviors, poor self-reported quality of life, criminality, and continued substance use during treatment.
Conclusions: Benzodiazepine misuse is a worldwide public health concern that is associated with a number of concerning consequences. Findings from the present review have implications for identifying subgroups who could benefit from prevention and treatment efforts, critical points for intervention, and treatment targets.
The novel antidepressant mirtazapine has a dual mode of action. It is a noradrenergic and specific serotonergic antidepressant (NaSSA) that acts by antagonizing the adrenergic α2-autoreceptors and α2-heteroreceptors as well as by blocking 5-HT2 and 5-HT3 receptors. It enhances, therefore, the release of norepinephrine and 5-HT1A-mediated serotonergic transmission. This dual mode of action may conceivably be responsible for mirtazapine's rapid onset of action. Mirtazapine is extensively metabolized in the liver. The cytochrome (CYP) P450 isoenzymes CYP1A2, CYP2D6, and CYP3A4 are mainly responsible for its metabolism. Using once daily dosing, steady-state concentrations are reached after 4 days in adults and 6 days in the elderly. In vitro studies suggest that mirtazapine is unlikely to cause clinically significant drug-drug interactions. Dry mouth, sedation, and increases in appetite and body weight are the most common adverse effects. In contrast to selective serotonin reuptake inhibitors (SSRIs), mirtazapine has no sexual side effects. The antidepressant efficacy of mirtazapine was established in several placebo-controlled trials. In major depression, its efficacy is comparable to that of amitriptyline, clomipramine, doxepin, fluoxetine, paroxetine, citalopram, or venlafaxine. Mirtazapine also appears to be useful in patients suffering from depression comorbid with anxiety symptoms and sleep disturbance. It seems to be safe and effective during long-term use.
The antinociceptive effects of trazodone (a triazolopyridine derivative with antidepressant activity) and its interaction with various opioid, noradrenaline and serotonin receptor subtypes were evaluated. Mice were tested with a hotplate analgesia meter. Trazodone induced a dose-dependent antinociceptive effect following i.p. administration. The ED50 for mice in the hotplate assay for trazodone was 24.8 mg/kg (9.8; 67.4; 95% CL). The effect of opioid, adrenergic and serotonergic receptor antagonists was examined as to their ability to block trazodone antinociception. Trazodone-induced antinociception was significantly inhibited by naloxone, β-FNA and naloxonazine, but not by nor-BNI or naltrindole, implying involvement of μ1- and μ2-opioid mechanisms. When adrenergic and serotonergic antagonists were used, metergoline (p
Despite their improved pharmacokinetic profile, the Z-drugs, zolpidem, zopiclone, and zaleplon, have a spectrum of adverse effects comparable to benzodiazepines. This review focuses on the impairment from Z-drugs on cognition, behavior, psychomotor performance, and driving ability. Z-drugs are short-acting GABA agonists that reduce sleep latency without disturbing sleep architecture. Bizarre behavioral effects have prompted warnings on the prescription, dispensation, and use of Z-drugs. Psychomotor impairment, falls, and hip fractures are more likely to occur with Z-drugs that have longer half-lives, that are taken at higher-than-recommended doses and when mixed with other psychoactive substances including alcohol. Zopiclone and higher doses of zolpidem are more likely to cause anterograde amnesia than zaleplon. Z-drugs, especially zolpidem, are associated with complex behaviors such as sleepwalking, sleep-driving, and hallucinations. Patients taking zopiclone and zolpidem have an increased risk of motor vehicle collisions, over double that of unexposed drivers. Driving impairment occurs with zopiclone and higher doses of zolpidem but is unlikely to occur after 4 h post-zaleplon administration. The residual effect of Z-drugs on next-day cognitive and psychomotor performance has significant impact on lifestyle, safety, and occupational considerations, including motor vehicle and machine operation. The risk-benefit analysis of Z-drugs in the treatment of insomnia, particularly in the elderly, may not favor treatment due to the increased risks of falls and motor vehicle collisions. Prescribers should warn patients taking Z-drugs of minimum time thresholds before they operate machinery or drive motor vehicles.
The opioid receptor binding in the human thalamic area was studied with U-69593 and naloxone as ligands for the kappa and mu receptors, respectively. The binding was inhibited by various tricyclic antidepressants including amitriptyline, nortriptyline, clomipramine and fluoxetine. The antidepressants tested had a slight selectivity for the kappa receptor type. The IC50-values for all tricyclic antidepressants tested were in the 10-6 M concentration range. Morphine and tricyclic antidepressants are substrates of a liver microsomal uridine diphosphate glucuronyl transferase (UDPGT). The interaction of the tricyclic antidepressants with morphine glucuronidation was investigated in human liver microsomal preparations. All drugs inhibited the morphine UDPGT. In Dixon plots inhibition of the formation of morphine-3-glucuronide and morphine-6-glucuronide was non-competitive for nortriptyline, and competitive or mixed for amitriptyline and clomipramine. Lubrol PX activated the morphine-UDPGT four to five times. The degree of activation of the enzyme(s) was unaltered in presence of the inhibiting drugs. The inhibition was also observed at a tricyclic antidepressant/morphine concentration ratio close to that achieved in plasma from patients treated with these drugs.
Withdrawal of benzodiazepines is currently advised for long-term benzodiazepine users because of doubts about continued efficacy, risks of adverse effects, including dependence and neuropsychological impairment and socio-economic costs. About half a million people in the UK may need advice on withdrawal. Successful withdrawal strategies should combine gradual dosage reduction and psychological support. The benzodiazepine dosage should be tapered at an individually titrated rate which should usually be under the patient's control. The whole process may take weeks or months. Withdrawal from diazepam is convenient because of available dosage strengths, but can be carried out directly from other benzodiazepines. Adjuvant medication may occasionally be required (antidepressants, propranolol) but no drugs have been proved to be of general utility in alleviating withdrawal-related symptoms. Psychological support should be available both during dosage reduction and for some months after cessation of drug use. Such support should include the provision of information about benzodiazepines, general encouragement, and measures to reduce anxiety and promote the learning of non-pharmacological ways of coping with stress. For many patients the degree of support required is minimal; a minority may need counselling or formal psychological therapy. Unwilling patients should not be forced to withdraw. With these methods, success rates of withdrawal are high and are unaffected by duration of usage, dosage or type of benzodiazepine, rate of withdrawal, symptom severity, psychiatric history or personality disorder. Longer-term outcome is less clear; a considerable proportion of patients may temporarily take benzodiazepines again and some need other psychotropic medication. However, the outcome may be improved by careful pharmacological and psychological handling of withdrawal and post-withdrawal phases.
Trazodone is an antidepressant drug with well established clinical efficacy in the treatment of depressive disorders, in addition to a marked anxiolytic activity. In contrast to tricyclic, and certain other antidepressant drugs, trazodone has been shown to have no effects on noradrenaline (NA) reuptake mechanisms. Whereas trazodone is a weak inhibitor of the in vitro uptake of [3H]-5-hydroxy-tryptamine (5-HT) into rat occipital cortex synaptosomes, a potent effect shown by this compound is the in vivo occupation of serotonergic [3H]-spiperone binding sites in the mouse frontal cortex; an activity shared by putative 5-HT antagonists and several other antidepressant drugs. The 5-HT antagonist activity of trazodone has been behaviourally verified by the antagonism of the serotonergic head-twitch response elicited by the 5-HT agonist, MK, 212, in mice. Trazodone also interacts with alpha-noradrenergic receptors as assessed by in vitro receptor binding experiments with the radioligands [3H]-WB 4101 and [3H]-dihydroergocryptine (DHE). Ex vivo experiments indicate that, after oral administration to rats, trazodone occupies cortical alpha2 receptor sites, but with a lower potency than either mianserin or yohimbine. Experiments with superfused rat occipital cortex mini-slices have shown that trazodone can enhance the potassium stimulated and spontaneous efflux of preloaded [3H]-NA. The combination of alpha2 antagonism and NA releasing properties, in the absence of reuptake inhibition, may be associated with the antidepressant activity of this drug, whereas the potent 5-HT antagonist activity may explain the anxiolytic effects. Finally, trazodone has been found to be devoid of muscarinie receptor affinity as measured by [3H]-quinuclidinyl benzilate (QNB) radioreceptor assays in accord with clinical observation of the absence of anticholinergic side-effects.
Multifunctional drugs are those with more than one therapeutic mechanism. Trazodone is a multifunctional drug with dose-dependent pharmacologic actions. That is, it has hypnotic actions at low doses due to blockade of 5-HT 2A receptors, as well as H 1 histamine receptors and α1 adrenergic receptors. Higher doses recruit the blockade of the serotonin transporter (SERT) and turn trazodone into an antidepressant. Although trazodone has traditionally been used as a low dose hypnotic, a new controlled release formulation that has the potential to improve the tolerability of high doses may provide an opportunity to revisit this multifunctional drug as an antidepressant as well.
Primary care physicians often do not document a psychiatric diagnosis when prescribing psychotropic medications. Recent literature suggests the potential benefit of tricyclic antidepressants (TCAs) in a number of nonpsychiatric conditions (low back pain, peptic disease, fibrositis, headache, peripheral neuropathy, rheumatoid disease, and irritable colon).
Data from the 1985 National Ambulatory Medical Care Survey (NAMCS) were used to categorize the primary diagnoses given during office visits in which tricyclic antidepressants were prescribed. Comparisons were made across specialties.
Primary care physicians prescribed tricyclic antidepressants in 1% of all visits (an estimated 2,892,000 visits per year). Whereas 50% of these visits at which TCAs were prescribed were for documented psychiatric illnesses or conditions, 15% were for nonpsychiatric TCA-responsive conditions. The majority of visits by patients with these disorders were to primary care physicians. The pattern of TCA prescribing for these disorders by primary care physicians parallels that of other medical specialties except that primary care physicians prescribed TCAs for nonpsychiatric TCA-responsive disorders less frequently than did other medical specialists.
When nonpsychiatric TCA-responsive disorders are included, primary care physicians document with appropriate diagnoses 15% more of their TCA prescriptions than previous studies have indicated. An understanding of the 35% of TCA prescriptions that do not show proper documentation will require further study and information not available from the NAMCS:
The analgesic effect of acute or chronic nortriptyline, amitriptyline and their effects on morphine induced analgesia were evaluated in the rat. Clomipramine and amitriptyline, but not Nortriptyline, induce analgesia, while all potentiate the effect of morphine when administered acutely. The analgesic effect of clomipramine is blunted by both the serotonin antagonist metergoline and the opiate receptor blocker naloxone, thus indicating an involvement of both the serotoninergic and endogenous opioid system. The involvement of the serotoninergic system is confirmed by the similar results obtained with the serotonin precursor 5-hydroxytryptophan administered alone or together with morphine. A relation between the serotoninergic and the endogenous opioid systems is also shown by the increase in hypothalamic beta-endorphin concentrations elicited by all the drugs used after acute or chronic treatment, with the only exception of nortriptyline, that has been shown to exert its effects mainly through the noradrenergic system. In conclusion, the analgesic effect of clomipramine and amitriptyline and their potentiation of morphine induced analgesia seems to be related to an activation of the endogenous opioid system mediated by serotonin.
Serotonin can induce analgesia when injected directly into the brain, but analgesia after peripheral administration has been more difficult to show. The pentobarbital anesthetized mouse (PAM) model, developed to alleviate some of the problems involved in the measurement of tail flick latency, was used to assess the action of peripherally administered serotonin. Mice were anesthetized with about 65 mg/kg of sodium pentobarbital IP and their tail flick latencies measured while they were in stage III anesthesia. In these anesthetized mice, IP serotonin induced a significant analgesia that was much more robust than that found in awake mice. The analgesic effect was dose-dependent from 0.25 mg/kg to 10 mg/kg but was not blocked by the antiopiate naltrexone. Of several psychotropic agents tested, only amitriptyline, mianserin, and trazodone had significant effects on analgesia in the PAM model. The analgesic effect of serotonin was reproduced by the 5HT2 agonist DOI and totally blocked by the 5HT2 antagonist NPP. These results show the utility of the PAM model in studying nonopiate analgesia and suggest that the analgesic action of serotonin is mediated primarily through the 5HT2 receptor.
Trycyclic antidepressants are often effective in the management of neuropathic pains. To elucidate the mechanism of tricyclic-induced analgesia, amitriptyline and other drugs were injected into lightly anesthetized rats either systemically or via lumbar intrathecal cannulas. Analgesia was assessed by measuring the latency of the tail flick reflex. Using this model, intrathecal amitriptyline (30 micrograms) significantly enhanced the analgesic effect of an intraperitoneal dose of morphine (0.5 mg/kg) that by itself produced no measurable effect. Given systemically, amitriptyline (30 or 100 micrograms intraperitoneally) was ineffective. Cocaine (30 micrograms) also potentiated morphine analgesia, but iprindole, a tricyclic antidepressant with a very weak inhibitory effect on monoamine uptake, was ineffective. This enhancement of analgesia by intrathecal amitriptyline was prevented by pretreating the rats with p-chlorophenylalanine (300 mg/kg). These results are consistent with the hypothesis that amitriptyline produces analgesia by blocking serotonin uptake and therefore enhancing the action of serotonin at the spinal terminals of an opioid-mediated intrinsic analgesia system.
Amitriptyline (median effective dose [ED50] 1.2 mg per kilogram of body weight), imipramine (ED50 2.3 mg/kg), and their demethylated derivatives nortriptyline (ED50 1.9 mg/kg) and desimipramine (ED50 3.2 mg/kg) are active analgesics as indicated by the mouse writhing assay. Although not as potent as morphine (ED50 0.2 mg/kg), the antidepressants were up to 70 times more potent than aspirin (ED50 91 mg/kg). The actions of amitriptyline were not affected by the specific opiate antagonist naloxone but were markedly attenuated in animals whose monoamine levels had been depleted with reserpine. Central mechanisms appear important since amitriptyline (ED50 4.6 micrograms) was potent when administered intracerebroventricularly.
Trazodone is a triazolopyridine derivative with antidepressant activity, that is chemically unrelated to other currently available antidepressants. Its pharmacological properties differ from those of most other antidepressants. Trazodone exhibits antiserotonin activity in animal studies, but its mechanism of action in depressive illness in humans is not clear. It has an overall therapeutic efficacy comparable with imipramine and amitriptyline in depressive illness but, at dosages which have achieved a similar overall clinical improvement, trazodone causes fewer anticholinergic side effects than the tricyclic antidepressants. Trazodone appears also to have activity against the concomitant anxiety in depressed patients and in limited studies was comparable with diazepam and chlordiazepoxide in anxiety neurosis. Trazodone has been reported to be of value in tremors and chronic alcoholism. Studies in animals, limited human studies and the low incidence of cardiovascular side effects in controlled therapeutic trials, suggest that trazodone is less likely than imipramine to cause cardiotoxicity at therapeutic doses, but the effects of overdosage are not known at present. Trazodone appears to be well tolerated by the elderly, seldom aggravates psychotic symptoms and does not produce neurological side effects.
Mirtazapine (Org 3770) is a new antidepressant with prominent alpha 2-adrenergic auto- and heteroreceptor antagonistic properties and no effect on monoamine reuptake. Mirtazapine increases noradrenergic and serotonergic transmission, as measured by on-line microdialysis and by enhancement of noradrenergic locus ceruleus and serotonergic raphe nucleus cell firing. Mirtazapine has a low affinity for 5-HT1A receptors but shows 5-HT1A-agonistic-like effects in a conditioned taste aversion test and by causing lower lip retraction in rats. Mirtazapine therefore causes enhancement of 5-HT1-mediated transmission. Other studies show that both 5-HT2 and 5-HT3 receptors are specifically blocked. The enhancement of both noradrenergic and serotonergic transmission probably underlies the therapeutic activity of mirtazapine. Blockade of 5-HT2 and 5-HT3 receptors possibly prevents side effects associated with nonselective 5-HT activation and may also contribute to the anxiolytic and sleep-improving properties of mirtazapine.
This paper presents the results of a survey carried out to investigate the benzodiazepine (BZD) prescribing patterns of the general practitioners (GP) in the catchment area of a Drug Dependence Unit located in a general hospital in Mataro (Barcelona, Spain). The aims of the survey were: (i) to obtain descriptive information on the knowledge of the GPs about BZD and its potential for dependence; (ii) to study the frequency of their prescribing; and (iii) to examine different factors linked to their prescribing. The study was carried out using a combination of a personal interview and a self-administered questionnaire. A total of 68 doctors (88.3%) completed the questionnaire. The results show that the GPs have, in general, correct knowledge about the therapeutic indications for BZD prescribing, but are far less aware of their potential to induce dependence and how to manage withdrawal. The rate of prescribing seems to be high. Furthermore, the results of the external check of validity point out that doctors tend to underestimate the number of prescriptions. The majority of GPs express the need for alternative resources to BZD prescribing. No significant associations have been found between doctor's characteristics, such as postgraduate training and type of practice, and their knowledge about BZD and frequency of their prescribing. In our view, a more accurate knowledge about BZD and alternatives to its use, both factors closely linked to training, together with the availability of non-pharmacological resources, are likely to improve the quality of doctors prescribing habits, thus preventing risks such as dependence of BZD.
This study was designed to investigate the antinociceptive effects of one of the most prescribed benzodiazepines (BZ) -i.e., alprazolam. Groups of CD-1, SWISS, BALB/c and C57BL mice were treated with alprazolam. Analgesia was assayed, using the radiant heat tailflick assay. Alprazolam given i.p. elicited analgesia in a dose-dependent manner only in the BALB/c mice (ED50 1.1 mg/kg). No analgesia was observed in CD-1 or C57BL mice. The sensitivity of SWISS mice was intermediate, but still very low. Intrathecally administered alprazolam elicited analgesia in BALB/c, Swiss and CD-1 mice with ED50 values of 10, 22.8 and 34.6 micrograms, respectively. No analgesia was observed in C57BL mice. Intracerebroventricular injections did not induce analgesia in any of the strains. In other sets of experiments with BALB/c mice, we found a supra-additivity increase in analgesia when a subthreshold dose of alprazolam was given with morphine (mu-subtype agonist). This interaction was antagonized by naloxone and less so by flumazenil. No effect was found when alprazolam was co-administered with other specific opioid agonists (delta and kappa). Our results demonstrate that injections of alprazolam can produce analgesia in different genetic subjects and can modify morphine-induced antinociception. The fact that the interaction between morphine and alprazolam analgesia was sensitive to naloxone but less to flumazenil indicates that the analgesic effects of alprazolam are mediated primarily by an opioid mechanism of action but less by benzodiazepines.
The alpha(2)-adrenoreceptor antagonist mirtazapine, which is also a 5-HT(2), 5-HT(3) and H(1) receptors antagonist and the selective serotonin (5-HT) reuptake inhibitor paroxetine are effective antidepressant drugs which enhance 5-HT neurotransmission via different mechanisms. The present studies were undertaken to determine whether the mirtazapine-paroxetine combination could induce an earlier and/or a greater effect on the 5-HT system than either drug alone. Using in vivo electrophysiological paradigms, the firing activity of dorsal raphe 5-HT neurons was decreased by 70% in rats treated with paroxetine (10 mg/kg/day, s.c.) for 2 days and was back to normal after 21 days. In contrast, a 2-day treatment with mirtazapine (5 mg/kg/day, s.c.) did not alter the firing of 5-HT neurons whereas it was increased by 60% after 21 days of treatment. A low dose of mirtazapine (5 mg/kg/day, s.c.x2 days) failed to offset the decremental effect of paroxetine on the 5-HT neuron firing activity, but a higher dose (10 mg/kg/day, s.c.x2 days) did attenuate the decremental effect of paroxetine. In the dorsal hippocampus, neither mirtazapine (5 mg/kg/day, s.c.) nor a paroxetine (10 mg/kg/day, s.c.) treatment altered the responsiveness of 5-HT(1A) receptors to microiontophoretically-applied 5-HT. Both in controls and in rats treated for 2 days with paroxetine alone, the administration of the 5-HT(1A) antagonist WAY 100635 (25-100 microg/kg, i.v.) did not change the firing activity of dorsal hippocampus CA(3) pyramidal neurons. However, WAY 100635 increased significantly the firing activity of these neurons in rats treated with mirtazapine alone but to a greater extent with both mirtazapine and paroxetine for 2 days. After 21 days of treatment, WAY 100635 increased to a greater degree the firing rate of CA(3) pyramidal neurons in rats which received the combination over rats given either drug alone. It is concluded that the mirtazapine-paroxetine combination shortened the delay in enhancing the tonic activation of postsynaptic 5-HT(1A) receptors and produced a greater activation of the postsynaptic 5-HT(1A) receptors than either drug given alone. The present results suggested that mirtazapine may have a faster onset of action than a SSRI, and that the co-administration of mirtazapine and paroxetine may accelerate the antidepressant response and as well as being more effective than either drug alone.
Hypnotics are commonly used by older adults, yet little is known about the patterns of their use and effectiveness in this population.
Three thousand eight hundred sixty anonymous, self-report surveys were distributed to community pharmacies (n=356) across Canada to obtain information on the patterns of use of hypnotics from elderly volunteers.
The mean age of respondents was 72+/-7 years (range 60 to 95 years) and 66% were women. In the past year, 53% of respondents used hypnotics. Prescription products accounted for 83% of the past year's use (66% benzodiazepines, 11% zopiclone, 4% antidepressants, 2% opioids), and 17% of the products used were over-the-counter (5% herbal, 5% antihistamines, 3% analgesics). Use was regular (50% daily) and chronic (mean duration six years: range two weeks to 30 years). Hypnotics significantly (P<0.001) improved subjective sleep latency (mean 32 min compared with 93 min), number of nocturnal awakenings (mean two compared with four) and total hours of sleep (mean 7 h compared with 4 h). Effectiveness was highly rated: at the most recent use of the product, mean 7.6 (SD+/-2.2) of 10; initially, 7.9 (SD+/-2.3) with a significance of P=0.02. Most respondents (59%) reported side effects, mainly dry mouth (30%), memory problems (22%) and daytime sleepiness (22%), although 60% rated the side effects as mild. The mean number of other medications used was five (range zero to 17). Of the 54 subjects who used nonprescription sleep products, only half (52%) indicated that their physician was aware of this use.
Prescription drugs were primarily used for sleep and were perceived to be effective even with long term use, despite mild side effects.
Insomnia is a common problem that for many sufferers persists chronically and may result from a wide range of causes. Specific treatments address particular underlying medical disorders. General therapeutic approaches, including pharmacologic and behavioral strategies, may have broad applicability to insomnia patients. Many different medications and substances have been used in an attempt to improve sleep. This article reviews the advantages and disadvantages of medications and other substances employed to promote improved sleep. Special emphasis is given to the use of the newer-generation benzodiazepine receptor agonist hypnotics.
Most Serotonin Selective Reuptake Inhibitors (SSRIs) have been found to possess secondary binding properties, while citalopram and its S-enantiomer (escitalopram) have been reconfirmed "purest SSRIs". Using the mouse model of acute pain hotplate analgesia meter, we evaluated the antinociceptive properties of fluoxetine, fluvoxamine, citalopram and escitalopram, injected i.p. Fluvoxamine induced a dose-dependent clear antinociceptive effect (with an ED(50) value of 6.4 mg/kg). Both fluoxetine and citalopram induced (separately) only a weak antinociceptive effect with an inverse "U" shape curve. All three drug's effects were not abolished by naloxone. Escitalopram did not elicit any effect at quasi-equipotent doses. These findings show that fluoxetine, fluvoxamine and citalopram given i.p. are weak antinociceptors, (not mediated through opioid mechanisms), while escitalopram possesses no antinociceptive properties when injected i.p. This difference between citalopram and escitalopram calls for further studies in order to assess the various differences between the two enantiomers of citalopram, and between each enantiomer and the racemic mixture.
New clinical drug evaluation unit meeting symposium
- Mendelson
Intrathecal morphine in mice: a new technique
- Hylden
The effects of the synthetic cannabinoid AB-FUBINACA on body temperature, nociceptive threshold, locomotor parameters and anxiety in mice
- Schreiber
The use of fluoxetine for chronic pain management: a six weeks comparison study with amitriptyline
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The analgesic effect of tricyclic antidepressants
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The antinociceptive effect of moclobemide in mice is mediated by noradrenergic pathways
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