What is the role of histamine in sleep regulation. How does low dose doxepin work as a selective H1 receptor antagonist. Why is doxepin considered a unique and rational treatment option for insomnia in adults and the elderly.

Understanding Insomnia: Prevalence, Classification, and Impact

Insomnia is a widespread sleep disorder affecting over 25% of the adult population, with approximately 10% experiencing associated daytime impairment. Studies have shown a high rate of comorbidity between chronic insomnia and various medical, cardiovascular, and psychiatric disorders.

Insomnia Classification

Insomnia can be classified based on duration:

• Transient insomnia: Lasting up to 7 days
• Short-term insomnia: Lasting less than 3 weeks
• Chronic insomnia: Lasting more than 3 weeks, sometimes exceeding 30 days

Alternatively, insomnia can be categorized based on etiology:

• Primary insomnia: Occurring without specific physical or mental conditions
• Secondary insomnia: Associated with other medical and psychiatric illnesses, medications, or sleep disorders

The International Classification of Sleep Disorders (ICSD) further categorizes insomnia into adjustment insomnia, behavioral insomnia of childhood, idiopathic insomnia, paradoxical insomnia, psychophysiological insomnia, inadequate sleep hygiene, and insomnia due to drugs, substances, medical conditions, or mental disorders.

The Role of Histamine in Sleep Regulation

Histamine plays a crucial role in regulating the sleep-wake cycle as an excitatory neurotransmitter in the central nervous system. The stimulation of H1 receptors is thought to mediate arousal, making histamine a key target for insomnia treatment.

Histamine and Sleep-Wake Cycle

How does histamine influence the sleep-wake cycle? Histamine acts as a wake-promoting neurotransmitter, increasing alertness and arousal when its levels are high. Conversely, a decrease in histamine activity promotes sleep onset and maintenance. This balance is essential for maintaining a healthy sleep-wake rhythm.

Doxepin: A Unique Approach to Insomnia Treatment

Doxepin, an antidepressant with sleep-promoting effects, offers a distinctive mechanism of action in treating insomnia. Unlike traditional sedatives, doxepin promotes sleep through resynchronization of the circadian cycle rather than through sedation.

Low Dose Doxepin as a Selective H1 Receptor Antagonist

What makes low dose doxepin effective for insomnia treatment? At low doses, doxepin exhibits a high affinity for the H1 receptor, acting as a selective H1 antagonist. This selectivity allows doxepin to display sedating properties without the broader effects associated with higher doses used in antidepressant therapy.

By blocking H1 receptors, low dose doxepin effectively reduces histamine-mediated arousal, promoting sleep onset and maintenance. This targeted approach distinguishes doxepin from other sedative antidepressants and traditional sleep medications.

Evidence-Based Efficacy of Low Dose Doxepin

Compared to other sedative antidepressants, low dose doxepin stands out as the only tricyclic drug evaluated through well-designed, randomized, double-blind, placebo-controlled studies in both adult and elderly populations. This robust clinical evidence supports its efficacy and safety profile in treating insomnia.

Advantages for Special Populations

Why might doxepin be particularly beneficial for certain patient groups? Doxepin is not designated as a controlled substance, making it a potentially advantageous option for patients with a history of substance abuse. This characteristic allows for greater flexibility in prescribing and reduces the risk of dependence associated with some other sleep medications.

Tolerability and Safety Profile of Low Dose Doxepin

The well-documented therapeutic efficacy of low dose doxepin is complemented by its favorable tolerability and safety profile. Unlike many sleep medications, doxepin at low doses has demonstrated a lack of significant adverse effects, making it suitable for long-term use in both adults and elderly patients.

Minimizing Side Effects

How does low dose doxepin minimize side effects commonly associated with sleep medications? By utilizing a low dose, the risk of adverse effects typically associated with higher doses of tricyclic antidepressants is significantly reduced. This allows for effective insomnia treatment without compromising patient safety or quality of life.

Doxepin’s Unique Position in Insomnia Treatment

The combination of selective H1 receptor antagonism, proven efficacy, and favorable safety profile positions low dose doxepin as a unique and rational choice for insomnia treatment. Its mechanism of action addresses the underlying sleep-wake cycle disruption without the drawbacks of traditional sedatives or higher-dose antidepressants.

Tailored Treatment for Diverse Patient Needs

How can doxepin be tailored to meet diverse patient needs? The flexibility of low dose doxepin allows for personalized treatment approaches. Clinicians can adjust dosages within the low-dose range to optimize efficacy while maintaining the drug’s favorable safety profile, making it suitable for a wide range of patients, including those with comorbid conditions or a history of substance abuse.

Future Directions in Insomnia Management with Doxepin

As research in sleep medicine continues to advance, the role of low dose doxepin in insomnia management may expand. Future studies may explore its efficacy in combination with other sleep-promoting interventions or its potential in treating specific subgroups of insomnia patients.

Potential for Combination Therapies

Can low dose doxepin be effectively combined with other insomnia treatments? While current evidence supports its use as a monotherapy, future research may investigate the potential synergistic effects of combining low dose doxepin with cognitive behavioral therapy for insomnia (CBT-I) or other non-pharmacological interventions. Such combinations could potentially offer more comprehensive and personalized treatment options for patients with complex sleep disorders.

Overcoming Challenges in Insomnia Treatment

Despite the promising profile of low dose doxepin, challenges remain in the broader landscape of insomnia treatment. These include addressing patient concerns about medication dependence, managing expectations regarding sleep improvement, and ensuring proper sleep hygiene practices alongside pharmacological interventions.

Educating Patients and Healthcare Providers

How can patient education improve outcomes in insomnia treatment? Comprehensive patient education about the mechanism of action, expected benefits, and proper use of low dose doxepin is crucial. Healthcare providers play a key role in dispelling myths about sleep medications and promoting a holistic approach to sleep health that includes both pharmacological and non-pharmacological strategies.

By emphasizing the unique properties of low dose doxepin, such as its selective action on histamine receptors and favorable safety profile, healthcare providers can help patients make informed decisions about their insomnia treatment. This education should extend to discussing the importance of consistent sleep schedules, proper sleep hygiene, and the potential need for long-term management strategies.

Addressing Comorbid Conditions

How does the presence of comorbid conditions impact insomnia treatment with doxepin? Many patients with chronic insomnia also suffer from concurrent medical or psychiatric conditions. The versatility of low dose doxepin makes it a potentially valuable option for these complex cases. Its mild antidepressant effects at higher doses suggest that it may offer additional benefits for patients with comorbid depression or anxiety, even when used primarily for insomnia at lower doses.

Healthcare providers should consider the full clinical picture when prescribing doxepin, taking into account potential interactions with other medications and the impact of insomnia treatment on coexisting conditions. This comprehensive approach can lead to more effective management of both insomnia and its associated comorbidities.

Optimizing Doxepin Use in Clinical Practice

To maximize the benefits of low dose doxepin in insomnia treatment, healthcare providers should adopt a patient-centered approach that considers individual sleep patterns, lifestyle factors, and treatment goals. This may involve careful dose titration, regular follow-ups to assess efficacy and tolerability, and adjustments based on patient response.

Personalized Treatment Strategies

How can treatment with low dose doxepin be personalized for optimal outcomes? Personalization strategies may include:

• Starting with the lowest effective dose and gradually titrating as needed
• Timing administration based on individual sleep-wake patterns and insomnia symptoms (e.g., difficulty falling asleep vs. maintaining sleep)
• Combining doxepin with non-pharmacological interventions tailored to the patient’s specific needs and preferences
• Regular reassessment of treatment efficacy and consideration of dose adjustments or treatment duration

By tailoring the use of low dose doxepin to each patient’s unique circumstances, healthcare providers can optimize its effectiveness while minimizing the risk of adverse effects or unnecessary long-term use.

Long-term Management Considerations

What factors should be considered in the long-term management of insomnia with doxepin? While low dose doxepin has demonstrated safety for extended use, long-term management should involve periodic reassessment of the need for continued pharmacological treatment. This may include:

1. Evaluating the ongoing effectiveness of the medication
2. Assessing for any changes in the patient’s overall health or sleep patterns
3. Considering gradual dose reduction or discontinuation when appropriate
4. Incorporating strategies to prevent relapse, such as maintaining good sleep hygiene practices

Long-term management should aim to balance the benefits of continued treatment with the goal of minimizing medication use when possible, always prioritizing the patient’s overall sleep health and quality of life.

Advancing Research in Insomnia Treatment

As our understanding of sleep disorders and their treatment continues to evolve, ongoing research into low dose doxepin and other novel approaches to insomnia management remains crucial. Future studies may focus on identifying specific patient subgroups that benefit most from doxepin treatment, exploring potential biomarkers for treatment response, and investigating long-term outcomes in diverse populations.

Emerging Trends in Sleep Medicine

What emerging trends in sleep medicine might impact the use of doxepin for insomnia? Several areas of research show promise for enhancing insomnia treatment:

• Precision medicine approaches that use genetic or other biomarkers to predict treatment response
• Development of new formulations or delivery methods for sleep medications
• Integration of digital health technologies for sleep monitoring and treatment optimization
• Investigation of the relationship between sleep disorders and other health conditions, potentially leading to more comprehensive treatment strategies

As these areas of research progress, they may offer new insights into optimizing the use of low dose doxepin and other insomnia treatments, potentially leading to more effective and personalized approaches to managing sleep disorders.

In conclusion, low dose doxepin represents a unique and rational approach to insomnia treatment, offering a combination of efficacy, safety, and versatility that addresses many of the challenges associated with traditional sleep medications. Its selective action on histamine receptors, coupled with a favorable side effect profile and suitability for diverse patient populations, positions doxepin as a valuable tool in the management of chronic insomnia. As research continues to advance our understanding of sleep disorders and their treatment, the role of doxepin in insomnia management may further evolve, potentially offering even more targeted and effective solutions for patients struggling with sleep disturbances.

Therapeutic rationale for low dose doxepin in insomnia patients

Asian Pac J Trop Dis. 2013 Aug; 3(4): 331–336.

,¹,²,³,¹ and ^1,*

¹All Saints University, College of Medicine, Kingstown, St. Vincent and the Grenadines

²All Saints University, School of Medicine, Roseau, Dominica

³Medical Services Department, Intas Pharmaceuticals Limited, Ahmadabad, India

Jigar Katwala

¹All Saints University, College of Medicine, Kingstown, St. Vincent and the Grenadines

Ananda K Kumar

²All Saints University, School of Medicine, Roseau, Dominica

Jaykumar J Sejpal

³Medical Services Department, Intas Pharmaceuticals Limited, Ahmadabad, India

Marcelle Terrence

¹All Saints University, College of Medicine, Kingstown, St. Vincent and the Grenadines

Manish Mishra

¹All Saints University, College of Medicine, Kingstown, St. Vincent and the Grenadines

Reviewed by Kamlakar Tripathi, MD, D.M., F.R.C.P.Professor, Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India., Tel: +91-9839044027, Fax: +91-5422307521, E-mail: ni.oc.oohay@ihtapirt_rakalmak*Corresponding author: Dr. Manish Mishra, Assistant Professor, All Saints University, College of Medicine, Kingstown, St. Vincent and the Grenadines. Tel: +1-784-492-5497, Fax: +1-784-458-4151.E-mail: moc.liamg@hsinamcmn

Received 2013 Jun 7; Accepted 2013 Jul 10.

Copyright © 2013 by the Asian Pacific Journal of Tropical Disease. All rights reserved.

Abstract

Histamine is an excitatory neurotransmitter in central nervous system. It plays an important role in the regulation of the sleep-wake cycle. Antidepressant with sleep-promoting effects, for example, doxepin, promotes sleep not through a sedative action but through resynchronisation of circadian cycle. The stimulation of the h2 receptor is thought to play an important role in mediating arousal. Doxepin has a high affinity for the h2 receptor, making it a selective h2 antagonist at low dose and it has been shown to display sedating properties. Compared to other sedative antidepressant, low dose doxepin is the only tricyclic drug which has been evaluated by well-designed, randomised, double blind, placebo controlled studies in both adult and elderly patients. Doxepin is not designated as controlled substance/unscheduled drugs and thus may be of special advantage to use in patients with a history of substance abuse. Hence, well-documented therapeutic efficacy, tolerability and lack of important adverse effects make the low dose doxepin as a unique, rational drug for the treatment of insomnia in adult and elderly patients.

Keywords: Insomnia, Doxepin, Histamine

1. Insomnia

1.1. A general idea

Insomnia is a most common sleep disorder. Insomnia is widespread, affecting more than 25% of the adult population. Approximately 10% of adults presented with insomnia symptoms have associated day time impairment. US national health interview survey and US national co-morbidity survey showed that there was a high rate of morbidity associated between chronic insomnia and medical disorder (e.g. pain) and heart disorder (e.g. heart failure) and psychiatric disorder (e.g. depression, mood, anxiety, and substance abuse disorder)[1]–[3].

1.2. Precipitating factors

There are multiple factors related with patients which make insomnia a vulnerable condition for them. These factors are divided into three category such as predisposing factors (e.g. middle-age, old age, female), personality factors (e.g. hyper excitability, anxious personality), and past and family history (e.g. medical or psychiatric illness) and genetic factors. Many times, psychological and behavioural factors also worsen insomnia (e.g. unexpected loss of loved one, loss of job)[1],[4]–[8].

2. Classification of insomnia

Insomnia has been classified as two ways: by the duration of the insomnia or by its etiology. Based on duration, insomnia is classified as transient insomnia (lasting no longer than 7 d), short-term insomnia (lasting for less than 3 weeks), and chronic insomnia. Transient and short-term insomnias are common during emotional distress. Chronic insomnia lasts for longer duration of usually more than 3 weeks, and some even more than 30 d. The other category of insomnia is based on etiology which includes primary insomnia (occurring without any specific physical and mental conditions) and secondary insomnia (associated with other medical and psychiatric illness, medications, or other sleep disorders)[8],[9].

The International Classification of Sleep Disorder (ICSD) has categorized insomnia as adjustment insomnia, behavioural insomnia of childhood, idiopathic, paradoxical, psychophysiological, and inadequate sleep hygiene, insomnia due to drug or substance, medical condition or mental disorder[10].

3. Symptoms and definition

Various working groups on sleep disorder such as The International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10), Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) and ICSD-2, agree on three main diagnostic criteria to define insomnia. These three chief complaints include difficulty initiating sleep, difficulty maintaining sleep, and waking up too early. Patient has a poor quality or non-restorative sleep. A consequent impairment in daytime functioning and associated subjective symptoms such as fatigue, daytime sleepiness, low energy level, mood irritability, difficulties in cognitive activity (e.g. concentration, memory and attention), lack of motivation, constant worry for sleep and tension headache[10]–[12].

4. Definition

According to the DSM-IV-TR diagnostic criteria for primary insomnia requires[12]:

(i) A predominant complaint of difficulty in initiating or maintaining sleep, or nonrestorative sleep, for at least one month.

(ii) The sleep disturbance (or associated daytime fatigue) causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.

(iii) The sleep disturbance does not occur exclusively during the course of another sleep disorder (narcolepsy, breathing-related sleep disorder, etc).

(iv) The disturbance is not due to the direct physiological effects of a substance (e.g. a drug of abuse, a medication) or another psychiatric or general medical condition.

5. Currently available treatments for insomnia

The British Association for Psychopharmacology guidelines recommended that it is extremely necessary to treat insomnia because the condition causing poor quality of life, is associated with impaired functioning in many areas, and leads to increased risk of psychological disorder (e.g. depression, anxiety) and possibly cardiovascular disorders. Main goals of insomnia treatment are to produce less suffering and to improve daytime function[4].

There are various methods of psychological and behavioural intervention for treatment of insomnia, including the sleep hygiene, stimulus control, sleep restriction, relaxation techniques, feedback, cognitive therapy, “chronotherapy”, and phytotherapy[5]. The British Association for Psychopharmacology Consensus, American Academy of Sleep Medicine, and the 2005 US National Institute of Health State-of Science Conference on insomnia concluded that cognitive behavioural therapy (CBT) and benzodiazepine receptor agonist have level a evidence for short-term treatment of chronic insomnia. CBT is effective for individual or a group of people[4],[6],[13]. The current mainstay for the pharmacotherapy of insomnia is as below[4]–[9],[13],[14]:

1. Enhancing the inhibitory wake-promoting neurotransmitter gamma amino benzoic acid (GABA).

A. Benzodiazepine receptors agonist: triazolam, temazepam, lorazepam, and flurazepam.

B. Non-benzodiazepine receptor agonist (Z-drug): zolpidem, zaleplon, eszopiclone.

2. Melatonin, ramelteon, almorexant.

3. Other agents.

A. Over the counter (OTC) products: diphenhydramine hydrochloride, diphenhydramine citrate, doxylamine succinate.

B. Tricyclic anti-depressant agents (TCAs): amitriptyline, nortriptyline, doxepin, trazodone.

6. Limitations of current therapies

6.1. Benzodiazepines and non-benzodiazepines agents

These hypnotic agents act by enhancing sleep promoting neurotransmitter (GABA). It causes high degree of inhibition of arousal. Therefore, the wake-promoting systems mediated via norepinephrine, acetylcholine, histamine, dopamine and serotonin are inhibited by GABA mechanisms. There is a balance between these two systems for safe functioning, such as driving, walking to the bathroom in dark without falling[9].

These compounds have reported efficacy and safety in terms of improvement in sleep quality. However, they are associated with numerous adverse events such as daytime sedation or next-day residual effects, motor incoordinataion, reduced psychomotor performance, cognitive impairment and related concerns about increases in risk of motor vehicle accidents and injuries from fall[9],[14].

Chronic administration of benzodiazepines agonists agent produces tolerance, psychological dependence. The adaptive changes in GABA receptor cause withdrawal, characterized by neurological, physical and cognitive symptoms, and rebound insomnia[4],[9],[14],[15].

These agents have also been associated with the potential for abuse and dependence in at risk populations, which led the US Drug Enforcement Agency to classify them as Schedule IV substances[16],[17].

6.2. Melatonin, ramelteon and almorexant

Newer approaches include ramelteon, the first and only nonscheduled drug approved by the US FDA for the treatment of insomnia, and in the future possibly by the orexin system, through agents such as almorexant. Ramelteon produces sleep through activation of melatonin 1 and melatonin 2 receptors in the suprachiasmatic nucleus of the hypothalamus. Almorexant produces selective antagonism of orexin OX1 and OX2 receptor. There is no adequate evidence that they are effective in the treatment of insomnia[15],[18].

6.3. Other agents

Anti-histaminics are the active ingredients of OTC sleep aids available in market (i.e. diphenhydramine, doxylamine). Disadvantages of the current OTC antihistamines are their relatively long duration of action and next-morning drowsiness, potential side effects, and insufficient receptor selectivity has risk of undesired anticholinergic side effect (i.e. dry mouth, dry eye, retention of urine, constipation)[16].

The most commonly used anti-depressants for co-morbid insomnia include sedating tricyclics anti-depressants (TCAs), such as amitriptyline, doxepin, and nortriptyline, and 5HT2 antagonist trazodone. They are effective for inducing sleep and improving sleep continuity. The TCAs can alter sleep architecture by reducing rapid eye movement (REM) sleep. In general, sedating properties of anti-depressant agents are related to antagonism of serotonin 5HT2, histamines, and α-1 adrenergic receptors[14]–[16].

Because of their non-selective antagonist action on 5HT2, histamines, and α-1 adrenergic receptors, these agents produce side effects such as anticholinergic, adrenergic blockade, and prolong cardiac conduction. These agents also cause potential side effects such as weight gain, increased suicidal ideation, hypomania or mania in patients with bipolar disorder.

There is short of evidence which proves that sedative anti-depressants are effective in the treatment of insomnia. Although due to lack of abuse potential, they are considered as unscheduled drug. They are cheaper and well studied drugs. Therefore, they are drug of choice for patients with co-morbid insomnia who is suffering from depression.

Although, the treatment of insomnia is widely used, many agents that block the histamine h2 receptor are considered to have therapeutic limitations, including the development of next-day carryover sedation, as well as problems with chronic use, such as the development of tolerance to sedative-hypnotic action and weight gain. TCAs like doxepin exert such potent histamine h2 blockade that it has been possible to optimize their hypnotic activity by using very low dose. Since March 2010, the US FDA has approved low dose doxepin for the indication of insomnia[19].

In this review, we have discussed the further details of role of histamine for wakefulness and blockade of histamine by doxepin to reduce the wakefulness. Effectiveness and safety of doxepin for the patients who have complaint of sleep maintenance and sleep onset insomnia.

7.

 Emerging trends

Recent research has revisited one of the oldest approaches to insomnia, namely by using anti-depressant and antihistaminic properties. Anti-histaminic such as diphenhydramine and doxylamine are used as sleep promoting agents. They are available as over the counter products. Anti-depressants with histamine antagonist action such as trazodon, doxepin, mirtazapine and antipsychotic with antihistaminic properties like quetiapine are used for the treatment of insomnia with co-morbid psychiatric condition like depression[14],[15].

7.1. Arousal pathway

Histamine is the key neurotransmitter for arousal. It is synthesized in the hypothalamus. It drives the wakefulness known as “wake-promoting” neurotransmitter. The major site of histaminic neurones is tuberomammillary nucleus (TMN). The distribution of histamine receptors in brain is very dense. Histamine h2 receptors are of high density in the cortex and in the limbic system, while histamine h3 receptors have high density in the striatum, cerebral cortex, and also in the limbic system; and finally, histamine h4 receptors, the autoreceptors, are dense in the striatum and the cortex. Histamine produces its action via direct and indirect stimulation of arousal pathway. Direct pathway causes stimulation of histamine receptor travelling via the ascending histaminergic neurones from hypothalamus to thalamic h2 and h3 receptors or in the cortex via histamine h2 receptor. The release of histamine causes calm wakefulness (i.e. well-rested state, the ability to focus on cognitive task, problem solving, learning, creativity). Secondly, histamine also produces indirect activation of basal forebrain cholinergic neurone via histamine h2 receptors. This stimulation causes release of acetylcholine which stimulated arousal (i.e. anxiety, fright, external vigilance) ()[14],[15],[20]–[22].

Arousal pathway and mechanism of action of hypnotic drugs.

Among anti-depressants, doxepin has the highest binding capacity to histamine receptors. Its potency to bind histamine is even stronger than classical antihistaminic. Doxepin had high binding to histamine in frontal cortex, amygdale, temporal cortex, and the hippocampus[20].

Low dose doxepin acts via blocking h2 receptors, which is very unique among the currently approved FDA drugs for the treatment of insomnia. Doxepin, 3 mg and 6 mg, were approved by USFDA in March, 2010 in both adult and elderly patients suffering from short and long term insomnia[19].

8. Low dose doxepin for insomnia

Doxepin is a three-decade old tricyclic anti-depressant agent. It is approved for the treatment of depression, depression with insomnia and anxiety disorders. Anti-depressant action produces with ≥25 mg of doxepin. Lower dosage produces anti-anxiety effect. Anti-depressant action of doxepin is because of reuptake inhibition of nor-epinephrine and serotonin. Higher dose ≥25 mg of doxepin is nonslective and responsible for undesired side effects such as anticholinergic, antiadrenergic, and potentiation of cardiac conduction ()[23],[24].

Chemical structure of doxepin hydrochloride.

Lower dose doxepin has a very high selectivity for h2 receptor. It binds with histamine receptors for 100 times more than that of nor-epinephrine and serotonin receptors. Antagonism of histamine receptors in TMN nucleus inhibits the arousal pathway. This produces hypnotic action. Thus low dose of doxepin (1, 3, 6 mg) can produce selective h2 blockade[19],[20],[23],[24],.

Low dose doxepin is advantages for the patients with complaint of objective and subjective measures of sleep maintenance and sleep onset insomnia. Sleep effects seem to be dose dependent, and among the very low-dose preparations being studied, the 3 mg and 6 mg doses appeared the most effective in adult as well as elderly patients; doxepin (@roneliS) has been approved for insomnia treatment in USA[19].

9. Clinical efficacy and safety of 1, 3, and 6 mg doxepin in insomnia

9.1. Efficacy

Doxepin 1, 3, and 6 mg is widely studied in both adult and elderly patients with difficulty in sleep onset and sleep maintenance insomnia. There were 1 423 subjects, with chronic insomnia (n=858) or transient (n=565) insomnia participated in 6 randomised, double-blind studied. These studies were up to 3 months in duration and included patients of both sex between 18 and 93 years of age.

Compared to placebo, all three Doxepin doses, 1, 3, and 6 mg produced significant improvement in sleep parameters such as wake time after sleep onset, total sleep time and sleep efficiency. These improvements were sustained throughout the duration of studies[19],[25]–[30].

In the 3-month clinical trial, the 3 mg dose produces significant improvement in sleep latency without evidence of next-day residual sedation[27]. In elderly patients, the 4-week study of 6 mg doxepin significantly improved total sleep time and sleep quality versus placebo and these improvements were sustained throughout the trial[25]. Clinical trial in transient insomnia patients (n=565) also demonstrated the effectiveness of doxepin 6 mg in sleep onset, sleep maintenance, sleep duration and sleep quality[28]. Thus doxepin is useful for both sleep maintenance and sleep onset or difficulty in falling sleep. It decreases the frequent waking at night and increase the total duration of sleep.

9.2. Tolerability

Low dose doxepin had an incidence of adverse effects compared to placebo. There were no reported anticholinergic effects, no memory impairment and no evidence of next day residual effects. Doxepin should be avoided in patients who take anti-depresants, alcohol and sedating antihistaminic. Doxepin is metabolized by CYP isoenzymes, co-administration of cimetidine and sertraline like CYP inhibitors may increase the plasma concentration of doxepin[19],[25]–[30].

9.3. Safety

Low dose doxepin is safe drug for short term and long term insomnia. Low dose doxepin is different from other anti-depressants in three effects. First, low dose doxepin has no reports of suicide in clinical trial. Therefore, low dose doxepin does not have a boxed warning for suicide risk. Second, doxepin is not associated with abuse potential in animals or in human. Third, there is no report of weight gaining or appetite increasing. The most common adverse reactions reported were sedation, somnolence, nausea and upper respiratory tract infection[19],[25]–[30]. During the clinical trial, there is no report for rebound insomnia/withdrawal syndrome after doxepin discontinuation. Thus doxepin does not produce physical dependence[19],[25]–[30]. Cardiac safety study showed no prolongation of QT interval with 50 mg dose of doxepin[31]. Doxepin is pregnancy category C drug. It is not a controlled substance like benzodiazepine drugs. In the elderly population and patients with hepatic insufficiency, 3 mg of starting dose is recommended. Mild renal impairment does not required dose adjustment. It should be avoided in patients with severe urinary retention, narrow angle glaucoma and who are currently taking monoamine oxidase inhibitors or has used MAOI for the past two weeks. The uncontrolled insomnia after 7-10 days of treatment may indicate possibility of secondary insomnia or co-morbid insomnia[19].

9.4. Dose administration

Doxepin dosage is very simple for insomnia patients. It is available in strength of 3 mg and 6 mg immediate release oral tablet. The recommended dose of doxepin for adults is 6 mg once daily. The starting dose for the elderly patients >65 years old is 3 mg once daily. The daily dose can be increased to 6 mg, if clinically required. It should be taken within 30 min of bedtime. To minimize the potential for next day effects, doxepin should not be taken within 3 h of a meal[19].

10. Benefits of low dose doxepin therapy for insomnia

Low doses doxepin 3 mg and 6 mg have several distinctive advantages over other available hypnotic agents for several reasons[19],[25]–[30].

1. It does not directly interfere with the other arousal systems[14],[15],[20].

2. The finding of trials confirmed that doxepin 3 mg and 6 mg is efficacious in improving sleep latency, sleep maintenance and sleep quality. Moreover, these improvements are sustained for long duration of 3 months.

3. It does not cause daytime sedation (no next-day sedation).

4. Published clinical trials demonstrated that it is effective in adult as well as elderly patients with primary insomnia and current data suggest that it is also safe and well tolerated at 6 mg dose[19],[25],[27],[29].

5. No incidence of withdrawal syndrome or rebound insomnia after discontinuing doxepin 3 mg or 6 mg[25]–[27].

6. Use of low dose doxepin is not associated with tolerance, and anti-cholinergic side effect. Further, it is not associated with weight gain and cardiac re-polarization[19],[25]–[30].

7. It is a non-controlled substance that enjoys virtually no risk of addiction or dependence[19]. This allows easier prescribing with fewer prescribing restrictions, as well as being potentially effective in high-risk patient populations (e.g. history of alcohol or drug abuse) and those who require a pharmacologic agent on a more chronic basis.

11. Conclusion

In conclusion, doxepin at low doses of 3 mg and 6 mg is effective and well tolerated. It is also safe and non-habit forming option for patients with insomnia. Doxepin is not a controlled substance and it has no risk of abuse. Unlike GABA agonists, low dose doxepin selectively blocks histaminergic action and its arousal property resulting in natural sleep. Low dose doxepin is a new armamentarium for managing chronic primary insomnia and transient insomnia characterized by difficulties with sleep maintenance in adult and elderly patients.

Notes

Comments

Background

Insomnia is an iceberg disease. Prevalence of insomnia is high among the adults as well as the elders. Majority of time, primary insomnia patients are unidentified, as the patients are ignorant to the sleep problems and avoid to visit the physicians. Insomnia is characterized by difficulty in initiating or maintaining sleep. Insomnia is associated with nonrestorative sleep and daytime fatigue, malaise, irritability and decreased memory and concentration. Morbidity of insomnia patients increased when they have associated co-morbid condition such as depression, psychosis and cardiac disease. Traditional hypnotic medications, benzodiazepines and nonbenzodiazepines, act via GABA inhibitory pathway in brain and they are associated with adverse events such as abuse potential, withdrawal syndrome on discontinuation of medication and rebound insomnia. They also developed tolerance and dependence. While, TCAs and anti-depressant agents have proven their effectiveness in improvement of sleep onset and sleep maintenance in healthy subjects as well as depressant patients even after long term use. During the clinical studies, these agents had low abuse potential and dependence. An old TCAs, doxepin, approved to treat depression and anxiety disorder. It also effectively cures insomnia patients with depression. Its potent h2 receptors blocking action is useful for sleep disorder. Low dose doxepin has open new frontier to treat primary insomnia and chronic insomnia patients. Doxepin in 3 mg and 6 mg doses was approved by USFDA in 2010 to treat sleep onset and sleep maintenance in adult and elderly with chronic insomnia.

Research frontiers

The review highlights new and important aspects of insomnia treatment. The authors performed a good review for the role of histamine receptors and their blockade with doxepin to treat insomnia. This approach is a novel compare to traditional therapy. This article focuses on recent developments in insomnia treatment and will be helpful for physician to decide their preferential hypnotic to treat insomnia patients.

Related reports

Zisapel, Loachimescu et al. and Sullivan recently discussed the emerging drugs for insomnia. They reported the advantage of unique action of doxepin when used in 3 mg and 6 mg. In this review, the authors also concluded that low dose doxepin is effective and safe in primary insomnia patients. They also discussed detailed pathophysiology of insomnia and described potential of histamine pathway to induce sleep, which was not the part of previously published articles of the other authors.

Innovations & breakthroughs

This review adds additional support to the use of low dose doxepin in primary insomnia. The authors had wisely covered pathophysiology and clinical data of low dose doxepin. It is a good article for physician for quick guide to hypnotic.

Applications

This review provides a glimpse on recent developments in insomnia treatment and it will be definitely helpful for physician to decide their preferential medication to treat insomnia patients.

Peer review

It is an appropriate review article which highlights newer pharmacological treatment option for insomnia. The authors had nicely discussed pathophysiology of sleep and their basis for developing new agent for insomnia. The pros and cons of low dose doxepin in insomnia are well evaluated. Over all it is a good article for clinician to decide their daily choice of agent for insomnia patients.

Footnotes

Conflict of interest statement: We declare that we have no conflict of interest.

References

2. Roth T, Jaeger S, Jin R, Kalsekar A, Stang PE, Kessler RC. Sleep problems, comorbid mental disorders, and role functioning in the national comorbidity survey replication. Biol Psychiatry. 2006;60:1364–1371. [PMC free article] [PubMed] [Google Scholar]3. Pearson NJ, Johnson LL, Nahin RL. Insomnia, trouble sleeping, and complementary and alternative medicine: analysis of the 2002 national health interview survey data. Arch Intern Med. 2006;166:1775–1782. [PubMed] [Google Scholar]4. Wilson SJ, Nutt DJ, Alford C, Argyropoulos SV, Baldwin DS, Bateson AN, et al. et al. British association for psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders. J Psychopharmacol. 2010;24:1577–1600. [PubMed] [Google Scholar]5. Schutte-Rodin S, Broch L, Buysse D, Dorsey C, Sateia M. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med. 2008;4:487–504. [PMC free article] [PubMed] [Google Scholar]6. Morgenthaler T, Kramer M, Alessi C, Friedman L, Boehlecke B, Brown T, et al. et al. Practice parameters for the psychological and behavioral treatment of insomnia: an update. Sleep. 2006;29:1415–1419. [PubMed] [Google Scholar]8. Galimi R. Insomnia in the elderly: an update and future challenges. G Gerontol. 2010;58:231–247. [Google Scholar]9. Charles AC, Winkelman JW, Richardson GS. Sleep disorders. In: Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, editors. Harrison’s internal medicine. 17th ed. New York: McGraw-Hill Publishing; 2005. pp. 153–161. [Google Scholar]10. American Academy of Sleep Medicine . International classification of sleep disorders: diagnostic and coding manual. 2nd ed. Westchester: American Academy of Sleep Medicine; 2005. [Google Scholar]11. World Health Organization . Geneva: WHO; 1992. The ICD-10 classification of mental and behavioral disorders: Clinical descriptions and diagnostic guidelines[R] [Google Scholar]12. American Psychiatric Association . Diagnostic and statistical manual of mental disorders. 4th ed. Washington DC: The American Psychiatric Association; 2000. [Google Scholar]14. Stahl SM. Selective histamine h2 antagonism: novel hypnotic and pharmacologic actions challenge classical notions of antihistamines. CNS Spectr. 2008;13:1027–1038. [PubMed] [Google Scholar]15. Owen RT. Selective histamine H (1) antagonism: A novel approach to insomnia using low-dose doxepin. Drugs Today (Barc) 2009;45:261–267. [PubMed] [Google Scholar]16. Pinto LR, Jr, Alves RC, Caixeta E, Fontenelle JA, Bacellar A, Poyares D, et al. et al. New guidelines for diagnosis and treatment of insomnia. Arq Neuropsiquiatr. 2010;68:666–675. [PubMed] [Google Scholar]17. Zammit G. Comparative tolerability of newer agents for insomnia. Drug Saf. 2009;32:735–748. [PubMed] [Google Scholar]18. Mets MA, van Deventer KR, Olivier B, Verster JC. Critical appraisal of ramelteon in the treatment of insomnia. Nat Sci Sleep. 2010;2:257–266. [PMC free article] [PubMed] [Google Scholar]21. Slats D, Claassen JA, Verbeek MM, Overeem S. Reciprocal interactions between sleep, circadian rhythms and Alzheimer’s disease: focus on the role of hypocretin and melatonin. Ageing Res Rev. 2013;12:188–200. [PubMed] [Google Scholar]23. Goforth HW. Low-dose doxepin for the treatment of insomnia: emerging data. Expert Opin Pharmacother. 2009;10:1649–1655. [PubMed] [Google Scholar]24. Markov D, Doghramji K. Doxepin for insomnia. Curr Psychiatry. 2010;9:67–77. [Google Scholar]25. Lankford A, Rogowski R, Essink B, Ludington E, Heith Durrence H, Roth T. Efficacy and safety of doxepin 6 mg in a four-week outpatient trial of elderly adults with chronic primary insomnia. Sleep Med. 2012;13:133–138. [PubMed] [Google Scholar]26. Krystal AD, Lankford A, Durrence HH, Ludington E, Jochelson P, Rogowski R, et al. et al. Efficacy and safety of doxepin 3 and 6 mg in a 35-day sleep laboratory trial in adults with chronic primary insomnia. Sleep. 2011;34:1433–1442. [PMC free article] [PubMed] [Google Scholar]27. Krystal AD, Durrence HH, Scharf M, Jochelson P, Rogowski R, Ludington E, et al. et al. Efficacy and safety of doxepin 1 mg and 3 mg in a 12-week sleep laboratory and outpatient trial of elderly subjects with chronic primary insomnia. Sleep. 2010;33:1553–1561. [PMC free article] [PubMed] [Google Scholar]28. Roth T, Heith Durrence H, Jochelson P, Peterson G, Ludington E, Rogowski R, et al. et al. Efficacy and safety of doxepin 6 mg in a model of transient insomnia. Sleep Med. 2010;11:843–847. [PubMed] [Google Scholar]29. Scharf M, Rogowski R, Hull S, Cohn M, Mayleben D, Feldman N, et al. et al. Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in elderly patients with primary insomnia: a randomized, double-blind, placebocontrolled crossover study. J Clin Psychiatry. 2008;69:1557–1564. [PubMed] [Google Scholar]30. Roth T, Rogowski R, Hull S, Schwartz H, Koshorek G, Corser B, et al. et al. Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in adults with primary insomnia. Sleep. 2007;30:1555–1561. [PMC free article] [PubMed] [Google Scholar]31. Mansbach RS, Ludington E, Rogowski R, Kittrelle JP, Jochelson P. A placebo- and active-controlled assessment of 6- and 50-mg oral doxepin on cardiac repolarization in healthy volunteers: A thorough QT evaluation. Clin Ther. 2011;33:851–862. [PubMed] [Google Scholar]

Therapeutic rationale for low dose doxepin in insomnia patients

Asian Pac J Trop Dis. 2013 Aug; 3(4): 331–336.

,¹,²,³,¹ and ^1,*

¹All Saints University, College of Medicine, Kingstown, St. Vincent and the Grenadines

²All Saints University, School of Medicine, Roseau, Dominica

³Medical Services Department, Intas Pharmaceuticals Limited, Ahmadabad, India

Jigar Katwala

¹All Saints University, College of Medicine, Kingstown, St. Vincent and the Grenadines

Ananda K Kumar

²All Saints University, School of Medicine, Roseau, Dominica

Jaykumar J Sejpal

³Medical Services Department, Intas Pharmaceuticals Limited, Ahmadabad, India

Marcelle Terrence

¹All Saints University, College of Medicine, Kingstown, St. Vincent and the Grenadines

Manish Mishra

¹All Saints University, College of Medicine, Kingstown, St. Vincent and the Grenadines

Reviewed by Kamlakar Tripathi, MD, D. M., F.R.C.P.Professor, Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India., Tel: +91-9839044027, Fax: +91-5422307521, E-mail: ni.oc.oohay@ihtapirt_rakalmak*Corresponding author: Dr. Manish Mishra, Assistant Professor, All Saints University, College of Medicine, Kingstown, St. Vincent and the Grenadines. Tel: +1-784-492-5497, Fax: +1-784-458-4151.E-mail: moc.liamg@hsinamcmn

Received 2013 Jun 7; Accepted 2013 Jul 10.

Copyright © 2013 by the Asian Pacific Journal of Tropical Disease. All rights reserved.

Abstract

Histamine is an excitatory neurotransmitter in central nervous system. It plays an important role in the regulation of the sleep-wake cycle. Antidepressant with sleep-promoting effects, for example, doxepin, promotes sleep not through a sedative action but through resynchronisation of circadian cycle. The stimulation of the h2 receptor is thought to play an important role in mediating arousal. Doxepin has a high affinity for the h2 receptor, making it a selective h2 antagonist at low dose and it has been shown to display sedating properties. Compared to other sedative antidepressant, low dose doxepin is the only tricyclic drug which has been evaluated by well-designed, randomised, double blind, placebo controlled studies in both adult and elderly patients. Doxepin is not designated as controlled substance/unscheduled drugs and thus may be of special advantage to use in patients with a history of substance abuse. Hence, well-documented therapeutic efficacy, tolerability and lack of important adverse effects make the low dose doxepin as a unique, rational drug for the treatment of insomnia in adult and elderly patients.

Keywords: Insomnia, Doxepin, Histamine

1. Insomnia

1.1. A general idea

Insomnia is a most common sleep disorder. Insomnia is widespread, affecting more than 25% of the adult population. Approximately 10% of adults presented with insomnia symptoms have associated day time impairment. US national health interview survey and US national co-morbidity survey showed that there was a high rate of morbidity associated between chronic insomnia and medical disorder (e.g. pain) and heart disorder (e.g. heart failure) and psychiatric disorder (e.g. depression, mood, anxiety, and substance abuse disorder)[1]–[3].

1.2. Precipitating factors

There are multiple factors related with patients which make insomnia a vulnerable condition for them. These factors are divided into three category such as predisposing factors (e.g. middle-age, old age, female), personality factors (e.g. hyper excitability, anxious personality), and past and family history (e.g. medical or psychiatric illness) and genetic factors. Many times, psychological and behavioural factors also worsen insomnia (e.g. unexpected loss of loved one, loss of job)[1],[4]–[8].

2. Classification of insomnia

Insomnia has been classified as two ways: by the duration of the insomnia or by its etiology. Based on duration, insomnia is classified as transient insomnia (lasting no longer than 7 d), short-term insomnia (lasting for less than 3 weeks), and chronic insomnia. Transient and short-term insomnias are common during emotional distress. Chronic insomnia lasts for longer duration of usually more than 3 weeks, and some even more than 30 d. The other category of insomnia is based on etiology which includes primary insomnia (occurring without any specific physical and mental conditions) and secondary insomnia (associated with other medical and psychiatric illness, medications, or other sleep disorders)[8],[9].

The International Classification of Sleep Disorder (ICSD) has categorized insomnia as adjustment insomnia, behavioural insomnia of childhood, idiopathic, paradoxical, psychophysiological, and inadequate sleep hygiene, insomnia due to drug or substance, medical condition or mental disorder[10].

3. Symptoms and definition

Various working groups on sleep disorder such as The International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10), Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) and ICSD-2, agree on three main diagnostic criteria to define insomnia. These three chief complaints include difficulty initiating sleep, difficulty maintaining sleep, and waking up too early. Patient has a poor quality or non-restorative sleep. A consequent impairment in daytime functioning and associated subjective symptoms such as fatigue, daytime sleepiness, low energy level, mood irritability, difficulties in cognitive activity (e.g. concentration, memory and attention), lack of motivation, constant worry for sleep and tension headache[10]–[12].

4. Definition

According to the DSM-IV-TR diagnostic criteria for primary insomnia requires[12]:

(i) A predominant complaint of difficulty in initiating or maintaining sleep, or nonrestorative sleep, for at least one month.

(ii) The sleep disturbance (or associated daytime fatigue) causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.

(iii) The sleep disturbance does not occur exclusively during the course of another sleep disorder (narcolepsy, breathing-related sleep disorder, etc).

(iv) The disturbance is not due to the direct physiological effects of a substance (e.g. a drug of abuse, a medication) or another psychiatric or general medical condition.

5. Currently available treatments for insomnia

The British Association for Psychopharmacology guidelines recommended that it is extremely necessary to treat insomnia because the condition causing poor quality of life, is associated with impaired functioning in many areas, and leads to increased risk of psychological disorder (e.g. depression, anxiety) and possibly cardiovascular disorders. Main goals of insomnia treatment are to produce less suffering and to improve daytime function[4].

There are various methods of psychological and behavioural intervention for treatment of insomnia, including the sleep hygiene, stimulus control, sleep restriction, relaxation techniques, feedback, cognitive therapy, “chronotherapy”, and phytotherapy[5]. The British Association for Psychopharmacology Consensus, American Academy of Sleep Medicine, and the 2005 US National Institute of Health State-of Science Conference on insomnia concluded that cognitive behavioural therapy (CBT) and benzodiazepine receptor agonist have level a evidence for short-term treatment of chronic insomnia. CBT is effective for individual or a group of people[4],[6],[13]. The current mainstay for the pharmacotherapy of insomnia is as below[4]–[9],[13],[14]:

1. Enhancing the inhibitory wake-promoting neurotransmitter gamma amino benzoic acid (GABA).

A. Benzodiazepine receptors agonist: triazolam, temazepam, lorazepam, and flurazepam.

B. Non-benzodiazepine receptor agonist (Z-drug): zolpidem, zaleplon, eszopiclone.

2. Melatonin, ramelteon, almorexant.

3. Other agents.

A. Over the counter (OTC) products: diphenhydramine hydrochloride, diphenhydramine citrate, doxylamine succinate.

B. Tricyclic anti-depressant agents (TCAs): amitriptyline, nortriptyline, doxepin, trazodone.

6. Limitations of current therapies

6.1. Benzodiazepines and non-benzodiazepines agents

These hypnotic agents act by enhancing sleep promoting neurotransmitter (GABA). It causes high degree of inhibition of arousal. Therefore, the wake-promoting systems mediated via norepinephrine, acetylcholine, histamine, dopamine and serotonin are inhibited by GABA mechanisms. There is a balance between these two systems for safe functioning, such as driving, walking to the bathroom in dark without falling[9].

These compounds have reported efficacy and safety in terms of improvement in sleep quality. However, they are associated with numerous adverse events such as daytime sedation or next-day residual effects, motor incoordinataion, reduced psychomotor performance, cognitive impairment and related concerns about increases in risk of motor vehicle accidents and injuries from fall[9],[14].

Chronic administration of benzodiazepines agonists agent produces tolerance, psychological dependence. The adaptive changes in GABA receptor cause withdrawal, characterized by neurological, physical and cognitive symptoms, and rebound insomnia[4],[9],[14],[15].

These agents have also been associated with the potential for abuse and dependence in at risk populations, which led the US Drug Enforcement Agency to classify them as Schedule IV substances[16],[17].

6.2. Melatonin, ramelteon and almorexant

Newer approaches include ramelteon, the first and only nonscheduled drug approved by the US FDA for the treatment of insomnia, and in the future possibly by the orexin system, through agents such as almorexant. Ramelteon produces sleep through activation of melatonin 1 and melatonin 2 receptors in the suprachiasmatic nucleus of the hypothalamus. Almorexant produces selective antagonism of orexin OX1 and OX2 receptor. There is no adequate evidence that they are effective in the treatment of insomnia[15],[18].

6.3. Other agents

Anti-histaminics are the active ingredients of OTC sleep aids available in market (i.e. diphenhydramine, doxylamine). Disadvantages of the current OTC antihistamines are their relatively long duration of action and next-morning drowsiness, potential side effects, and insufficient receptor selectivity has risk of undesired anticholinergic side effect (i.e. dry mouth, dry eye, retention of urine, constipation)[16].

The most commonly used anti-depressants for co-morbid insomnia include sedating tricyclics anti-depressants (TCAs), such as amitriptyline, doxepin, and nortriptyline, and 5HT2 antagonist trazodone. They are effective for inducing sleep and improving sleep continuity. The TCAs can alter sleep architecture by reducing rapid eye movement (REM) sleep. In general, sedating properties of anti-depressant agents are related to antagonism of serotonin 5HT2, histamines, and α-1 adrenergic receptors[14]–[16].

Because of their non-selective antagonist action on 5HT2, histamines, and α-1 adrenergic receptors, these agents produce side effects such as anticholinergic, adrenergic blockade, and prolong cardiac conduction. These agents also cause potential side effects such as weight gain, increased suicidal ideation, hypomania or mania in patients with bipolar disorder.

There is short of evidence which proves that sedative anti-depressants are effective in the treatment of insomnia. Although due to lack of abuse potential, they are considered as unscheduled drug. They are cheaper and well studied drugs. Therefore, they are drug of choice for patients with co-morbid insomnia who is suffering from depression.

Although, the treatment of insomnia is widely used, many agents that block the histamine h2 receptor are considered to have therapeutic limitations, including the development of next-day carryover sedation, as well as problems with chronic use, such as the development of tolerance to sedative-hypnotic action and weight gain. TCAs like doxepin exert such potent histamine h2 blockade that it has been possible to optimize their hypnotic activity by using very low dose. Since March 2010, the US FDA has approved low dose doxepin for the indication of insomnia[19].

In this review, we have discussed the further details of role of histamine for wakefulness and blockade of histamine by doxepin to reduce the wakefulness. Effectiveness and safety of doxepin for the patients who have complaint of sleep maintenance and sleep onset insomnia.

7. Emerging trends

Recent research has revisited one of the oldest approaches to insomnia, namely by using anti-depressant and antihistaminic properties. Anti-histaminic such as diphenhydramine and doxylamine are used as sleep promoting agents. They are available as over the counter products. Anti-depressants with histamine antagonist action such as trazodon, doxepin, mirtazapine and antipsychotic with antihistaminic properties like quetiapine are used for the treatment of insomnia with co-morbid psychiatric condition like depression[14],[15].

7.1. Arousal pathway

Histamine is the key neurotransmitter for arousal. It is synthesized in the hypothalamus. It drives the wakefulness known as “wake-promoting” neurotransmitter. The major site of histaminic neurones is tuberomammillary nucleus (TMN). The distribution of histamine receptors in brain is very dense. Histamine h2 receptors are of high density in the cortex and in the limbic system, while histamine h3 receptors have high density in the striatum, cerebral cortex, and also in the limbic system; and finally, histamine h4 receptors, the autoreceptors, are dense in the striatum and the cortex. Histamine produces its action via direct and indirect stimulation of arousal pathway. Direct pathway causes stimulation of histamine receptor travelling via the ascending histaminergic neurones from hypothalamus to thalamic h2 and h3 receptors or in the cortex via histamine h2 receptor. The release of histamine causes calm wakefulness (i.e. well-rested state, the ability to focus on cognitive task, problem solving, learning, creativity). Secondly, histamine also produces indirect activation of basal forebrain cholinergic neurone via histamine h2 receptors. This stimulation causes release of acetylcholine which stimulated arousal (i.e. anxiety, fright, external vigilance) ()[14],[15],[20]–[22].

Arousal pathway and mechanism of action of hypnotic drugs.

Among anti-depressants, doxepin has the highest binding capacity to histamine receptors. Its potency to bind histamine is even stronger than classical antihistaminic. Doxepin had high binding to histamine in frontal cortex, amygdale, temporal cortex, and the hippocampus[20].

Low dose doxepin acts via blocking h2 receptors, which is very unique among the currently approved FDA drugs for the treatment of insomnia. Doxepin, 3 mg and 6 mg, were approved by USFDA in March, 2010 in both adult and elderly patients suffering from short and long term insomnia[19].

8. Low dose doxepin for insomnia

Doxepin is a three-decade old tricyclic anti-depressant agent. It is approved for the treatment of depression, depression with insomnia and anxiety disorders. Anti-depressant action produces with ≥25 mg of doxepin. Lower dosage produces anti-anxiety effect. Anti-depressant action of doxepin is because of reuptake inhibition of nor-epinephrine and serotonin. Higher dose ≥25 mg of doxepin is nonslective and responsible for undesired side effects such as anticholinergic, antiadrenergic, and potentiation of cardiac conduction ()[23],[24].

Chemical structure of doxepin hydrochloride.

Lower dose doxepin has a very high selectivity for h2 receptor. It binds with histamine receptors for 100 times more than that of nor-epinephrine and serotonin receptors. Antagonism of histamine receptors in TMN nucleus inhibits the arousal pathway. This produces hypnotic action. Thus low dose of doxepin (1, 3, 6 mg) can produce selective h2 blockade[19],[20],[23],[24],.

Low dose doxepin is advantages for the patients with complaint of objective and subjective measures of sleep maintenance and sleep onset insomnia. Sleep effects seem to be dose dependent, and among the very low-dose preparations being studied, the 3 mg and 6 mg doses appeared the most effective in adult as well as elderly patients; doxepin (@roneliS) has been approved for insomnia treatment in USA[19].

9. Clinical efficacy and safety of 1, 3, and 6 mg doxepin in insomnia

9.1. Efficacy

Doxepin 1, 3, and 6 mg is widely studied in both adult and elderly patients with difficulty in sleep onset and sleep maintenance insomnia. There were 1 423 subjects, with chronic insomnia (n=858) or transient (n=565) insomnia participated in 6 randomised, double-blind studied. These studies were up to 3 months in duration and included patients of both sex between 18 and 93 years of age.

Compared to placebo, all three Doxepin doses, 1, 3, and 6 mg produced significant improvement in sleep parameters such as wake time after sleep onset, total sleep time and sleep efficiency. These improvements were sustained throughout the duration of studies[19],[25]–[30].

In the 3-month clinical trial, the 3 mg dose produces significant improvement in sleep latency without evidence of next-day residual sedation[27]. In elderly patients, the 4-week study of 6 mg doxepin significantly improved total sleep time and sleep quality versus placebo and these improvements were sustained throughout the trial[25]. Clinical trial in transient insomnia patients (n=565) also demonstrated the effectiveness of doxepin 6 mg in sleep onset, sleep maintenance, sleep duration and sleep quality[28]. Thus doxepin is useful for both sleep maintenance and sleep onset or difficulty in falling sleep. It decreases the frequent waking at night and increase the total duration of sleep.

9.2. Tolerability

Low dose doxepin had an incidence of adverse effects compared to placebo. There were no reported anticholinergic effects, no memory impairment and no evidence of next day residual effects. Doxepin should be avoided in patients who take anti-depresants, alcohol and sedating antihistaminic. Doxepin is metabolized by CYP isoenzymes, co-administration of cimetidine and sertraline like CYP inhibitors may increase the plasma concentration of doxepin[19],[25]–[30].

9.3. Safety

Low dose doxepin is safe drug for short term and long term insomnia. Low dose doxepin is different from other anti-depressants in three effects. First, low dose doxepin has no reports of suicide in clinical trial. Therefore, low dose doxepin does not have a boxed warning for suicide risk. Second, doxepin is not associated with abuse potential in animals or in human. Third, there is no report of weight gaining or appetite increasing. The most common adverse reactions reported were sedation, somnolence, nausea and upper respiratory tract infection[19],[25]–[30]. During the clinical trial, there is no report for rebound insomnia/withdrawal syndrome after doxepin discontinuation. Thus doxepin does not produce physical dependence[19],[25]–[30]. Cardiac safety study showed no prolongation of QT interval with 50 mg dose of doxepin[31]. Doxepin is pregnancy category C drug. It is not a controlled substance like benzodiazepine drugs. In the elderly population and patients with hepatic insufficiency, 3 mg of starting dose is recommended. Mild renal impairment does not required dose adjustment. It should be avoided in patients with severe urinary retention, narrow angle glaucoma and who are currently taking monoamine oxidase inhibitors or has used MAOI for the past two weeks. The uncontrolled insomnia after 7-10 days of treatment may indicate possibility of secondary insomnia or co-morbid insomnia[19].

9.4. Dose administration

Doxepin dosage is very simple for insomnia patients. It is available in strength of 3 mg and 6 mg immediate release oral tablet. The recommended dose of doxepin for adults is 6 mg once daily. The starting dose for the elderly patients >65 years old is 3 mg once daily. The daily dose can be increased to 6 mg, if clinically required. It should be taken within 30 min of bedtime. To minimize the potential for next day effects, doxepin should not be taken within 3 h of a meal[19].

10. Benefits of low dose doxepin therapy for insomnia

Low doses doxepin 3 mg and 6 mg have several distinctive advantages over other available hypnotic agents for several reasons[19],[25]–[30].

1. It does not directly interfere with the other arousal systems[14],[15],[20].

2. The finding of trials confirmed that doxepin 3 mg and 6 mg is efficacious in improving sleep latency, sleep maintenance and sleep quality. Moreover, these improvements are sustained for long duration of 3 months.

3. It does not cause daytime sedation (no next-day sedation).

4. Published clinical trials demonstrated that it is effective in adult as well as elderly patients with primary insomnia and current data suggest that it is also safe and well tolerated at 6 mg dose[19],[25],[27],[29].

5. No incidence of withdrawal syndrome or rebound insomnia after discontinuing doxepin 3 mg or 6 mg[25]–[27].

6. Use of low dose doxepin is not associated with tolerance, and anti-cholinergic side effect. Further, it is not associated with weight gain and cardiac re-polarization[19],[25]–[30].

7. It is a non-controlled substance that enjoys virtually no risk of addiction or dependence[19]. This allows easier prescribing with fewer prescribing restrictions, as well as being potentially effective in high-risk patient populations (e.g. history of alcohol or drug abuse) and those who require a pharmacologic agent on a more chronic basis.

11. Conclusion

In conclusion, doxepin at low doses of 3 mg and 6 mg is effective and well tolerated. It is also safe and non-habit forming option for patients with insomnia. Doxepin is not a controlled substance and it has no risk of abuse. Unlike GABA agonists, low dose doxepin selectively blocks histaminergic action and its arousal property resulting in natural sleep. Low dose doxepin is a new armamentarium for managing chronic primary insomnia and transient insomnia characterized by difficulties with sleep maintenance in adult and elderly patients.

Notes

Comments

Background

Insomnia is an iceberg disease. Prevalence of insomnia is high among the adults as well as the elders. Majority of time, primary insomnia patients are unidentified, as the patients are ignorant to the sleep problems and avoid to visit the physicians. Insomnia is characterized by difficulty in initiating or maintaining sleep. Insomnia is associated with nonrestorative sleep and daytime fatigue, malaise, irritability and decreased memory and concentration. Morbidity of insomnia patients increased when they have associated co-morbid condition such as depression, psychosis and cardiac disease. Traditional hypnotic medications, benzodiazepines and nonbenzodiazepines, act via GABA inhibitory pathway in brain and they are associated with adverse events such as abuse potential, withdrawal syndrome on discontinuation of medication and rebound insomnia. They also developed tolerance and dependence. While, TCAs and anti-depressant agents have proven their effectiveness in improvement of sleep onset and sleep maintenance in healthy subjects as well as depressant patients even after long term use. During the clinical studies, these agents had low abuse potential and dependence. An old TCAs, doxepin, approved to treat depression and anxiety disorder. It also effectively cures insomnia patients with depression. Its potent h2 receptors blocking action is useful for sleep disorder. Low dose doxepin has open new frontier to treat primary insomnia and chronic insomnia patients. Doxepin in 3 mg and 6 mg doses was approved by USFDA in 2010 to treat sleep onset and sleep maintenance in adult and elderly with chronic insomnia.

Research frontiers

The review highlights new and important aspects of insomnia treatment. The authors performed a good review for the role of histamine receptors and their blockade with doxepin to treat insomnia. This approach is a novel compare to traditional therapy. This article focuses on recent developments in insomnia treatment and will be helpful for physician to decide their preferential hypnotic to treat insomnia patients.

Related reports

Zisapel, Loachimescu et al. and Sullivan recently discussed the emerging drugs for insomnia. They reported the advantage of unique action of doxepin when used in 3 mg and 6 mg. In this review, the authors also concluded that low dose doxepin is effective and safe in primary insomnia patients. They also discussed detailed pathophysiology of insomnia and described potential of histamine pathway to induce sleep, which was not the part of previously published articles of the other authors.

Innovations & breakthroughs

This review adds additional support to the use of low dose doxepin in primary insomnia. The authors had wisely covered pathophysiology and clinical data of low dose doxepin. It is a good article for physician for quick guide to hypnotic.

Applications

This review provides a glimpse on recent developments in insomnia treatment and it will be definitely helpful for physician to decide their preferential medication to treat insomnia patients.

Peer review

It is an appropriate review article which highlights newer pharmacological treatment option for insomnia. The authors had nicely discussed pathophysiology of sleep and their basis for developing new agent for insomnia. The pros and cons of low dose doxepin in insomnia are well evaluated. Over all it is a good article for clinician to decide their daily choice of agent for insomnia patients.

Footnotes

Conflict of interest statement: We declare that we have no conflict of interest.

References

2. Roth T, Jaeger S, Jin R, Kalsekar A, Stang PE, Kessler RC. Sleep problems, comorbid mental disorders, and role functioning in the national comorbidity survey replication. Biol Psychiatry. 2006;60:1364–1371. [PMC free article] [PubMed] [Google Scholar]3. Pearson NJ, Johnson LL, Nahin RL. Insomnia, trouble sleeping, and complementary and alternative medicine: analysis of the 2002 national health interview survey data. Arch Intern Med. 2006;166:1775–1782. [PubMed] [Google Scholar]4. Wilson SJ, Nutt DJ, Alford C, Argyropoulos SV, Baldwin DS, Bateson AN, et al. et al. British association for psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders. J Psychopharmacol. 2010;24:1577–1600. [PubMed] [Google Scholar]5. Schutte-Rodin S, Broch L, Buysse D, Dorsey C, Sateia M. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med. 2008;4:487–504. [PMC free article] [PubMed] [Google Scholar]6. Morgenthaler T, Kramer M, Alessi C, Friedman L, Boehlecke B, Brown T, et al. et al. Practice parameters for the psychological and behavioral treatment of insomnia: an update. Sleep. 2006;29:1415–1419. [PubMed] [Google Scholar]8. Galimi R. Insomnia in the elderly: an update and future challenges. G Gerontol. 2010;58:231–247. [Google Scholar]9. Charles AC, Winkelman JW, Richardson GS. Sleep disorders. In: Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, editors. Harrison’s internal medicine. 17th ed. New York: McGraw-Hill Publishing; 2005. pp. 153–161. [Google Scholar]10. American Academy of Sleep Medicine . International classification of sleep disorders: diagnostic and coding manual. 2nd ed. Westchester: American Academy of Sleep Medicine; 2005. [Google Scholar]11. World Health Organization . Geneva: WHO; 1992. The ICD-10 classification of mental and behavioral disorders: Clinical descriptions and diagnostic guidelines[R] [Google Scholar]12. American Psychiatric Association . Diagnostic and statistical manual of mental disorders. 4th ed. Washington DC: The American Psychiatric Association; 2000. [Google Scholar]14. Stahl SM. Selective histamine h2 antagonism: novel hypnotic and pharmacologic actions challenge classical notions of antihistamines. CNS Spectr. 2008;13:1027–1038. [PubMed] [Google Scholar]15. Owen RT. Selective histamine H (1) antagonism: A novel approach to insomnia using low-dose doxepin. Drugs Today (Barc) 2009;45:261–267. [PubMed] [Google Scholar]16. Pinto LR, Jr, Alves RC, Caixeta E, Fontenelle JA, Bacellar A, Poyares D, et al. et al. New guidelines for diagnosis and treatment of insomnia. Arq Neuropsiquiatr. 2010;68:666–675. [PubMed] [Google Scholar]17. Zammit G. Comparative tolerability of newer agents for insomnia. Drug Saf. 2009;32:735–748. [PubMed] [Google Scholar]18. Mets MA, van Deventer KR, Olivier B, Verster JC. Critical appraisal of ramelteon in the treatment of insomnia. Nat Sci Sleep. 2010;2:257–266. [PMC free article] [PubMed] [Google Scholar]21. Slats D, Claassen JA, Verbeek MM, Overeem S. Reciprocal interactions between sleep, circadian rhythms and Alzheimer’s disease: focus on the role of hypocretin and melatonin. Ageing Res Rev. 2013;12:188–200. [PubMed] [Google Scholar]23. Goforth HW. Low-dose doxepin for the treatment of insomnia: emerging data. Expert Opin Pharmacother. 2009;10:1649–1655. [PubMed] [Google Scholar]24. Markov D, Doghramji K. Doxepin for insomnia. Curr Psychiatry. 2010;9:67–77. [Google Scholar]25. Lankford A, Rogowski R, Essink B, Ludington E, Heith Durrence H, Roth T. Efficacy and safety of doxepin 6 mg in a four-week outpatient trial of elderly adults with chronic primary insomnia. Sleep Med. 2012;13:133–138. [PubMed] [Google Scholar]26. Krystal AD, Lankford A, Durrence HH, Ludington E, Jochelson P, Rogowski R, et al. et al. Efficacy and safety of doxepin 3 and 6 mg in a 35-day sleep laboratory trial in adults with chronic primary insomnia. Sleep. 2011;34:1433–1442. [PMC free article] [PubMed] [Google Scholar]27. Krystal AD, Durrence HH, Scharf M, Jochelson P, Rogowski R, Ludington E, et al. et al. Efficacy and safety of doxepin 1 mg and 3 mg in a 12-week sleep laboratory and outpatient trial of elderly subjects with chronic primary insomnia. Sleep. 2010;33:1553–1561. [PMC free article] [PubMed] [Google Scholar]28. Roth T, Heith Durrence H, Jochelson P, Peterson G, Ludington E, Rogowski R, et al. et al. Efficacy and safety of doxepin 6 mg in a model of transient insomnia. Sleep Med. 2010;11:843–847. [PubMed] [Google Scholar]29. Scharf M, Rogowski R, Hull S, Cohn M, Mayleben D, Feldman N, et al. et al. Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in elderly patients with primary insomnia: a randomized, double-blind, placebocontrolled crossover study. J Clin Psychiatry. 2008;69:1557–1564. [PubMed] [Google Scholar]30. Roth T, Rogowski R, Hull S, Schwartz H, Koshorek G, Corser B, et al. et al. Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in adults with primary insomnia. Sleep. 2007;30:1555–1561. [PMC free article] [PubMed] [Google Scholar]31. Mansbach RS, Ludington E, Rogowski R, Kittrelle JP, Jochelson P. A placebo- and active-controlled assessment of 6- and 50-mg oral doxepin on cardiac repolarization in healthy volunteers: A thorough QT evaluation. Clin Ther. 2011;33:851–862. [PubMed] [Google Scholar]

Therapeutic rationale for low dose doxepin in insomnia patients

Asian Pac J Trop Dis. 2013 Aug; 3(4): 331–336.

,¹,²,³,¹ and ^1,*

¹All Saints University, College of Medicine, Kingstown, St. Vincent and the Grenadines

²All Saints University, School of Medicine, Roseau, Dominica

³Medical Services Department, Intas Pharmaceuticals Limited, Ahmadabad, India

Jigar Katwala

¹All Saints University, College of Medicine, Kingstown, St. Vincent and the Grenadines

Ananda K Kumar

²All Saints University, School of Medicine, Roseau, Dominica

Jaykumar J Sejpal

³Medical Services Department, Intas Pharmaceuticals Limited, Ahmadabad, India

Marcelle Terrence

¹All Saints University, College of Medicine, Kingstown, St. Vincent and the Grenadines

Manish Mishra

¹All Saints University, College of Medicine, Kingstown, St. Vincent and the Grenadines

Reviewed by Kamlakar Tripathi, MD, D.M., F.R.C.P.Professor, Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India., Tel: +91-9839044027, Fax: +91-5422307521, E-mail: ni.oc.oohay@ihtapirt_rakalmak*Corresponding author: Dr. Manish Mishra, Assistant Professor, All Saints University, College of Medicine, Kingstown, St. Vincent and the Grenadines. Tel: +1-784-492-5497, Fax: +1-784-458-4151.E-mail: moc.liamg@hsinamcmn

Received 2013 Jun 7; Accepted 2013 Jul 10.

Copyright © 2013 by the Asian Pacific Journal of Tropical Disease. All rights reserved.

Abstract

Histamine is an excitatory neurotransmitter in central nervous system. It plays an important role in the regulation of the sleep-wake cycle. Antidepressant with sleep-promoting effects, for example, doxepin, promotes sleep not through a sedative action but through resynchronisation of circadian cycle. The stimulation of the h2 receptor is thought to play an important role in mediating arousal. Doxepin has a high affinity for the h2 receptor, making it a selective h2 antagonist at low dose and it has been shown to display sedating properties. Compared to other sedative antidepressant, low dose doxepin is the only tricyclic drug which has been evaluated by well-designed, randomised, double blind, placebo controlled studies in both adult and elderly patients. Doxepin is not designated as controlled substance/unscheduled drugs and thus may be of special advantage to use in patients with a history of substance abuse. Hence, well-documented therapeutic efficacy, tolerability and lack of important adverse effects make the low dose doxepin as a unique, rational drug for the treatment of insomnia in adult and elderly patients.

Keywords: Insomnia, Doxepin, Histamine

1. Insomnia

1.1. A general idea

Insomnia is a most common sleep disorder. Insomnia is widespread, affecting more than 25% of the adult population. Approximately 10% of adults presented with insomnia symptoms have associated day time impairment. US national health interview survey and US national co-morbidity survey showed that there was a high rate of morbidity associated between chronic insomnia and medical disorder (e.g. pain) and heart disorder (e.g. heart failure) and psychiatric disorder (e.g. depression, mood, anxiety, and substance abuse disorder)[1]–[3].

1.2. Precipitating factors

There are multiple factors related with patients which make insomnia a vulnerable condition for them. These factors are divided into three category such as predisposing factors (e.g. middle-age, old age, female), personality factors (e.g. hyper excitability, anxious personality), and past and family history (e.g. medical or psychiatric illness) and genetic factors. Many times, psychological and behavioural factors also worsen insomnia (e.g. unexpected loss of loved one, loss of job)[1],[4]–[8].

2. Classification of insomnia

Insomnia has been classified as two ways: by the duration of the insomnia or by its etiology. Based on duration, insomnia is classified as transient insomnia (lasting no longer than 7 d), short-term insomnia (lasting for less than 3 weeks), and chronic insomnia. Transient and short-term insomnias are common during emotional distress. Chronic insomnia lasts for longer duration of usually more than 3 weeks, and some even more than 30 d. The other category of insomnia is based on etiology which includes primary insomnia (occurring without any specific physical and mental conditions) and secondary insomnia (associated with other medical and psychiatric illness, medications, or other sleep disorders)[8],[9].

The International Classification of Sleep Disorder (ICSD) has categorized insomnia as adjustment insomnia, behavioural insomnia of childhood, idiopathic, paradoxical, psychophysiological, and inadequate sleep hygiene, insomnia due to drug or substance, medical condition or mental disorder[10].

3. Symptoms and definition

Various working groups on sleep disorder such as The International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10), Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) and ICSD-2, agree on three main diagnostic criteria to define insomnia. These three chief complaints include difficulty initiating sleep, difficulty maintaining sleep, and waking up too early. Patient has a poor quality or non-restorative sleep. A consequent impairment in daytime functioning and associated subjective symptoms such as fatigue, daytime sleepiness, low energy level, mood irritability, difficulties in cognitive activity (e.g. concentration, memory and attention), lack of motivation, constant worry for sleep and tension headache[10]–[12].

4. Definition

According to the DSM-IV-TR diagnostic criteria for primary insomnia requires[12]:

(i) A predominant complaint of difficulty in initiating or maintaining sleep, or nonrestorative sleep, for at least one month.

(ii) The sleep disturbance (or associated daytime fatigue) causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.

(iii) The sleep disturbance does not occur exclusively during the course of another sleep disorder (narcolepsy, breathing-related sleep disorder, etc).

(iv) The disturbance is not due to the direct physiological effects of a substance (e.g. a drug of abuse, a medication) or another psychiatric or general medical condition.

5. Currently available treatments for insomnia

The British Association for Psychopharmacology guidelines recommended that it is extremely necessary to treat insomnia because the condition causing poor quality of life, is associated with impaired functioning in many areas, and leads to increased risk of psychological disorder (e.g. depression, anxiety) and possibly cardiovascular disorders. Main goals of insomnia treatment are to produce less suffering and to improve daytime function[4].

There are various methods of psychological and behavioural intervention for treatment of insomnia, including the sleep hygiene, stimulus control, sleep restriction, relaxation techniques, feedback, cognitive therapy, “chronotherapy”, and phytotherapy[5]. The British Association for Psychopharmacology Consensus, American Academy of Sleep Medicine, and the 2005 US National Institute of Health State-of Science Conference on insomnia concluded that cognitive behavioural therapy (CBT) and benzodiazepine receptor agonist have level a evidence for short-term treatment of chronic insomnia. CBT is effective for individual or a group of people[4],[6],[13]. The current mainstay for the pharmacotherapy of insomnia is as below[4]–[9],[13],[14]:

1. Enhancing the inhibitory wake-promoting neurotransmitter gamma amino benzoic acid (GABA).

A. Benzodiazepine receptors agonist: triazolam, temazepam, lorazepam, and flurazepam.

B. Non-benzodiazepine receptor agonist (Z-drug): zolpidem, zaleplon, eszopiclone.

2. Melatonin, ramelteon, almorexant.

3. Other agents.

A. Over the counter (OTC) products: diphenhydramine hydrochloride, diphenhydramine citrate, doxylamine succinate.

B. Tricyclic anti-depressant agents (TCAs): amitriptyline, nortriptyline, doxepin, trazodone.

6. Limitations of current therapies

6.1. Benzodiazepines and non-benzodiazepines agents

These hypnotic agents act by enhancing sleep promoting neurotransmitter (GABA). It causes high degree of inhibition of arousal. Therefore, the wake-promoting systems mediated via norepinephrine, acetylcholine, histamine, dopamine and serotonin are inhibited by GABA mechanisms. There is a balance between these two systems for safe functioning, such as driving, walking to the bathroom in dark without falling[9].

These compounds have reported efficacy and safety in terms of improvement in sleep quality. However, they are associated with numerous adverse events such as daytime sedation or next-day residual effects, motor incoordinataion, reduced psychomotor performance, cognitive impairment and related concerns about increases in risk of motor vehicle accidents and injuries from fall[9],[14].

Chronic administration of benzodiazepines agonists agent produces tolerance, psychological dependence. The adaptive changes in GABA receptor cause withdrawal, characterized by neurological, physical and cognitive symptoms, and rebound insomnia[4],[9],[14],[15].

These agents have also been associated with the potential for abuse and dependence in at risk populations, which led the US Drug Enforcement Agency to classify them as Schedule IV substances[16],[17].

6.2. Melatonin, ramelteon and almorexant

Newer approaches include ramelteon, the first and only nonscheduled drug approved by the US FDA for the treatment of insomnia, and in the future possibly by the orexin system, through agents such as almorexant. Ramelteon produces sleep through activation of melatonin 1 and melatonin 2 receptors in the suprachiasmatic nucleus of the hypothalamus. Almorexant produces selective antagonism of orexin OX1 and OX2 receptor. There is no adequate evidence that they are effective in the treatment of insomnia[15],[18].

6.3. Other agents

Anti-histaminics are the active ingredients of OTC sleep aids available in market (i.e. diphenhydramine, doxylamine). Disadvantages of the current OTC antihistamines are their relatively long duration of action and next-morning drowsiness, potential side effects, and insufficient receptor selectivity has risk of undesired anticholinergic side effect (i.e. dry mouth, dry eye, retention of urine, constipation)[16].

The most commonly used anti-depressants for co-morbid insomnia include sedating tricyclics anti-depressants (TCAs), such as amitriptyline, doxepin, and nortriptyline, and 5HT2 antagonist trazodone. They are effective for inducing sleep and improving sleep continuity. The TCAs can alter sleep architecture by reducing rapid eye movement (REM) sleep. In general, sedating properties of anti-depressant agents are related to antagonism of serotonin 5HT2, histamines, and α-1 adrenergic receptors[14]–[16].

Because of their non-selective antagonist action on 5HT2, histamines, and α-1 adrenergic receptors, these agents produce side effects such as anticholinergic, adrenergic blockade, and prolong cardiac conduction. These agents also cause potential side effects such as weight gain, increased suicidal ideation, hypomania or mania in patients with bipolar disorder.

There is short of evidence which proves that sedative anti-depressants are effective in the treatment of insomnia. Although due to lack of abuse potential, they are considered as unscheduled drug. They are cheaper and well studied drugs. Therefore, they are drug of choice for patients with co-morbid insomnia who is suffering from depression.

Although, the treatment of insomnia is widely used, many agents that block the histamine h2 receptor are considered to have therapeutic limitations, including the development of next-day carryover sedation, as well as problems with chronic use, such as the development of tolerance to sedative-hypnotic action and weight gain. TCAs like doxepin exert such potent histamine h2 blockade that it has been possible to optimize their hypnotic activity by using very low dose. Since March 2010, the US FDA has approved low dose doxepin for the indication of insomnia[19].

In this review, we have discussed the further details of role of histamine for wakefulness and blockade of histamine by doxepin to reduce the wakefulness. Effectiveness and safety of doxepin for the patients who have complaint of sleep maintenance and sleep onset insomnia.

7. Emerging trends

Recent research has revisited one of the oldest approaches to insomnia, namely by using anti-depressant and antihistaminic properties. Anti-histaminic such as diphenhydramine and doxylamine are used as sleep promoting agents. They are available as over the counter products. Anti-depressants with histamine antagonist action such as trazodon, doxepin, mirtazapine and antipsychotic with antihistaminic properties like quetiapine are used for the treatment of insomnia with co-morbid psychiatric condition like depression[14],[15].

7.1. Arousal pathway

Histamine is the key neurotransmitter for arousal. It is synthesized in the hypothalamus. It drives the wakefulness known as “wake-promoting” neurotransmitter. The major site of histaminic neurones is tuberomammillary nucleus (TMN). The distribution of histamine receptors in brain is very dense. Histamine h2 receptors are of high density in the cortex and in the limbic system, while histamine h3 receptors have high density in the striatum, cerebral cortex, and also in the limbic system; and finally, histamine h4 receptors, the autoreceptors, are dense in the striatum and the cortex. Histamine produces its action via direct and indirect stimulation of arousal pathway. Direct pathway causes stimulation of histamine receptor travelling via the ascending histaminergic neurones from hypothalamus to thalamic h2 and h3 receptors or in the cortex via histamine h2 receptor. The release of histamine causes calm wakefulness (i.e. well-rested state, the ability to focus on cognitive task, problem solving, learning, creativity). Secondly, histamine also produces indirect activation of basal forebrain cholinergic neurone via histamine h2 receptors. This stimulation causes release of acetylcholine which stimulated arousal (i.e. anxiety, fright, external vigilance) ()[14],[15],[20]–[22].

Arousal pathway and mechanism of action of hypnotic drugs.

Among anti-depressants, doxepin has the highest binding capacity to histamine receptors. Its potency to bind histamine is even stronger than classical antihistaminic. Doxepin had high binding to histamine in frontal cortex, amygdale, temporal cortex, and the hippocampus[20].

Low dose doxepin acts via blocking h2 receptors, which is very unique among the currently approved FDA drugs for the treatment of insomnia. Doxepin, 3 mg and 6 mg, were approved by USFDA in March, 2010 in both adult and elderly patients suffering from short and long term insomnia[19].

8. Low dose doxepin for insomnia

Doxepin is a three-decade old tricyclic anti-depressant agent. It is approved for the treatment of depression, depression with insomnia and anxiety disorders. Anti-depressant action produces with ≥25 mg of doxepin. Lower dosage produces anti-anxiety effect. Anti-depressant action of doxepin is because of reuptake inhibition of nor-epinephrine and serotonin. Higher dose ≥25 mg of doxepin is nonslective and responsible for undesired side effects such as anticholinergic, antiadrenergic, and potentiation of cardiac conduction ()[23],[24].

Chemical structure of doxepin hydrochloride.

Lower dose doxepin has a very high selectivity for h2 receptor. It binds with histamine receptors for 100 times more than that of nor-epinephrine and serotonin receptors. Antagonism of histamine receptors in TMN nucleus inhibits the arousal pathway. This produces hypnotic action. Thus low dose of doxepin (1, 3, 6 mg) can produce selective h2 blockade[19],[20],[23],[24],.

Low dose doxepin is advantages for the patients with complaint of objective and subjective measures of sleep maintenance and sleep onset insomnia. Sleep effects seem to be dose dependent, and among the very low-dose preparations being studied, the 3 mg and 6 mg doses appeared the most effective in adult as well as elderly patients; doxepin (@roneliS) has been approved for insomnia treatment in USA[19].

9. Clinical efficacy and safety of 1, 3, and 6 mg doxepin in insomnia

9.1. Efficacy

Doxepin 1, 3, and 6 mg is widely studied in both adult and elderly patients with difficulty in sleep onset and sleep maintenance insomnia. There were 1 423 subjects, with chronic insomnia (n=858) or transient (n=565) insomnia participated in 6 randomised, double-blind studied. These studies were up to 3 months in duration and included patients of both sex between 18 and 93 years of age.

Compared to placebo, all three Doxepin doses, 1, 3, and 6 mg produced significant improvement in sleep parameters such as wake time after sleep onset, total sleep time and sleep efficiency. These improvements were sustained throughout the duration of studies[19],[25]–[30].

In the 3-month clinical trial, the 3 mg dose produces significant improvement in sleep latency without evidence of next-day residual sedation[27]. In elderly patients, the 4-week study of 6 mg doxepin significantly improved total sleep time and sleep quality versus placebo and these improvements were sustained throughout the trial[25]. Clinical trial in transient insomnia patients (n=565) also demonstrated the effectiveness of doxepin 6 mg in sleep onset, sleep maintenance, sleep duration and sleep quality[28]. Thus doxepin is useful for both sleep maintenance and sleep onset or difficulty in falling sleep. It decreases the frequent waking at night and increase the total duration of sleep.

9.2. Tolerability

Low dose doxepin had an incidence of adverse effects compared to placebo. There were no reported anticholinergic effects, no memory impairment and no evidence of next day residual effects. Doxepin should be avoided in patients who take anti-depresants, alcohol and sedating antihistaminic. Doxepin is metabolized by CYP isoenzymes, co-administration of cimetidine and sertraline like CYP inhibitors may increase the plasma concentration of doxepin[19],[25]–[30].

9.3. Safety

Low dose doxepin is safe drug for short term and long term insomnia. Low dose doxepin is different from other anti-depressants in three effects. First, low dose doxepin has no reports of suicide in clinical trial. Therefore, low dose doxepin does not have a boxed warning for suicide risk. Second, doxepin is not associated with abuse potential in animals or in human. Third, there is no report of weight gaining or appetite increasing. The most common adverse reactions reported were sedation, somnolence, nausea and upper respiratory tract infection[19],[25]–[30]. During the clinical trial, there is no report for rebound insomnia/withdrawal syndrome after doxepin discontinuation. Thus doxepin does not produce physical dependence[19],[25]–[30]. Cardiac safety study showed no prolongation of QT interval with 50 mg dose of doxepin[31]. Doxepin is pregnancy category C drug. It is not a controlled substance like benzodiazepine drugs. In the elderly population and patients with hepatic insufficiency, 3 mg of starting dose is recommended. Mild renal impairment does not required dose adjustment. It should be avoided in patients with severe urinary retention, narrow angle glaucoma and who are currently taking monoamine oxidase inhibitors or has used MAOI for the past two weeks. The uncontrolled insomnia after 7-10 days of treatment may indicate possibility of secondary insomnia or co-morbid insomnia[19].

9.4. Dose administration

Doxepin dosage is very simple for insomnia patients. It is available in strength of 3 mg and 6 mg immediate release oral tablet. The recommended dose of doxepin for adults is 6 mg once daily. The starting dose for the elderly patients >65 years old is 3 mg once daily. The daily dose can be increased to 6 mg, if clinically required. It should be taken within 30 min of bedtime. To minimize the potential for next day effects, doxepin should not be taken within 3 h of a meal[19].

10. Benefits of low dose doxepin therapy for insomnia

Low doses doxepin 3 mg and 6 mg have several distinctive advantages over other available hypnotic agents for several reasons[19],[25]–[30].

1. It does not directly interfere with the other arousal systems[14],[15],[20].

2. The finding of trials confirmed that doxepin 3 mg and 6 mg is efficacious in improving sleep latency, sleep maintenance and sleep quality. Moreover, these improvements are sustained for long duration of 3 months.

3. It does not cause daytime sedation (no next-day sedation).

4. Published clinical trials demonstrated that it is effective in adult as well as elderly patients with primary insomnia and current data suggest that it is also safe and well tolerated at 6 mg dose[19],[25],[27],[29].

5. No incidence of withdrawal syndrome or rebound insomnia after discontinuing doxepin 3 mg or 6 mg[25]–[27].

6. Use of low dose doxepin is not associated with tolerance, and anti-cholinergic side effect. Further, it is not associated with weight gain and cardiac re-polarization[19],[25]–[30].

7. It is a non-controlled substance that enjoys virtually no risk of addiction or dependence[19]. This allows easier prescribing with fewer prescribing restrictions, as well as being potentially effective in high-risk patient populations (e.g. history of alcohol or drug abuse) and those who require a pharmacologic agent on a more chronic basis.

11. Conclusion

In conclusion, doxepin at low doses of 3 mg and 6 mg is effective and well tolerated. It is also safe and non-habit forming option for patients with insomnia. Doxepin is not a controlled substance and it has no risk of abuse. Unlike GABA agonists, low dose doxepin selectively blocks histaminergic action and its arousal property resulting in natural sleep. Low dose doxepin is a new armamentarium for managing chronic primary insomnia and transient insomnia characterized by difficulties with sleep maintenance in adult and elderly patients.

Notes

Comments

Background

Insomnia is an iceberg disease. Prevalence of insomnia is high among the adults as well as the elders. Majority of time, primary insomnia patients are unidentified, as the patients are ignorant to the sleep problems and avoid to visit the physicians. Insomnia is characterized by difficulty in initiating or maintaining sleep. Insomnia is associated with nonrestorative sleep and daytime fatigue, malaise, irritability and decreased memory and concentration. Morbidity of insomnia patients increased when they have associated co-morbid condition such as depression, psychosis and cardiac disease. Traditional hypnotic medications, benzodiazepines and nonbenzodiazepines, act via GABA inhibitory pathway in brain and they are associated with adverse events such as abuse potential, withdrawal syndrome on discontinuation of medication and rebound insomnia. They also developed tolerance and dependence. While, TCAs and anti-depressant agents have proven their effectiveness in improvement of sleep onset and sleep maintenance in healthy subjects as well as depressant patients even after long term use. During the clinical studies, these agents had low abuse potential and dependence. An old TCAs, doxepin, approved to treat depression and anxiety disorder. It also effectively cures insomnia patients with depression. Its potent h2 receptors blocking action is useful for sleep disorder. Low dose doxepin has open new frontier to treat primary insomnia and chronic insomnia patients. Doxepin in 3 mg and 6 mg doses was approved by USFDA in 2010 to treat sleep onset and sleep maintenance in adult and elderly with chronic insomnia.

Research frontiers

The review highlights new and important aspects of insomnia treatment. The authors performed a good review for the role of histamine receptors and their blockade with doxepin to treat insomnia. This approach is a novel compare to traditional therapy. This article focuses on recent developments in insomnia treatment and will be helpful for physician to decide their preferential hypnotic to treat insomnia patients.

Related reports

Zisapel, Loachimescu et al. and Sullivan recently discussed the emerging drugs for insomnia. They reported the advantage of unique action of doxepin when used in 3 mg and 6 mg. In this review, the authors also concluded that low dose doxepin is effective and safe in primary insomnia patients. They also discussed detailed pathophysiology of insomnia and described potential of histamine pathway to induce sleep, which was not the part of previously published articles of the other authors.

Innovations & breakthroughs

This review adds additional support to the use of low dose doxepin in primary insomnia. The authors had wisely covered pathophysiology and clinical data of low dose doxepin. It is a good article for physician for quick guide to hypnotic.

Applications

This review provides a glimpse on recent developments in insomnia treatment and it will be definitely helpful for physician to decide their preferential medication to treat insomnia patients.

Peer review

It is an appropriate review article which highlights newer pharmacological treatment option for insomnia. The authors had nicely discussed pathophysiology of sleep and their basis for developing new agent for insomnia. The pros and cons of low dose doxepin in insomnia are well evaluated. Over all it is a good article for clinician to decide their daily choice of agent for insomnia patients.

Footnotes

Conflict of interest statement: We declare that we have no conflict of interest.

References

2. Roth T, Jaeger S, Jin R, Kalsekar A, Stang PE, Kessler RC. Sleep problems, comorbid mental disorders, and role functioning in the national comorbidity survey replication. Biol Psychiatry. 2006;60:1364–1371. [PMC free article] [PubMed] [Google Scholar]3. Pearson NJ, Johnson LL, Nahin RL. Insomnia, trouble sleeping, and complementary and alternative medicine: analysis of the 2002 national health interview survey data. Arch Intern Med. 2006;166:1775–1782. [PubMed] [Google Scholar]4. Wilson SJ, Nutt DJ, Alford C, Argyropoulos SV, Baldwin DS, Bateson AN, et al. et al. British association for psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders. J Psychopharmacol. 2010;24:1577–1600. [PubMed] [Google Scholar]5. Schutte-Rodin S, Broch L, Buysse D, Dorsey C, Sateia M. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med. 2008;4:487–504. [PMC free article] [PubMed] [Google Scholar]6. Morgenthaler T, Kramer M, Alessi C, Friedman L, Boehlecke B, Brown T, et al. et al. Practice parameters for the psychological and behavioral treatment of insomnia: an update. Sleep. 2006;29:1415–1419. [PubMed] [Google Scholar]8. Galimi R. Insomnia in the elderly: an update and future challenges. G Gerontol. 2010;58:231–247. [Google Scholar]9. Charles AC, Winkelman JW, Richardson GS. Sleep disorders. In: Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, editors. Harrison’s internal medicine. 17th ed. New York: McGraw-Hill Publishing; 2005. pp. 153–161. [Google Scholar]10. American Academy of Sleep Medicine . International classification of sleep disorders: diagnostic and coding manual. 2nd ed. Westchester: American Academy of Sleep Medicine; 2005. [Google Scholar]11. World Health Organization . Geneva: WHO; 1992. The ICD-10 classification of mental and behavioral disorders: Clinical descriptions and diagnostic guidelines[R] [Google Scholar]12. American Psychiatric Association . Diagnostic and statistical manual of mental disorders. 4th ed. Washington DC: The American Psychiatric Association; 2000. [Google Scholar]14. Stahl SM. Selective histamine h2 antagonism: novel hypnotic and pharmacologic actions challenge classical notions of antihistamines. CNS Spectr. 2008;13:1027–1038. [PubMed] [Google Scholar]15. Owen RT. Selective histamine H (1) antagonism: A novel approach to insomnia using low-dose doxepin. Drugs Today (Barc) 2009;45:261–267. [PubMed] [Google Scholar]16. Pinto LR, Jr, Alves RC, Caixeta E, Fontenelle JA, Bacellar A, Poyares D, et al. et al. New guidelines for diagnosis and treatment of insomnia. Arq Neuropsiquiatr. 2010;68:666–675. [PubMed] [Google Scholar]17. Zammit G. Comparative tolerability of newer agents for insomnia. Drug Saf. 2009;32:735–748. [PubMed] [Google Scholar]18. Mets MA, van Deventer KR, Olivier B, Verster JC. Critical appraisal of ramelteon in the treatment of insomnia. Nat Sci Sleep. 2010;2:257–266. [PMC free article] [PubMed] [Google Scholar]21. Slats D, Claassen JA, Verbeek MM, Overeem S. Reciprocal interactions between sleep, circadian rhythms and Alzheimer’s disease: focus on the role of hypocretin and melatonin. Ageing Res Rev. 2013;12:188–200. [PubMed] [Google Scholar]23. Goforth HW. Low-dose doxepin for the treatment of insomnia: emerging data. Expert Opin Pharmacother. 2009;10:1649–1655. [PubMed] [Google Scholar]24. Markov D, Doghramji K. Doxepin for insomnia. Curr Psychiatry. 2010;9:67–77. [Google Scholar]25. Lankford A, Rogowski R, Essink B, Ludington E, Heith Durrence H, Roth T. Efficacy and safety of doxepin 6 mg in a four-week outpatient trial of elderly adults with chronic primary insomnia. Sleep Med. 2012;13:133–138. [PubMed] [Google Scholar]26. Krystal AD, Lankford A, Durrence HH, Ludington E, Jochelson P, Rogowski R, et al. et al. Efficacy and safety of doxepin 3 and 6 mg in a 35-day sleep laboratory trial in adults with chronic primary insomnia. Sleep. 2011;34:1433–1442. [PMC free article] [PubMed] [Google Scholar]27. Krystal AD, Durrence HH, Scharf M, Jochelson P, Rogowski R, Ludington E, et al. et al. Efficacy and safety of doxepin 1 mg and 3 mg in a 12-week sleep laboratory and outpatient trial of elderly subjects with chronic primary insomnia. Sleep. 2010;33:1553–1561. [PMC free article] [PubMed] [Google Scholar]28. Roth T, Heith Durrence H, Jochelson P, Peterson G, Ludington E, Rogowski R, et al. et al. Efficacy and safety of doxepin 6 mg in a model of transient insomnia. Sleep Med. 2010;11:843–847. [PubMed] [Google Scholar]29. Scharf M, Rogowski R, Hull S, Cohn M, Mayleben D, Feldman N, et al. et al. Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in elderly patients with primary insomnia: a randomized, double-blind, placebocontrolled crossover study. J Clin Psychiatry. 2008;69:1557–1564. [PubMed] [Google Scholar]30. Roth T, Rogowski R, Hull S, Schwartz H, Koshorek G, Corser B, et al. et al. Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in adults with primary insomnia. Sleep. 2007;30:1555–1561. [PMC free article] [PubMed] [Google Scholar]31. Mansbach RS, Ludington E, Rogowski R, Kittrelle JP, Jochelson P. A placebo- and active-controlled assessment of 6- and 50-mg oral doxepin on cardiac repolarization in healthy volunteers: A thorough QT evaluation. Clin Ther. 2011;33:851–862. [PubMed] [Google Scholar]

Common and Rare Side Effects for doxepin oral

COMMON side effects

If experienced, these tend to have a Severe expression i

Sorry, we have no data available. Please contact your doctor or pharmacist.

If experienced, these tend to have a Less Severe expression i

• dry mouth
• drowsiness
• dizziness
• taste impairment
• weight gain
• increased hunger
• headache

INFREQUENT side effects

If experienced, these tend to have a Severe expression i

• confusion
• abnormal sexual function
• a type of movement disorder called parkinsonism
• blurred vision
• slow heartbeat
• abnormal heart rhythm
• low blood pressure
• the inability to have an erection
• hallucinations
• muscle tremors
• difficult or painful urination
• nervousness

If experienced, these tend to have a Less Severe expression i

• altered interest in having sexual intercourse
• a common cold
• constipation
• difficulty sleeping
• excessive sweating
• vomiting
• heartburn
• diarrhea

RARE side effects

If experienced, these tend to have a Severe expression i

• a disorder with excess antidiuretic hormone called syndrome of inappropriate antidiuretic hormone
• large purple or brown skin blotches
• very low levels of granulocytes, a type of white blood cell
• increased eosinophils in the blood
• a blood disorder
• mental problems from taking the drug
• panic disorder
• suicidal thoughts
• serotonin syndrome, a type of disorder with high serotonin levels
• ringing in the ears
• a heart attack
• a type of slowed heart rhythm disorder called heart block
• abnormal heart electrical signals
• rapid ventricular heartbeat
• ventricular fibrillation, a heart rhythm disorder
• prolonged QT interval on EKG
• a stroke
• swelling of the testicles
• enlarged breasts
• breastmilk production not associated with childbirth or nursing
• increased sensitivity of the skin to the sun
• inflammation of the skin due to an allergy
• itching
• hair loss
• seizures
• a skin rash
• high amount of bilirubin in the blood
• abnormal liver function tests
• a type of allergic reaction called angioedema
• secondary angle-closure glaucoma, a type of eye disorder
• accidental falls
• fast heartbeat

If experienced, these tend to have a Less Severe expression i

• delusions
• nightmares
• agitation
• aggressive behavior
• feelings of hostility
• dilated pupils
• high blood pressure
• decreased appetite
• heart throbbing or pounding
• nausea
• a feeling of pins and needles on skin
• irritability
• an inability to control impulsive behavior
• anxious feelings

Side Effects of Sinequan (Doxepin), Warnings, Uses

003781049_PB

capsule, buff, imprinted with MYLAN 1049, MYLAN 1049

003783125_PB

capsule, white/yellow, imprinted with MYLAN 3125, MYLAN 3125

003784250_PB

capsule, white, imprinted with MYLAN 4250, MYLAN 4250

003785375_PB

capsule, green, imprinted with MYLAN 5375, MYLAN 5375

003786410_PB

capsule, green/white, imprinted with MYLAN 6410, MYLAN 6410

422910247_PB

capsule, blue/white, imprinted with Par 222, Par 222

498840222_PB

capsule, blue/white, imprinted with par 222, par 222

510790436_PB

capsule, white, imprinted with MYLAN 1049, MYLAN 1049

510790437_PB

capsule, white/yellow, imprinted with MYLAN 3125, MYLAN 3125

510790438_PB

capsule, white, imprinted with MYLAN 4250, MYLAN 4250

510790651_PB

capsule, green/white, imprinted with MYLAN 6410, MYLAN 6410

Doxepin 10 mg 692381166

capsule, yellow, imprinted with AMNEAL, 1166

Doxepin 10 mg-MYL

capsule, white, imprinted with MYLAN 1049, MYLAN 1049

Doxepin 10 mg-PAR

capsule, white, imprinted with par 217, par 217

Doxepin 10 mg-WAT

capsule, beige, imprinted with DAN 5629, DAN 5629

Doxepin 100 mg 692381173

capsule, green/white, imprinted with AMNEAL, 1173

Doxepin 100 mg-MYL

capsule, green/white, imprinted with MYLAN 6410, MYLAN 6410

Doxepin 100 mg-PAR

capsule, green/white, imprinted with par 221, par 221

Doxepin 100 mg-WAT

capsule, green/white, imprinted with DAN 5633, DAN 5633

Doxepin 150 mg-PAR

capsule, blue/white, imprinted with par 222, par 222

Doxepin 25 mg 692381170

capsule, yellow/white, imprinted with AMNEAL, 1170

Doxepin 25 mg-MYL

capsule, white/yellow, imprinted with MYLAN 3125, MYLAN 3125

Doxepin 25 mg-PAR

capsule, white/yellow, imprinted with par 218, par 218

Doxepin 25 mg-WAT

capsule, white/yellow, imprinted with DAN 5630, DAN 5630

Doxepin 50 mg 692381171

capsule, yellow, imprinted with AMNEAL, 1171

Doxepin 50 mg-MYL

capsule, white, imprinted with MYLAN 4250, MYLAN 4250

Doxepin 50 mg-PAR

capsule, white, imprinted with par 219, par 219

Doxepin 50 mg-WAT

capsule, yellow, imprinted with DAN 5631, DAN 5631

Doxepin 75 mg 692381172

capsule, green, imprinted with AMNEAL, 1172

Doxepin 75 mg-MYL

capsule, green, imprinted with MYLAN 5375, MYLAN 5375

Doxepin 75 mg-PAR

capsule, green, imprinted with par 220, par 220

Doxepin 75 mg-WAT

capsule, green, imprinted with DAN 5632, DAN 5632

Doxepin Hcl 100mg 009046973

capsule, green/white, imprinted with Par 221, Par 221

Doxepin Hcl 50mg 009046972

capsule, ivory, imprinted with Par 219, Par 219

Doxepin Weight Gain, [Weight] Explore Denver, NC Homes

Doxepin Weight Gain, [Weight] Explore Denver, NC Homes

When Viscount Gibran doxepin weight gain was exposed, he obviously knew that his death was approaching. It is estimated that Kree s sword just doxepin weight gain now, Can directly wipe out half of his body. The buzzing sound keeps on, although they are now panic, they are even more curious. Just around them, groups of light cavalry appeared in the darkness, like the same prairie wolves, roaring out of the night, toward the small road ahead, the Weight Loss Story already nervous transportation team rushed. of course, Even resistance has no effect, In the end, the water pirates were slaughtered, and the disintegrated infantry was not an opponent of the cavalry at all. Anyway, those guys didn t look like Weight robbers, There is also a key point, Even if it is robbery, it has nothing to do with them anyway, Inside are the warehouses of those foreign merchants. In this dark night, the light source is a must, Otherwise, it is very possible to slander the fast march and die and keto diet dry mouth stampede. But even if Doxepin Weight Gain they were cold, tired, and hungry, these cavalrymen had not forgotten to take care of their close-up horses. Now, although this car formation is not composed of Khergits, relying on the rock-like Rhodoks, the Ravenstons who are good at rapid shooting, and the powerful heavy-riding Muluks are basically safe. Dragging their exhausted bodies, the knights fought with all their strength and desperately broke through. As long as he could control it well, he might not have a great impact, At the very least, this Bertram doxepin weight gain s father is still a court baron, and the contacts he generated alton brown diet plan doxepin weight gain protein foods with no fat can also help maintain stability. Simply put, they were just a group of hunters, Fort Avile is close to the Sangvaya Mountains, so the farmers there are also potassium nutrition hunters. Even Doxepin Weight Gain Korod swallowed, and his heart Weight Loss Story was obviously extremely shocked, Although they have filled keto detox pills doxepin weight gain most of the southern county leader, seeming to be attacking the city, and the strong and powerful main force of the southern county doxepin weight gain leader dare not confront them, but in fact they know in their hearts that what they are sweeping now Doxepin Weight Gain is just a bunch of villages stationed by militias, and A large number of unarmed villagers did not match up with the regular army of the nobles at all. He how many calories are in chicken? intends doxepin weight gain to sleep for two hours first, Then shout again, You can sleep till dawn, Fifty tharion lion knights, under the obscure Doxepin Weight Gain moonlight, turned into a best weight loss pills for someone with high blood pressure doxepin weight gain shadow, quietly doxepin weight gain came under the south gate tower. Now it seems that even the North County leader is not as complicated as the East County leader. Even if it is past, disturbed and vigilant targets will not allow them dr colbert keto diet recipes doxepin weight gain to assassinate easily.

But these desert bandits deal with it, They dared to resist and took their lives Weight Loss Story directly Doxepin Weight Gain with a spear or a scimitar. calories in bacon slice After all, the mother of the Baron Kree was framed Doxepin Weight Gain by some nobles in the South County As for the body, it is sunken, He vomited blood and convulsed to death, Well-trained, lined up in long lines, walked lightly and quickly among them, put the silver plate on the doxepin weight gain long table in the middle, opened the lid, and then retreated to the wall respectfully and waited quietly.

Weight But the Rhodoks didn t care, they doxepin weight gain still rushed up, Weight.

where can you buy keto diet pills?

facing the big foot that was doxepin weight gain raised and stepped on, they didn nutrition 53 t hesitate to stab with a spear, low carb granola slash with a garcinia weight loss pills side effects sword, even if they died, they would delay, let this hell demon Wait a few seconds in place. At the salt mine station, calories in corned beef at least 2 royal knights, 500 doxepin weight gain Swadia heavy cavalry, burn stomach fat fast and 50 desert bandits Doxepin Weight Gain are so easy. As a red flame wall instantly dispersed, the arrow rain was hit and dropped in pieces. Kree muttered to himself: My, father? This is a very vague impression, In retrospect, what makes Kree s memory more what percent of your daily calories should come from fat profound is the majestic, almost suffocating pressure that suppressed him. A group of well-equipped infantry with excellent battlefield skills slaughtered a group of poorly equipped and weak armed militias.

Well-trained, lined up in long lines, walked lightly ans nutrition and quickly among them, put the silver plate on the doxepin weight gain long table in the middle, opened the lid, and then retreated to the wall respectfully and waited quietly. But what he was wearing was activate diet pills gray-black, with a weird armor filled with black mist Although he is older, the majesty he bones and raw food diet for dog once left on the battlefield doxepin weight gain is more and more intense. The horn, which is also Doxepin Weight Gain engraved with a golden Doxepin Weight Gain Doxepin Weight Gain lion on a red background, is also pinned to his waist. The sound of footsteps and shouts gradually appeared around the tent, Many desert robbers acted as retinues and fetched water from a stream not far away to provide daily e z weight loss pills reddit doxepin weight gain drinking for nearly 3,000 people and horses, and to prepare for the following breakfast. In the face of the upcoming sect knights, Kree has only one way to face them: war. As long as the defending forces work together, they can use it to counteract even in the face of tens of thousands of troops. But Sergeant Rodok swept them indifferently, without any intention of responding at all. But the factor to become a level 3 cavalry is the advantage that the low carb granola undead does not need to eat and drink and has no physical limitations. Yes! Fattis nodded, At the same time, he continued: When I came to Hard Rock Pass, I did not simply stay here. The main reason is that these things are not Kree s doxepin weight gain own, They were all keto white chocolate fat bombs found in the warehouses of the mansion at Hard Rock Pass. If there is a new round of invasion, facing the troops of the Yinpan Kingdom, the nobles in the lion Principality are unlikely to unite and resist, but they will wait doxepin weight gain for the price to see if they can take refuge in the Yinpan Kingdom. But it was precisely the doxepin weight gain fact that most of the skeleton warriors and skeleton soldiers were swept away, and all the undead infantry who Doxepin Weight Gain invaded the sentry herbal weight loss pills oasis were swept away. That would be terrible, According to Kree s understanding of the strength of the Mage Association, even if they were all dispatched, they would not be able to do so at all. The ancient and modern Doxepin Weight Gain concepts of urban low carb granola defense at home and abroad were Doxepin Weight Gain implemented and constructed by Kree. The nobles do not blindly know the hostility, Especially at the critical point. The golden light of the king s divine might was mixed with body fat analyzer sacred white light, and the sacred realm was enveloped around. Now that the Dark Red sect is destroyed, no one needs to continue to bear it. It is easy to get more silver coins, low carb granola No matter doxepin weight gain how other people think, there doxepin weight gain is no doxepin weight gain way to prevent the rise of aristocrats with such strength. So he didn t care about this old guy at all, The brilliance thousands of years ago. This war is a sky show, Kree how to lose weight fast naturally doxepin weight gain led the lower army as the leading role, and the 15,000 heavy cavalry led by the South County, who was promoted to the strongest state, served as the villain, and the aristocratic coalition led by the North County and the East County served as supporting v8 juice nutrition actors. Even the medal made by a majestic lion on the chest is already pinned on it. Even Nord s strongest level 6 Nord Royal Guards can contend for a long Weight Loss Story time. Viscount Gibran roared like a whimper, Saliva flowed at the corner of his mouth, and now he does not look like a human being: Unexpectedly, you have such power how to get rid of lower chest fat and deceived everyone, ketosis metabolism doxepin weight gain hahaha, you deceived everyone. These people are placed Abstract, (1) This Classic: The main heart is qi, the wound is full, the stomach collaterals are absolutely at the end of the team, Doxepin Weight Gain Rolf knew that if these people Doxepin.

how to have coconut oil for weight loss?

were arranged to act as Doxepin cannon fodder in the forefront, it nutrition month 2020 was estimated that a small piece of death would Weight Loss Story be edamame nutrition frightened and collapsed. doxepin weight gain But at the moment, Kree looked at an altar in the depths of the big hole and squinted slightly: The disc of the sun. No, we keep a certain distance, The gate knight shrugged, After a pause, looking at the butler s doxepin weight gain ugly face, he still muttered: Just let them wait outside, and didn t dare to let them into the city directly. Nominally, Baron Dylan took a deep breath: I can dedicate it to Countess Agatha. A layer of snow-white keto pantry shopping list mist rolled doxepin weight gain on the surface of the distant river, showing a misty atmosphere. Once they dr colbert keto diet recipes doxepin weight gain were relaxed, they could no longer hold back their bodies and spirits. This is the easiest, Hahaha Bestur laughed and looked at Kree: My lord, I think there are smart people among these guys, and I think they can make the most reasonable judgments. Even the skeletons of the undead will be directly destroyed, causing the army of these skeletons to overflow and scatter the bones that should be dissipated. This order was repeated by ten Swadia royal knights from the previous order, and it was immediately issued by Fatis. This is a problem doxepin weight gain that needs to be paid attention to, and Kree has no intention of questioning or questioning. Sure enough, after a while, there was a flat and soft voice under dr colbert keto diet recipes doxepin weight gain the crown of respected Kree from the crystal doxepin weight gain ball. Fallen knight, Kree understands this, The lion knights of Sarion from Pande know better, After all, in their world, even though they are in the Age of bcaa weight loss Doom, the extraordinary power Doxepin Weight Gain still exists, Doxepin Weight Gain so there are still a few void gaps between the underworld and the Pande continent, which can seep out the power of the underworld. The power was actually controlled by Viscount Gibran at that time, only knowing the irritability and killing, and hysterical madness. The complicated environment naturally ketogenic diet pcos leads to chaos, Correspondingly, Rolf s penetration of doxepin weight gain the lion duchy is like a fish in water. The most important thing is that the undead also belong to the existence of negative energy gathering, which is almost the same as the devil. Kree has confidence in himself! But looking at these ten fearful and Weight Loss Story sad guys, he found that he might be able to leave Doxepin Weight Gain a few hidden children. And just in the distance of the noble coalition forces in a slightly sunken ancient river channel, thousands of cavalry were staying. Bandak nodded behind: It meal replacement bar diet s really big, Welcome back, Lord Kree, Doxepin Weight Gain starr jones weight loss and, Bandak? Manid was walking out quickly.

Doxepin Weight Gain Weight loss without face change, And on the hillside, Hundreds of inflammation weight gain sand grouses were flapping their wings and running back and forth Most people did not suffer the slightest harm from the sudden explosion just now. The spies suddenly changed color, No spies like them do not artificial sweeteners and obesity recognize this badge. But now is not the time to blame each other, The village chief is obviously older and more knowledgeable: It s better to report to the castle. This kind of banquet is not only a time to draw the relationship between Baron Kree, but also a good opportunity for everyone to build a relationship with each other. The desert bandits, who had keen eyes and were wary of the East County leader, noticed the strangeness from how to lose stomach fat quickly a distance. At this time, the fleet quietly docked on the Swissniston River near the Navy Barracks, like a fierce beast crawling in the darkness, although lamb nutrition quiet, Weight loss pills for truck drivers it was council for responsible nutrition very dangerous. But they did not relax their vigilance, Manid, in particular, has completely delegated the salt trade to Jocelyn, the former caravan leader, and low carb granola let him take his place in hydroxycut lose weight the salt trade with Hard Rock Pass. The cavalry of Doxepin those savages like to use this kind of thing the most, What they said is naturally the wilderness of pork ribs nutrition the extreme west.

weight loss group name Of course, if you wait, And there are also transfer stations for materials, It s the underground city, Kree has arranged for people to go there in advance and prepare to transform the underground city His eyes were full of horror and unexpectedness, Viscount Gibran, who pretended to be crazy, also swung his sword helplessly, and a golden light shot out instantly. Doxepin Weight Gain obesity rate in california, vegan keto diet recipes.

Doxepin Weight Gain | Dod Studio

Doxepin Weight Gain Dod studio, The two also returned to Prison Demon Star, Ye Xuan used the Nine Flames to burn the sky, causing him to consume too much.

Belly fat quora. At present, the Shadow God has ordered that all the realms of the Holy Spirit Star enter a doxepin weight gain state of first-level combat readiness.

Moreover, where can you buy phentermine diet pills if these people are not killed, then jym fat burner from the perspective of China s human relations, they mens body fat chart are likely to reduce their sentences through relationships or lawyers, and they will not be punished as they deserve. You call the police first and thrive patches weight loss tell the police everything here, I will chase that person now! Ye Xiaochen said, What does he look like and where did he go. Before he went to India, he had booked a ticket estimate body fat percentage to Europe on the lose your belly fat diet book website in advance, and he could fly doxepin weight gain away as soon best way to get rid of back fat as he got off the doxepin weight gain car hemp hearts nutrition and went to the airport. Very good, From today onwards, your assassin s code name will be Shura, The young man sat alone on the roof of a bungalow, and his memories of the past lose your belly fat diet book replayed in his mind like a movie over best liquid diet to lose weight fast doxepin weight gain and over again. doxepin weight gain doxepin weight gain Enough has been gained from you, there is nothing else, Wuying nodded and said: Keto diet with shrimp Well, you go upstairs to help Xiaoya clean vegan meal replacement safeway up a room, and make the bed by the way, don t let the girl think we are stingy.

lowfat meal plan doxepin weight gain, Doxepin Weight Gain At this time, his upper body was naked, When he was running his divine power, his upper burning fat calories doxepin weight gain body had doxepin weight gain three weird doxepin weight gain black lines, and his arm also had doxepin weight gain two identical black lines fibroid diet plan.

And doxepin weight gain as far doxepin weight gain as the current situation is concerned, you best rated fat burners I m stuck here, and I m forced by you to be unable to attack, so I can passively defend.

Doxepin Weight Gain how much protien and fatper day on keto diet? But when he saw there were so many people, he strengthened himself and Keto diet with shrimp said: You.

what what type of diet is associated with the development of ketosis are nonos on cheap keto meals reddit keto diet? Doxepin Weight Gain After all, the crisis this time has been lifted, lose your belly fat diet book and the doxepin weight gain Holy Spirit Star is also in a stage of recovery, and they doxepin weight gain don t need their help for the time Doxepin Weight Gain. However, the laughter from the big pit pulled everyone s thoughts back, They doxepin weight gain had heard that voice before, and the heart that had been put down suddenly rose.

i can t lose weight no matter what i try?

About half a month after the Purgatory Incident, the entire Holy Spirit Star was in a closed state, and there was hardly any communication with the outside world doxepin weight gain. being.

But Xiaochen has There is generally no weight loss department in the hospital, even if there is, it is essentially an endocrinology department, Most of the obese patients who come here for treatment have endocrine problems Shura s blood inheritance, and the doxepin weight gain killing will stay with him until he can control this murderous aura. doxepin weight gain Even me, I must suffer a failure when I was young, the doxepin weight gain so-called It s nothing more than that to gain one s wisdom Doxepin Weight Gain by eating a ditch. He drew the long knife behind him, pointed at the ground diagonally, and said: I remember I said before, I won t keep my hands. riding a stationary bike to lose weight What are you doing? Xiaoya was taken aback doxepin weight gain when she saw the silver needle in Ye 10 days detox diet for weight loss Xiaochen s hand. For him, Wuying is the only existence that truly makes him feel scared, If feeder weight gain there is a second one, I am afraid it doxepin weight gain can only be the man with sunglasses in front of him.

After speaking, he How to keep track of weight loss without a scale rushed over desperately, doxepin weight gain Ye doxepin weight gain Xiaochen was a little surprised at once, did not expect Nata to have such a hand. now, there is this guy here, and the words he just said made me a little bit not want to suppress the murderous aura. If you really want to fight hard, it s impossible for everyone to Doxepin beat him together. Besides, I Doxepin Weight Gain weight loss pills supplement really can t think of any other reasons for you, Xiaoya thought about it carefully, and indeed, as Ye Xiaochen said, apart from the above two reasons, she couldn t find any other reasons. The man Keto diet with shrimp with sunglasses frowned again: This flame, is it, This is my mele all natural meal replacement original fire, named Shura Ghost Flame.

Lucifer! Hehe hehe, Lucifer looked at Ye Xuan, grinning grimly: I didn t expect Ye Xuan, I was standing weight lifting and weight loss in front of you well. Oh? Yang Lihuan s narrow and beautiful paleo diet for kids eyes glanced at Joad Carr who was lose your belly fat diet book sitting in the seat. In other words, Shura s move completely tied can the keto diet affect your kidneys them here, doxepin weight gain Even doxepin weight gain the rigorously trained armed police soldiers can t stand such a long wait. At that time, I was less than one paleo diet in tamil year old, Babies, basically have no memory. On his fist, there seemed to be weight loss for men over 40 a 7 keto beverly international reviews faint air current doxepin weight gain surging, Ye Xiaochen immediately judged it.

As soon as the voice fell, an extremely rich keto diet pills review doxepin weight gain purple light suddenly enveloped the surroundings, and the divine power of all the divine envoys that was rapidly gathering suddenly stopped flowing and gradually collapsed. Among these fires, there is calories in mozzarella sticks doxepin weight gain also my blood in them, You drink it, and you should be able to avoid the Doxepin Weight Gain burns of the Asura ghost flame. doxepin weight gain At this moment, Doxepin there seemed to be countless lose your belly fat diet book knives destroying the body of the best liquid diet to lose weight fast doxepin weight gain man in the red-eyed cloak, and countless red blood stains appeared on his body at the same time, looking what is the fastest way to lose belly fat shocking. At the same time, his body began to burn with blue-violet flames, and the surrounding temperature gradually increased with doxepin weight gain the temperature of the flames. However, a gun shadow flashed by at this moment, and instantly knocked the long-handled sickle in his Keto diet with shrimp hand.

Ye Xuan s expression doxepin weight gain suddenly became dignified, and he could clearly feel that the magic power emitted by each demon shadow was at least the doxepin weight gain level kit kat minis calories of doxepin weight gain a god king. At this moment, the entire room was ruined in an improper way, and the big gap on the best liquid diet to lose weight fast doxepin weight gain wall gave Ye doxepin weight gain Xiaochen a chance. He heard it, This was Wang Xinya s Doxepin Weight Gain voice, He felt that when Wang Xinya was doxepin weight gain healthy diet chart walking, someone must suddenly rush doxepin weight gain out and snatch Wang Xinya s bag, and then escaped. weight loss pills in the light blue bottle At this moment, the slit on Ye Xiaochen s doxepin weight gain forehead slowly opened, revealing a blood-red vertical eye. And the blue-haired youth in front of him was unscathed by heart healthy diet foods this blow! You know, this one of your own uses at least best liquid diet to lose weight fast doxepin weight gain 70% of the power, and fit tea fat burner it didn t cause any weight loss pills dangerous harm to him.

Thinking of this, Xiaoya s heart suddenly relaxed and nodded: Okay, But, excel advanced diet pills Xiaoya seemed to have thought of something, Looking at this room, Yu Yan showed a touch of embarrassment, There is only one bed in the whole room doxepin weight gain This kind of power, At that time, you won t leave so decently, Asshole, I am also an old man high calorie meal replacement drinks weight gain in this company anyway, I have been dismissed for so many years without credit and hard work, and I have to use the unilateral dismissal Doxepin Weight Gain after you are fat adapted on keto diet how much protein do you need?? procedure! This is the style of the Tianyan Technology Group, fit lean fat burning meal replacement which is soybeans nutrition doxepin weight gain so doxepin weight gain chilling! Liu Chengen patted the table angrily, his cheeks becoming extremely red.

keto weekly Doxepin Weight Gain meal plan free doxepin weight gain Call him out and you will die, Xiaoya s face was cold, and the doxepin weight gain aura emanating from her body dr phil weight loss books became stronger again.

However, at this time, a white shadow fell from the sky, and Keto diet with shrimp the target was aimed at Shura s head. After ten zoloft weight gain minutes, Ye Xiaochen immediately got doxepin weight gain the information he wanted, Yang Doxepin Weight Gain Lihuan asked, Have you got any results. diet meal replacement shakes recipes Doxepin Weight Gain I have already seen this, Xiaoya doxepin weight gain said, At that time, you can directly become an adult, which will lead to the security doxepin weight gain safe over the counter weight loss pills that work personnel present. I survived because I had enough strength and gained the trust of that woman, Wuying s tone also became tough, doxepin weight gain But what about you now? month meal plan Face a doxepin weight gain soul eater. He was very sure in his heart that he had never seen the woman in front of him, ketosis and liver but where did the kindness come from.

You Ying was taken coca cola nutrition facts aback, and quickly maximized her perception, and found that Keto diet with shrimp Ye Xiaochen s breath best liquid diet to lose weight fast doxepin weight gain was constantly moving around her, but the naked eye could hardly see anything, only felt the airflow continuously moving in one lose your belly fat diet book direction. Drive! The man sitting in the passenger seat obesity rate in france shouted, and the car drove out of the capital city at a speed of 130 kilometers per hour. And when the domain replenishes you with energy, you lose it, His vitality is back, even stronger doxepin weight gain than before. The seal formation set by the creation god requires the doxepin weight gain divine power doxepin weight gain of a god king-level powerhouse to operate. When saying this, Ye Xiaochen s left eye released a faint blue light, You, how did you know! You Ying was shocked, It doesn t matter how best liquid diet to lose weight fast doxepin weight gain I know, keto diet and strength training your weakness has already been seen through by me.

Ye Xiaochen glanced at her and said: I saw a particularly gorgeous white palace. At doxepin weight gain the same time they landed on the ground, panting heavily, Just to block the knife, Li Huan itself consumed a lot of money. Yang Lihuan did not answer his question immediately, but asked: Have you heard of elves. Soul Eater is not nuts on keto diet weak, It s just that Ye Xiaochen has a natural advantage, His left eye can not only see through the opponent s psychology, but also clearly see the opponent yam calories s weakness. At the same time, outside the door of the hotel room, the sound of hitting the door became louder and louder, and there were countless cracks in the barrier set by Ye Xiaochen, and it was about to collapse completely.

Doxepin Weight Gain Bodybuilding Meal Replacement Shake.

Scale muscle syndrome – treatment, symptoms, causes, diagnosis

Scalene syndrome (also called scalenus syndrome) is a group of symptoms that include pain, numbness and weakness in the neck, shoulder or arm. Symptoms are caused by compression or damage to the nerves or blood vessels in the costoclavicular space. The costoclavicular space is located between the clavicle and the upper rib, on both sides of the body. Most of the vessels (arteries and veins) and nerves that feed the arm pass through this space.Narrowing of this space can cause compression of the nerves and blood vessels, which disrupts the normal functioning of the upper limb. The narrowing can be caused by various conditions, such as: trauma, obesity, congenital anomalies, posture disorders. But sometimes, it is not possible to find out the specific reason for the narrowing.

Types of scalene syndrome.

• Neurogenic – in which compression of the brachial plexus occurs. This is the most common type of SLM
• Venous – with this type, the subclavian vein is compressed.It occurs in 4% of cases.
• Arterial type – the most rare in which compression of the subclavian artery occurs.

The syndrome of the scalene muscle can cause severe pain and often the diagnosis is difficult. SLM can affect many aspects of life (performance, rest, physical activity). In the absence of adequate treatment, this syndrome can lead to damage to the nerves of the vessels and even sometimes to atrophy of the limb.But at present, the treatment of this syndrome is quite successful.

Causes of the disease

The vessels and nerves need a certain amount of space to work properly. Compression of blood vessels in the costoclavicular space can lead to injury or, in rare cases, loss of a limb. In order to function properly, the nerves and blood vessels need adequate space. When compressed, accordingly, their function is impaired. Compression of blood vessels as they exit the chest can impair blood flow to and from the arm.It can also contribute to the formation of a blood clot (thrombus), which can further slow or completely block blood flow through the damaged vessel. If a clot ruptures, it can descend into the arm, blocking small blood vessels in the arm. Sometimes, the blood clot migrates to the lungs – a life-threatening condition called pulmonary embolism. Nerves also need space to stretch when the arm is moving. If the nerve exiting the chest is compressed or unable to move freely, the patient will not be able to move the arm normally.Pain and sensory disturbances in the hand often accompany this condition.

Risk factors for scalene muscle syndrome (SLM):

• Gender – Women are more likely to have SLM syndrome than men.
• Age – The syndrome often develops between the ages of 20-50.
• Diseases – SLM – the syndrome is often associated with other diseases, such as damage to the rotator cuff of the shoulder, osteochondrosis of the cervical spine, brachial plexus injury, diabetes mellitus, hypothyroidism.

Reasons

SLM occurs as a result of compression of nerves or blood vessels at the exit from the chest. Root reasons:

• Trauma – A traumatic episode can cause damage to bone or soft tissue as it exits the chest. Most people with SLM have a history of one or another episode of an accident, injury at work or at home.
• Congenital anomalies – such as an extra rib or a dense ligament connecting the vertebral column to the rib, can reduce the costoclavicular gap.
• Poor posture – sagging shoulders or excessive forward tilt of the head can compress the site of the exit of nerves and blood vessels from the chest.
• Frequent repetitive movements can wear tissue and lead to SLM. An example would be movements associated with lifting the arm (the collarbone drops and the costoclavicular gap decreases), such as swimming, baseball, tennis, weightlifting.
• Other Causes – Weight gain (during pregnancy or obesity), overdeveloped neck muscles (from weightlifting or martial arts), or prolonged arm fixation (using a computer) can put additional pressure on nerves and blood vessels.Diseases in which nerve function is impaired, such as hypothyroidism and diabetes, may be predisposing factors for neurogenic SLM.

Symptoms

The symptoms of SLM vary depending on whether the blood vessels or nerves are compressed.

Symptoms of nerve compression

• Pain or soreness in the neck, shoulder, arm
• Numbness or tingling in the neck, shoulder, arm
• Muscle weakness or areas of muscle failure in the arm
• Difficulty performing fine motor tasks; fast fatigability

Arterial Compression Symptoms

• Swelling of the hand
• Pain or deep soreness in the neck, shoulder or arm
• Numbness, tingling or heaviness in the hand
• Changes in skin color – the hand or fingers turn pale
• Changes in skin temperature – hand or fingers colder than the rest of the skin
• Small black spots on fingers
• Weak or absent pulse in the hand
• Pulsating tumor in the clavicle

Venous Compression Symptoms

• Hand swelling
• Pain or deep soreness in the neck, shoulder or arm
• Numbness, tingling or heaviness in the hand
• Changes in skin color – the hand or fingers become bluish
• Seal in the subclavian vein area
• Visually noticeable venous network in the chest.

Complications

For a long time, some patients reflexively respond to pain with muscle fixation. They have to maintain a rigid, defined posture in order to relieve pain. But, unfortunately, this reflex muscle defense aggravates the course of the disease and, as a result, leads to an increase in pain. Muscular defense then, in turn, requires separate treatment. It is important to start treatment early in SLM. If untreated, SLM can lead to significant damage to nerves or blood vessels, up to and including loss of a limb.

Diagnostics

Diagnosing an SLM can be difficult. Symptoms vary in nature and severity, depending on the individual. In addition, the symptoms are similar to those of other diseases (for example, damage to the rotator cuff, diseases of the cervical spine, leading to compression of the roots, etc.). The medical history and physical examination helps to find out the onset of the disease, the nature of the symptoms, and their dependence on body position.In addition, there are external signs of this disease (swelling of the hand, discoloration, impaired sensitivity, limited range of motion in the shoulder). During the physical examination, the doctor can perform procedures (manipulations) to identify symptoms (pulse pressure on the hands in various positions of the hand, both sick and healthy).

Instrumental research methods

• Electromyography (EMG) – EMGs help check how nerves and muscles are functioning.Small needle electrodes are inserted into the muscle where the problem is. Electrodes measure the electrical activity of a muscle that is innervated by a particular nerve. The pathological reaction of a muscle provides information about the state of the nerve going into that muscle. In addition, EMG allows you to determine the speed of the impulse along the nerve fiber. This is done using electrodes placed on the skin. The speed of the impulse along each nerve fiber has a certain average value, and the deviation indicates damage to the nerve fiber.
• X-ray allows you to diagnose bone changes in the chest and ribs (the presence of an additional cervical rib).
• Laboratory examinations – general blood tests, blood for hormones, blood for sugar help in the diagnosis of SLM.
• Magnetic resonance imaging (MRI) – allows you to visualize the soft tissues of the body MRI to find out the cause of compression of a nerve or vessel.
• Computed tomography (CT) – allows you to more clearly visualize changes in bone tissue.
• Ultrasound examination – With the help of an ultrasound wave it is possible to visualize the soft tissues of the vessels, the presence of thrombi, stenoses.
• Angiography – Contrast X-ray is used to diagnose vascular lesions. Angiography of the arteries and veins is used to diagnose blocks and other problems in the blood vessels.

Treatment

Drug treatment

• NSAIDs are non-steroidal anti-inflammatory drugs.These medications help reduce pain and inflammation (swelling, redness). For example: aspirin, ibuprofen (Advil), naproxen (Aleve), and celecoxib (Celebrex) Movalis
• Muscle relaxants – Often used to treat muscle spasms, these drugs can relieve pain by relaxing the muscles. Cyclobenzaprine (Flexeril), carisoprodol (Soma), diazepam (Valium), methocarbamol (Robaxin), and tizanidine (Zanaflex).
• Neuropathic drugs – The principle of their action is based on changes in the neurotransmitter transmission of pain impulses to the spinal cord and brain.Medicines that can help reduce pain by affecting neurotransmitters include fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), citalopram (Celexa), venlafaxine (Effexor), amitriptyline (Elavil), imipramine (Tofranil), desipramine (Norpramine) ), doxepin (Sinequan), and amoxapine (Ascendin).
• Opioids – Narcotic analgesics are used only for very severe pain after the use of conventional analgesics has been exhausted. A combination of opiates with NSAIDs is possible (to enhance the analgesic effect).

LFC

Physiotherapy is one of the most important components of SLM treatment. The selection of certain exercises helps to improve posture, the correct distribution of muscle loads. Exercise helps to increase the range of motion in the limb. Stretching and strengthening the shoulder and pectoral muscles can help increase and relieve pressure on the nerves and blood vessels in the costoclavicular space.
• There is a wide range of motion, both passive and active.

Physiotherapy

Various physiotherapy techniques can relieve swelling, inflammation, restore blood circulation and reduce nerve compression.

Manual therapy

The use of certain techniques of manual therapy allows the mobilization of the spine and ribs to increase the range of motion in the shoulder joint.

Blockade

Sometimes used for differential diagnosis and treatment. But, given the anatomical features of this zone, injections should be carried out by a doctor with experience in carrying out such manipulations.

Acupuncture (acupuncture)

Acupuncturists believe that a healthy body contains channels through which energy flows. When these channels are closed, the energy is blocked, which leads to various diseases. The needles are inserted at specific points (biologically active). In certain cases, acupuncture can reduce pain and restore conduction in nerve fibers.

Massage can help relieve stress and relax tense muscles.Massage helps to increase blood flow to the tissues of the body and helps the muscles to get rid of metabolic waste products.

(PDF) ANTIHISTAMINES IN TREATMENT OF CHRONIC URTICARIA. REVIEW OF MODERN RECOMMENDATIONS

57

BRONCHOPULMONOLOGY, ENT, ALLERGOLOGY

REFERENCES

1. Zuberbier T. et al. The EAACI / GA2LEN / EDF / WAO

guideline for the definition, classification, diag-

nosis, and management of urticarial: the 2013

revision and update.Allergy 2014, 69: 868-887.

2. Vestergaard C, Deleuran M. Chronic spontane-

ous urticarial: latest developments in aetiology,

diagnosis and therapy. Therapeutic Advances in

Chronic Disease, 2015, 6 (6): 304-313

3. Tharp MD. The clinical efficacy of antihista-

mines in the skin. Allergy 2000,55: 11-16.

4. Kaplan AP. Chronic urticaria: pathogenesis and

treatment. J Allergy Clin Immunol, 2004, 114 (3):

465-474.

5. Arabian E.R., Sokolovsky E.V., Gallyamova

Yu.E. Federal clinical guidelines

for the management of patients with urticaria. M., 2015.

6. Skripkin Yu.K., Butov Yu.S., Ivanov O.L.

Dermatovenereology– national guide-

. M .: GEOTAR-Media, 2013: 694-702.

7. KolkhirPV. The causes of chronic urticaria are

. Attending physician, 2012, 10: 80.

8. Bernstein J.A. Chronic Urticaria: An Evolving

Story.IMAJ, 2005, 7: 774-777.

9. Humphreys F, Hunter JA. The characteristics of

urticaria in 390 patients. Br J Dermatol 1998,

138 (4): 635-8.

10. Ortonne J-P. Urticaria and its subtypes: The role

of second-generation antihistamines. Eur J

Intern Med, 2012, 23: 26-30.

11. O’Donnell BF, Lawlor F, Simpson J et al. The

impact of chronic urticaria on quality of life. Br J

Dermatol 1997,136: 197-201.

12. Grob JJ, Gaudy-Marqueste C. Urticaria and quality

of life. Clin Rev Allergy Immunol, 2006,30 (1): 47-51.

13. Grob J-J, Revuz J, Ortonne J-P, et al. Comparative

study of the impact of chronic urticaria, psoria-

sis and atopic dermatitis on the quality of life.

Br J Dermatol 2005,152: 289-295.

14. Perkowska J, Kruszewski J, Gutkowski P et al.

Occurrence of sleep-related breathing disorders

in patients with chronic urticaria at its asymp-

tomatic or oligosymptomatic stages.Adv

Dermatol Allergol 2016, XXXIII (1): 63-67.

15. Zuberbier T, Asero R, Bindslev-Jensen C et al.

EAACI / GA2LEN / EDF / WAO guideline: manage-

ment of urticarial. Allergy 2009, 64: 1427-1443.

16. Zuberbier T, Aberer W, Asero R et al. The EAACI /

GA2LEN / EDF / WAO Guideline for the definition,

classification, diagnosis, and management of

urticaria: the 2013 revision and update. Allergy,

2014, 69: 868-887.

17. Bernstein JA, Lang DM, Khan DA. The diagnosis and

management of acute and chronic urticaria: 2014

update. J Allergy Clin Immunol 2014,133: 1270-1277.

18.

Jáuregui I., Ferrer M., Montoro J et al. Antihista mines

in the treatment of chronic urticaria. J Investig

Allergol Clin Immunol 2007,17 (Suppl. 2): 41-52.

19. Simons FE, Silver NA, Gu X, Simons KJ. Clinical

pharmacology of h2- antihistamines in the skin.

J Allergy Clin Immunol 2002,110: 777-783.

20. Holgate ST, Canonica GW, Simons FER et al.

Consensus Group on New-Generation Antihista-

mines (CONGA): present status and recommenda-

tions. Clin Exp Allergy 2003,33: 1305-1324.

21. Hayashi S, Hashimoto S. Anti-inflammatory

actions of new antihistamines. Clin Exp Allergy,

1999,29: 1593-1596.

22. Walsh GM. The clinical relevance of the anti-

inflammatory properties of antihistamines.

Allergy, 2000, 55 (suppl. 60): 53-61.

23. Leurs R, Church MK, Taglialatela M. h2-antihista mines:

inverse agonism, anti-inflammatory actions and cardi-

ac effects. Clin Exp Allergy 2002,32: 489-498.

24. Wolthers OD. Bilastine: A New Nonsedating Oral

h2 Antihistamine for treatment of allergic rhino-

conjunctivitis and urticaria. BioMed Research

International, 2013, Article ID 626837, 6 p.

25.Bakker RA, Schoonus SBJ, Smit MJ et al.

Histamine h2-receptor activation of nuclear

factor-kB: roles for Gβγ- and Gα (q / 11) -subunits in

constitutive and agonist-mediated signaling.

Mol Pharmacol 2001, 60: 1133-1142.

26. Agrawal DK. Anti-inflammatory properties of

desloratadine. Clin Exp Allergy 2004, 34: 1342-1348.

27. Picado C. Rupatadine: pharmacological profile and

its use in the treatment of allergic disorders.

Expert Opin. Pharmacother., 2006,7 (14): 1989-2001.

28. Wang XY, Lim-Jurado M, Prepageran N et al. Treat-

ment of allergic rhinitis and urticaria: a review of

the newest antihistamine drug bilastine. Therapeu-

tics and Clinical Risk Management, 2016, 12: 585-597.

29. Khan DA. Chronic urticaria: diagnosis and manage-

ment. Allergy Asthma Proc. 2008,29 (5): 439-446.

30. Liu H, Farley JM. Effects of first and second gen-

eration antihistamines on muscarinic induced

mucus gland cell ion transport.BMC

Pharmacology 2005 5: 1-10.

31. Gillard M, Christophe B, Wels B et al. h2 antago-

nists: receptor affinity versus selectivity.

Inflamm. Res 2003, 52 (Suppl. 1): S49-S50.

32. Monroe E. Review of h2 antihistamines in the

treatment of chronic idiopathic urticaria. Cutis,

2005, 76: 118-126.

33. Kavosh ER, Khan DA. Second-generation h2-anti-

histamines in chronic urticaria an evidence-based

review.Am J Clin Dermatol. 2011,12 (6): 361-376.

34. Skripkin Yu.K., Dvornikov A.S., Kruglova L.S.,

Skripkina P.A. A modern view of the pathogenic therapy of atopic dermatitis. Vest-

Nickname of Dermatology and Venereology, 2006, 4: 36-39.

35. Simons FERS, Simons KJ. h2 Antihistamines:

current status and future directions. WAO

Journal, 2008: 145-155.

36. Cuvillo A, Mullol J, Bartra J et al. Comparative

pharmacology of the h2 antihistamines.J Investig

Allergol Clin Immunol 2006,16 (Suppl 1): 3-12.

37. Jáuregui I, Ortiz de Frutos FJ, Ferrer M. Assess ment

of severity and quality of life in chronic urticaria. J

Investig Allergol Clin Immunol 2014, 24 (2): 80-86.

38. Baiardini I, Pasquali M, Braido F. A new tool to

evaluate the impact of chronic urticaria on quality

of life: chronic urticaria quality of life question-

naire (CU-QoL).Allergy 2005,60 (8): 1073-1078.

39. Finlay AY, Khan GK. Dermatology Life Quality Index

(DLQI) – a simple practical measure for routine

clinical use. Clin Exp Dermatol 1994 19: 210-216.

40. Nekrasova E.E., Razvalyaeva A.V., Malyuzhinskaya

N.V. Development of the Russian version of the questionnaire

CU-QoL to study the quality of life in patients

with chronic urticaria. Saratov Scientific

–

Medical Journal, 2010, 6 (3): 566-569.

41. Grob J-J, Lachapelle J-M. Non-sedating antihista-

mines in the treatment of chronic idiopathic urticar-

ia using patient-reported outcomes. Current Medical

Research and Opinion, 2008, 24 (8): 2423-2428.

42. Kapp A, Pichler WJ. Pharmacology and therapeu-

tics levocetirizine is an effective treatment in

patients suffering from chronic idiopathic urti-

caria: a randomized, double-blind, placebo-con-

trolled, parallel, multicenter study.Int J

Dermatol, 2006, 45: 469-474.

43. Spector SL, Shikiar R, Harding G et al. The effect

of fexofenadine hydrochloride on productivity

and quality of life in patients with chronic idio-

pathic urticaria. Cutis 2007, 79 (2): 157-162.

44. Zuberbier T, Oanta A, Bogacka E et al.

Comparison of the efficacy and safety of bilas-

tine 20 mg vs levocetirizine 5 mg for the treat-

ment of chronic idiopathic urticaria: a multicen-

tre, double-blind, randomized, placebo-con-

trolled study.Allergy 2010, 65 (4): 516-528.

45. Juhlin L. A comparison of the pharmacodynamics of

h2-receptor antagonists as assessed by the induced

wheal-and-flare model. Allergy, 1995, 50: 24-30.

46. Kruszewski J, Kłos K, Sułek K. Inhibition of hista-

mine-induced wheel after a recommended single

dose administration of 10 mg cetirizine, 5 mg

desloratadine, 120 and 180 mg fexofenadine, 5

mg levocetirizine and 10 mg loratadine – a rand-

omized, double-blind, placebo controlled trial.

Pol Merkur Lekarski 2006, 21 (125): 443-448.

47. Kłos K, Kruszewski J, Kruszewski R, Sułek K. The

effect of 5-days of cetirizine, desloratadine, fex-

ofenadine 120 and 180 mg, levocetirizine, lorat-

adine treatment on the histamine -induced skin

reaction and skin blood flow – a randomized,

double-blind, placebo controlled trial. Pol

Merkur Lekarski, 2006, 21 (125): 449-453.

48. Simons FE, McMillan JL, Simons KJ.A double-

blind, single-dose, crossover comparison of ceti-

rizine, terfenadine, loratadine, astemizole, and

chlorpheniramine versus placebo: suppressive

effects on histamine-induced wheals and flares

during 24 hours in normal subjects. J Allergy

Clin Immunol 1990,86: 540-7.

49. Rosenzwey P, Caplain H, Chofour S et al.

Comparative wheal and flare study of mizolas –

tine vs terfenadine, cetirizine, loratadine and

placebo in healthy volunteers.Br J Clin

Pharmacol, 1995,40: 459-465.

50. Grant JA, Danielson L, Rihoux JP, DeVos C. A dou-

ble-blind, single-dose, crossover comparison of

cetirizine, ebastine, epinastine, fexofenadine,

terfenadine, and loratadine versus placebo : sup-

pression of histamine-induced wheal and flare

response for 24 h in healthy male subjects.

Allergy ,. 1999, 54: 700-707.

51. Grant JA, Riethuisen JM, Moulaert B, DeVos C.A dou-

ble-blind, randomized, single-dose, crossover com-

parison of levocetirizine with ebastine, fexofena-

dine, loratadine, mizolastine, and placebo: suppres-

sion of histamine-induced wheal- andflare response

during 24 hours in healthy male subjects. Ann

Allergy Asthma Immunol 2002, 88 (2): 190-197.

52. Popov TA, Dumitrascu D, Bachvarova A et al. A

comparison of levocetirizine and desloratadine

in the histamine-induced wheal and flare

response in human skin in vivo.Inflamm Res,

2006, 55 (6): 241-244.

53. Roongapinun S, Wajajamreon S, Fooanant S.

Comparative efficacy of wheal-and-flare sup-

pression among various non-sedating antihista-

mines and the pharmacologic insights toffic their

eacy. J Med Assoc Thai, 2004, 87 (5): 551-6.

54. Meltzer EO, ​​Gillman SA. Efficacy of fexofenadine

versus desloratadine in suppressing histamine –

induced wheal and flare.Allergy Asthma Proc,

2007, 28: 67-73.

55. Kaliner MA, White MV, Economides A et al.

Relative potency of fexofenadine HCl 180 mg,

loratadine 10 mg, and placebo using a skin test

model of wheal-and-flare suppression. Ann

Allergy Asthma Immunol 2003,90: 629-634.

56. Frossard N, Strolin-Benedetti M, Purohit A, Pauli

G. Inhibition of allergen-induced wheal and flare

reactions by levocetirizine and desloratadine.Br J

Clin Pharmacol. 2007, 65 (2): 172-179.

57. Fadel R, David B, Heprin-Richard N et al. In vivo

effects of cetirizine on cutaneous reactivity and

eosinophil migration induced by platelet acti-

vating factor in man. J Allergy Clin Immunol,

1990, 86: 314-320.

58. Charlesworth EN, Massey WA, Kagey-Sobotka A

et al. Effect of h2 receptor blockade on the early

and late response to cutaneous allergen chal-

lenge.J Pharmacol Exp Ther 1992,262: 964-970.

59. Walsh GM. The anti-inflammatory effects of lev-

ocetirizine– are they clinically relevant or just

an interesting additional effect? Allergy, Asthma

& Clinical Immunology, 2009, 5: 14.

60. Caproni M, Volpi W, Giomi B et al. Cellular adhe-

sion molecules in chronic urticaria: modulation

of serum levels occurs during levocetirizine

treatment.Br J Dermatol 2006,155: 1270-1274.

61. Simons FER, Silver NA, Gu X, Simons KJ. Skin

concentrations of h2-receptor antagonists. J

Allergy Clin Immunol. 2001, 107: 526-530.

62. Sharma M, Bennett C, Cohen SN, Carter B. h2-anti –

hista mines for chronic spontaneous urticaria. Coch-

rane Database of Systematic Reviews, 2014, Issue 11.

63. Kozel MM, Mekkes JR, Bossuyt PM, Bos JD.

Natural course of physical and chronic urticaria

and angioedema in 220 patients.J Am Acad

Dermatol 2001,45 (3): 387-391.

64. Kameyoshi Y, Tanaka T, Mihara S et al. Increasing

the dose of cetirizine may lead to better control

of chronic idiopathic urticaria: An open study of

21 patients. Br J Dermatol. 2007,157: 803-804.

65. Asero R. Chronic unremitting urticaria: Is the use of

antihistamines above the licensed dose effective? A

preliminary study of cetirizine at licensed and above-

licensed doses.Clin Exp Dermatol. 2007,32: 34-38.

66. Staevska M, Popov TA, Kralimarkova T et al. The

effectiveness of levocetirizine and desloratadine in

up to 4 times conventional doses in difficult-to-treat

urticaria. J Allergy Clin Immunol 2010,125: 676-682.

Doxepin: description, recipe, instruction

Doxepin

Analogues (generics, synonyms)

Active ingredient

Doxepinum

Pharmacological group

Antidepressants

Recipe

International:

Rp.Caps. Doxepini 25 mg
D.t.d. No. 4
S. 1 capsule 1-2 times / day

Russia:

Prescription form 107-1 / y

Pharmacological action

Antidepressant of tricyclic structure, derivative of dibenzoxepine. The mechanism of action, apparently, is associated with the effect on adrenergic transmission in the central nervous system, in particular, with the blockade of neuronal uptake of norepinephrine. It also has anxiolytic, sedative activity, has an m-anticholinergic effect.Does not have a stimulating effect on the central nervous system. Does not inhibit MAO. Initially, the anxiolytic effect of doxepin is manifested, the optimal antidepressant effect develops after 2-3 weeks of treatment.

Pharmacodynamics

There is no data for this section. We are currently processing information, please come back later.

Pharmacokinetics

There is no data for this section. We are currently processing information, please come back later.

Method of application

For adults:

Individual.With a moderate degree of depression and / or anxiety, the initial dose is 75 mg / day. In the future, the effective dose is individually selected, which is usually 75-150 mg / day. The dose is increased gradually. With significant depression and / or anxiety, the effective dose can reach 300 mg / day. In patients with minimally severe impairment, lower doses of 25-50 mg / day may be effective.

Doxepin is taken orally 1-2 times / day (with a single dose during the day, the dose of doxepin should not exceed 150 mg).For sleep disorders, most of the daily dose is taken in the evening.

Readings

– Depression and / or anxiety with neuroses, alcoholism, organic diseases of the central nervous system, psychosis (including involutive depression and manic-depressive psychosis).

Contraindications

– Glaucoma
– A tendency to urinary retention
– Left bundle branch block
– III degree AV block
– Pregnancy, lactation, childhood (up to 12 years)
– Hypersensitivity to doxepin.

Special instructions

There is no data for this section. We are currently processing information, please come back later.

Side effects

– From the side of the digestive system: dry mouth, nausea, vomiting, anorexia, taste disturbances, diarrhea, constipation, aphthous stomatitis; rarely, jaundice.
– From the side of the central nervous system and peripheral nervous system: dizziness, tinnitus, headache, visual disturbances, drowsiness, disorientation, hallucinations, paresthesia, ataxia, extrapyramidal disorders, convulsions, tardive dyskinesia, tremor.
– From the side of the cardiovascular system: arterial hypotension, hypertension, tachycardia.
– From the hematopoietic system: rarely – leukopenia, agranulocytosis, thrombocytopenia.
– From the endocrine system: rarely – an increase or decrease in libido, testicular edema, gynecomastia (in men), an increase in the mammary glands, galactorrhea (in women), an increase or decrease in blood sugar levels, syndrome of inadequate secretion of ADH, weight loss.
– Allergic reactions: skin rash, itching, photosensitivity, angioedema, eosinophilia.
– Other: rarely – urinary retention, increased sweating, chills, general weakness, a feeling of flushing, alopecia, aggravation of the course of bronchial asthma.

Overdose

There is no data for this section. We are currently processing information, please come back later.

Drug interactions

There is no data for this section. We are currently processing information, please come back later.

Form of issue

10 capsules in a blister, 3 blisters in a carton box.
Capsules: white powder in cylindrical capsules with rounded ends and size No. 4. For 10 mg capsules – body – blue cap – cherry; for 25 mg capsules – body – pink cap – cherry.
Active ingredient: doxepin; 1 capsule contains Doxepin 10 mg or 25 mg in the form of Doxepin hydrochloride auxiliary substances: corn starch lactose magnesium sodium stearate lauryl sulfate; capsule shell: indigo (E 132) titanium dioxide (E 171) gelatin erythrosine (E 127) for 10 mg capsules patented blue V (E 131) is added.

90,000 Doxepin • – alchetron, the free social encyclopedia

Doxepin is a drug used to treat serious depressive disorders, unpleasant disorders, chronic seizures and sleep problems. For hares, this is a less tentative alternative to antihistamines. It has softness to benefit for sleeping problems. It is used as a cream for itching due to atopic dermatitis or lichen chronicus.

Common side effects include drowsiness, dry mouth, constipation, nausea, and blurry vision.Serious side effects may include an increased risk of suicide in those under 25 years of age, mania, and urinary retention. Diversion syndrome can occur if the dose is rapidly reduced. Use during pregnancy and breastfeeding is generally not recommended. Doxepin is a tricyclic antidepressant (TCA). While how it works to treat depression remains an area of ​​active investigation, it could include raising norepinephrine levels, along with bloomistamine, acetylcholine, and serotonin.

Doxepin was approved for medical use in the United States in 1969. It is available as a generic medicine. In 2017, it was the 240th most commonly prescribed drug in the United States, with over two million prescriptions.

Medical Uses

Doxepin is used as a pill for the treatment of major depressive disorders, unpleasant disturbances and chronic seizures, and for short-term relief with sleep problems after sleep (a form of insomnia).As a cream, it is used for the short-term treatment of itching due to atopic dermatitis or lichen chronicus.

In 2016, the American College of Physiologists recommended treating insomnia first by treating comorbid conditions, then with cognitive behavioral therapy and behavioral changes, and then with medication; doxepin was among those recommended for short-term sleep aid based on weak evidence. The 2017 American Academy of Sleep Medicine guidelines for drug treatment were similar.A 2015 AHRQ review of insomnia treatment had similar results.

A 2010 review found topical doxepin to be beneficial for the treatment of pruritus.

A 2010 review of the treatment of chronic patients found that doxepin had been replaced by better drugs, but was still sometimes useful as a second-line treatment.

Directions

Known designations include:

• Hypersensitivity to doxepin, other TCAs, or any of the excipients within the product being used
• Zhkoma
• Predisposition to urinary retention, such as in benign prostatic hyperplasia

hyperplasia 70008 last 14 days

Pregnancy and lactation

Its use in pregnant and lactating women is recommended, although available evidence suggests that it cannot cause adverse effects on fetal development.However, the lack of evidence from human studies means that no risk to the fetus can be ruled out at this time and it is known to cross the placenta. Doxepin is secreted in breast milk, and neonatal cases of respiratory depression have been reported in association with maternal doxepin use.

Side effects

See also: List of side effects of doxepin.

The side effect profile of doxepin may differ from the list below in some countries where it is licensed for use at much lower doses (viz., 3 mg and 6 mg).

• Central nervous system: fatiga, dizziness, drowsiness, lightness, confusion, nightmares, agitation, hyperactivity, difficult drowsiness, res (infrequently), temporary confusion (rium), rare induction of hypomania and schizophrenia (discontinue medication immediately) extrapyramidal side effects (rarrarearely), patient abuse
• Anticholinergics: dry mouth, constipation, even il (rare), difficulty urinating, sweating, pre-meal coma
• Antiadrenergic: low blood pressure (if the patient moves too quickly out of position lying / sitting in a standing position known as orthostatic hypotension), abnormal heart rhythms (eg, sinus tachycardia, bradycardia, and atrioventricular block)
• Allergic / toxic: Skin rash, photosensitivity, cholestatic-type gross lesion (very rare), hepatitis (rare) , co- or thrombocytopene oia (rare), agranulocytosis (very rare), hypoplastic anemia (rare)
• Others: often increased appetite and weight gain, rare nausea, rare high blood pressure.May increase or decrease liver function in some people.

Overdoze

Like other TCAs, doxepin is very toxic in cases of overdose. Mild symptoms include drowsiness, persistence, blurry vision, and excessive dry mouth. More serious effects of obesity include respiratory depression, hypotension, coma, seizures, cardiac arrhythmia, and tachycardia. Retention of urination, decreased gastrointestinal motility (paralytic or heat), hyperthermia (or hypothermia), hypertension, enlarged umbilicals, and hyperactive referencing are other possible symptoms of an overdose of doxepin.Overdose treatment is mostly supportive and symptomatic, and may include the administration of gastrointestinal levage to reduce the absorption of doxepin. It is also recommended to take supportive measures to prevent respiratory aspiration. Antiarchimics may be an appropriate measure for the treatment of cardiac arrhemias resulting from an overdose of doxepin. Slow intravenous administration of fistostigmine can restore some of the toxic effects of overdose, such as anticholinergic effects.Hemodialysis is not recommended due to the high protein content of doxepin. ECG monitoring is recommended for several days after doxepin overdose due to the possibility of cardiac conduction abnormalities.

Interactions

Doxepin should not be used within 14 days after using a monoamine oxidase inhibitor (MAOI) such as phenelzine, due to the possibility of developing a hypertensive crisis or serotonin syndrome. Its use in those taking strong CYP2D6 inhibitors such as fluoxetine, paroxetine, sertraline, duloxetine, bupropion and quinidine is advised against being associated with the potential for its accumulation in the absence of the full catalytic activity of CYP2D6.Hepatic enzyme-inducing enzymes such as carbamazepine, phenytoin, and barbiturates are recommended for patients receiving TCA, such as doxepin, due to the potential for problematic rapid metabolism of doxepin in these individuals. Sympathomimetic agents may have their effects enhanced by TCAs such as doxepin. Doxepin may also potentiate the adeno effects of anticholinergic agents such as benztropine, atropine, and hyoscine (scopolamine). Tolazamide, when used in conjugation with doxepin, has been associated with a case of severe hypoglycemia in a type II diabetic individual.Cimetidine may interfere with the absorption of doxepin. Alcohol may potentiate some of the CNS depressive effects of doxepin. Antihypertensive drugs may have effects of doxepin. Concomitant treatment with CNS depressants such as benzodiazepines can cause additive CNS depression. Joint treatment with thyroid hormones can also increase the potential for adreactions.

Pharmacology

Doxepin is a tricyclic antidepressant (TCA). Acts as serotonin – a norepinephrine reuptake inhibitor (SNRI) (serotonin and norepinephrine reuptake inhibitor), with additional antiadrenergic, antihistamine, antiserotonergic and anticholinergic activity.

Pharmacodynamics

Doxepin is a serotonin and norepinephrine reuptake inhibitor, or serotonin reuptake inhibitor (SNRI), and has additional antiadrenergic, antihistamine, serotonergic and anticholinergic activity. In particular, it is an anagonist of histamine H1 and H2 receptors, serotonin 5-HT2A and 5-HT2C receptors, α1-adrenergic receptors and muscarinic acetylcholine receptors (M1-M5). Like other tricyclic antidepressants, doxepin is often prescribed as an effective alternative to SSRI drugs.Doxepin is also a potent sodium channel hemorrhage, and this action is thought to be involved both in its lethality when overdossed and in its efficacy as an analogy (including in the treatment of neuropathic pain and as a local anesthetic). The activity of doxepin in terms of its receptor anagonism is specifically as follows:

Based on its values ​​for inhibiting monoamine reuptake, doxepin is relatively selective for inhibiting norepinephrine reuptake, with a much weaker effect on serotonin.Although there is a significant effect that occurs in one of the specific serotonergic sites, the serotonin receptor subtype 5-HT2A. There is a negative impact on dopamine reuptake.

The main metabolite of doxepin, nordoxepine (desmethyldoxepine), is pharmacologically active in a similar manner, but is far more selective than doxepin as a norepinephrine reuptake inhibitor. In general, demethylated variants of tertiary amine TCAs such as nordoxepine are much more potent norepinephrine reuptake inhibitors, less potent serotonin reuptake inhibitors, and less potent antiadrenergic, antihistaminic, and anticholinergic activity.

Doxepin antidepressants are defined as 25 to 300 mg / day, although they usually exceed 75 mg / day. Antihistamines, including for dermatological use and as a sedative / hypnotic for insomnia, are considered 3-25 mg, although higher doses between 25 and 50 mg and in some cases even up to 150 mg have been used to treat insomnia. At low doses, below 25 mg, doxepin is a pure antihistamine and rather sedative. At antidepressant doses over 75 mg, doxepin is more stimulated by antiadrenergic, serotonergic and anticholinergic effects, and these activities contribute to its side effects.

Doxepin is a mixture of (E) and (Z) stereoisomers with an approximate ratio of 85:15. When doxepin was developed, no effort was made to separate or balance the mixture after synthesis, resulting in an asymm c. ( Z ) -doxepine is more active as a serotonin and norepinephrine reuptake inhibitor than (E) -doxepine. The selectivity of doxepin for inhibiting norepinephrine reuptake over serotonin is probably due to 85% of the presence of ( E ) -doxepin in the mixture.Most other tertiary amine TCAs, such as amitriptyline and imipramine, do not exhibit E-Z isomerism or mixture asymmetry and are comparatively more balanced serotonin and norepinephrine reuptake inhibitors.

As a hypnotic

Doxepin is a highly effective antihistamine, and it is its strongest activity. In fact, doxepin has been said to be the most or one of the most potent h2 receptor anagonists available, with one study finding a Ki in vitro of 0.17 nM.It is the most potent and selective TCA h2 receptor anagonist (although tetracyclic antidepressant (TeCA) Mirtazapine and another anti-osidiopotic). The affinity of doxepin for the h2 receptor is much greater than its affinity for other sites, and higher doses of 10 to 100 folds are required for antidepressant effects. Consistent with this, although it is often described as “dirty medicine” due to its highly lecherous profile, doxepin acts as a highly selective H1 receptor anagonist at very low doses (less than 10 mg; usually 3 to 6 mg).At these doses, it does not appear to have clinically significant anticholinergic effects such as dry mouth or cognitive / memory impairment, unlike most other sedative antihistamines, and similarly does not affect other receptors such as adrenergic and serotonin receptors. …

Doxepin H1 receptor anagonism is responsible for its hypnotic effects and its effectiveness in the treatment of insomnia at low doses. Inca side effects with doxepin and its safety at these doses were similar to those of placebo in clinical trials; the most common side effects were headache and hesitation / sedation, both with insi less than 5%.Other side effects sometimes associated with antihistamines, including daily sedation, increased appetite, and weight gain, were not observed. Clinical evidence of h2 and TCA receptor anagonists for the treatment of insomnia shows mixed efficacy and is limited in quality due to weaknesses such as small sample size and poor generalizability. However, doxepin is a unique and notable exception, it has been well studied in the treatment of insomnia and has shown consistent benefits with excellent tolerability and safety.Aside of diphenhydromine and doxylamine, both of which have historical approval as hypnotics, doxepin is the only h2 receptor anagonist specifically approved for the treatment of insomnia in the United States.

Effect sizes of very low-dose doxepin in the treatment of insomnia range from small to moderate. These include subjective and objective measures of sleep maintenance, sleep duration, and sleep efficiency. Conversely, very low doxepin levels show relatively little effect on sleep initiation and are not significantly different from placebo at this measure.This is in contrast to benzodiazepines and non-benzodiazepine (Z-drug) hypnotics, which are additionally effective in improving sleep latency. However, this is also in contrast to higher doses of doxepin (50 to 300 mg / day), which have been found to significantly reduce sleep retention in sleep. A positive dose-response relationship on sleep performance has been observed for doxepin doses of 1 to 6 mg in clinical trials, while the Inca effects have remained constant in this range in both young and elderly people.However, it seems that the number of effects increases with the duration of treatment. Doxepin doses up to 1 mg / day were found to significantly improve most of the sleep scores assessed, but unlike doses of 3 and 6 mg / day, they were unable to improve wakefulness during sleep. This, along with the larger effect sizes with higher doses, was likely the basis for approval of the 3 and 6 mg doses of doxepin for insomnia rather than the 1 mg dose.

At very low doses, doxepin did not exhibit discontinuities or elimination effects, nor did it reset insomnia.Continued efficacy without overt tolerance has been demonstrated in clinical studies up to 12 weeks in duration. This appears to be in contrast to over-the-counter antihistamines such as diphenhydromine and doxylamine and all other first generation antihistamines that are associated with the rapid development of tolerance and dependence (by 3 or 4 days of continuous dosing) and loss of hypnotic efficacy. It is for this reason, unlike doxepin, that they are not recommended for the chronic treatment of insomnia and are only recommended for short-term treatment (i.e.e. 1 week). It is not entirely clear why doxepin and first generation antihistamines differ in this regard, but it has been suggested that this may be due to a lack of selectivity for the latter’s h2 receptor, or may be due to the use of optimal doses. Unlike very low-dose doxepin, most first-generation antihistamines also have significant anticholinergic activity as well as associated side effects such as dry mouth, constipation, urinary retention and confusion.This is especially true in the elderly, and antihistamines with concomitant anticholinergic effects are not recommended for adults over the age of 65. Anticholinergic activity appears to interact with the sleep-promoting effects of h2-receptor blockade.

Anagonism of h2, 5-HT2A, 5-HT2C and α1-adrenergic receptors is thought to have a sleep-promoting effect and is responsible for the sedative effects of TCA, including the effects of doxepin. Although doxepin is selective for the H1 receptor at doses below 25 mg, blockade of serotonin and adrenergic receptors may also be implicated in the hypnotic effects of doxepin at higher doses.However, in contrast to very low doses of doxepin, rebound insomnia and diurnal sedation are significantly more frequent than placebo doses (25 to 50 mg / day) of the drug. In addition, one study found that while such doses of doxepin improved sleep performance initially, most of the benefits were lost with chronic treatment (by 4 weeks). However, due to limited data, more research is needed on the potential tolerance and effects of doxepin dose withdrawal.Dry mouth, anticholinergic effects (71%), and other side effects such as headache (25%), increased appetite (21%), and dizziness (21%) were also common at these doses of doxepin, although these adenous effects were noticeably no more frequent than with placebo in the study in question. In any case, taken together, higher doses of doxepin than very low doses are associated with an increased rate of side effects, as well as an apparent loss of hypnotic efficacy in chronic treatment.

Doxepin 25 mg / day for 3 weeks was found to reduce cortisol levels by 16% in adults with chronic insomnia and increase melatonin production by 26% in healthy volunteers. In individuals with neuroendocrine dysregulation in the form of nocytic melatonin deficiency, presumably due to chronic insomnia, very low doxepin levels have been found to restore melatonin levels to near normal values ​​after 3 weeks of treatment. These results indicate that normalization of the hypothalamic adrenal axis and the circadian sleep-wake cycle may be associated with the beneficial effects of doxepin on sleep and insomnia.

Inhibition of CYP2D6

Doxepin was identified as an inhibitor of CYP2D6 in vivo in a study of human patients receiving 75 to 250 mg / day for depression. While it significantly disrupted metabolic ratios for spart and its metabolic testes, doxepin did not convert any of the patients into a different metabolic zer phenotype (eg, extensive for sideshow or poor). Unproblematic inhibition of CYP2D6 by doxepin may be of clinical relevance.

Pharmacokinetics

Absorption

Doxepin is well dispersed from the gastrointestinal tract, but between 55 and 87% of the foothills is metabolized in the liver for the first time, which results in an average bioavailability of about 29%.After one very low dose of 6 mg, peak plasma levels of doxepin were 0.854 ng / ml (3.06 nmol / L) for 3 hours without food and 0.951 ng / ml (3.40 nmol / L) for 6 hours with food. The plasma concentration of doxepin with antidepressants is much higher and ranges from 50 to 250 ng / ml (from 180 to 900 nmol / L). When the drug is taken with food, levels of insufficient curvature are significantly increased.

Distribution

Doxepin is widely distributed throughout the body and accounts for approximately 80% of the plasma protein bond, especially to albumin and α1-acid glycoprotein.

Metabcm

Doxepin is intensively metabolized by liver through oxidation and N-demethylation. His metab sm is very stereoselective. Based on in vitro studies , the main enzymes involved in doxepin metadata are citochrome P450 CYP2D6 and CYP2C19, with CYP1A2, CYP2C9 and CYP3A4 also involved to a lesser extent. The main active metabolite of doxepin, nordoxepine, is formed mainly by CYP2C19 (contribution> 50%), while CYP1A2 and CYP2C9 are less involved and CYP2D6 and CYP3A4 are not.Both doxepin and nordoxepine are hydroxylated primarily by CYP2D6, and both doxepin and nordoxepine are also converted to glucuronide conjugates. The half-life of doxepin is approximately 15-18 hours, while the half-life of nordoxepine is approximately 28-31 hours. Up to 10% of Caucasian specimens exhibit significantly reduced doxepin metabolism, which can lead to an 8-fold increased plasma concentration of the drug compared to normal.

Nordoxepine is a mixture of (E) and (Z) stereoisomers similar to doxepin.While pharmacological doxepin is supplied in a ratio of approximately 85:15 of the mixture ( E ) – and (Z) -stereoisomers and the plasma concentration of doxepin remains the same as this treatment ratio, plasma levels of (E) – and (Z ) -stereoisomers of nordoxepine, due to the stereoselective metabolism of doxepin, cytochenoxochm1, approximately 50.

Doxepin is excreted mainly in the urine and mainly in the form of glucuronide conjugates, and less than 3% of the ointment is excreted unchanged in the form of doxepin or nordoxepine.

Pharmacogenetics

Since doxepin is mainly metabolized by CYP2D6, CYP2C9 and CYP2C19, genetic variations in the genes encoding these enzymes can affect its metabolism, leading to changes in the concentration of the drug in the body. An increased concentration of doxepin may increase the risk of side effects, including anticholinergic and systemic nerve effects, while a decreased concentration may decrease the effectiveness of the drug.

Individuals can be classified into different types of citochrome P450 metabase depending on what genetic variation they carry.These types of metabesers include bad, intermedian, extensive, and ultyapid metabesers. Most people are extensive metabasers, and have a “normal” metabolite of doxepin. Poor and mediated metabasers have decreased drug metabolism compared to extensive metabasers; patients with these metabosers may have an increased likelihood of side effects. Metab zers ult apid break down doxepin much faster than extensive metab zers; patients with this type of metab zer may be more likely to experience pharmacological deficiency.

A study evaluated the metastasis of a single 75 mg oral dose of doxepin in healthy voluntarists with genetic polymorphisms in the CYP2D6, CYP2C9 and CYP2C19 enzymes. In the extensive, mediated and poor metabolites of CYP2D6, the mean clearance rates of ( E ) -doxepin were 406, 247, and 127 L / h, respectively (3 fold difference between extensive and poor). In addition, the bioavailability of ( E ) -doxepine was approximately 2 folds lower in extensive versus poor metabolites of CYP2D6, indicating a significant role for CYP2D6 in first-pass metabolism of (E) -doxepin.The clearance of ( E ) -doxepin in the slow metabolizers of CYP2C9 was also significantly reduced at 238 L / h. CYP2C19 was implicated in ( Z ) -doxepine metadata, with clearance rates of 191 L / h in extensive CYP2C19 metabolizers and 73 L / h in poor metabasers (~ 5 fold difference). The levels of nordoxepine under the curvature (0-48 hours) depended on the CYP2D6 genotype, with mean values ​​of 1.28, 1.35, and 5.28 nM • L / h in the extensive, intermedial and poor metabolites of CYP2D6, respectively (~ 4-fold difference between the extensive and the poor).Taken together, the metab sm of doxepin appears to be very stereoselective, and the CYP2D6 genotype has a large influence on the pharmacokinetics of ( E ) -doxepin. In addition, poor metabolizers of CYP2D6, as well as patients taking potent inhibitors of CYP2D6 (which can potentially convert the extensive CYP2D6 metabolizer into a poor metabeser), may be at increased risk of doxepin’s adeno effects due to their slower clearance of the drug.

Another study evaluated doxepin and nordoxepine metabolism in hyperfast, extensive, and poor metabolites of CYP2D6 after a single 75 mg oral dose.They found up to more than 10-fold variation in the overall effects of doxepin and nordoxepine between the different groups. The researchers hypothesized that to achieve an equivalent effect, based on an average dose of 100%, the doxepin dose could be adjusted to 250% in ultrafast metabolizers, 150% in extensive metabasers, 50% in intermediate metabolizers, and 30% in poor metabasers.

Chemistry

Doxepin is a tricyclic compound, in particular dibenzoxepine, and has three rings fused together with a side chain attached in its chemical structure.This is the only TCA with a dibenzoxepine ring system that has been sold. Doxepin is a TCA tertiary amine, with its side chain demethylated metabitnordoxepine being a secondary amine. Other tertiary amine TCAs include amitriptyline, imipramine, clomipramine, dosulepine (dotiepine), and trimipramine. Doxepin is a mixture of the (E) and (Z) stereoisomers (the latter is known as cidoxepin or cis-doxepin) and is used neat in a ratio of approximately 85:15.The chemical name of doxepin is (E / Z) -3- (dibenzo [ b, e] oxepin-11 (6H) -ylidene) -N, N-dimethylpropan-1-amine and its free basic form has the chemical formula C19h31NO with molecular weight 279.376 g / mol. The drug is used practically as a hydrochloride salt; the free base is rarely used. Free base CAS registration number – 1668-19-5, hydrochloride – 1229-29-4.

History

Doxepin was discovered in Germany in 1963 and introduced to the United States as an antidepressant in 1969.It was subsequently approved at very low doses in the United States for the treatment of insomnia in 2010.

Society and culture

General names

Doxepin is the general name of the drug in English and German and his and, while doxepin hydrochloride is his ,,, and. Its generic name in Spanish and Italian and it is doxepin , in French and its doxepin , and in Latin doxepinum .

Cis or ( Z ) doxepin’s stereoisomer is known as cidoxepine and this is it, while cidoxepine hydrochloride is it.

Trade names

Was introduced under the trade names Quitaxon and Aponal by Bo inger and as Sinequan by P er.

, Doxepin is traded under many brands around the world: Adnor, Anten, Antidoxe, Colian, Deptran, Doneurin, Dospin, Doxal, Doxepini, Doxesom, Doxderm, Jilex, Ichderm, Li e ning, Ning, Mardereen, Sadereen, Saxoxin, non, Noa, Sa, Saya, Saua, So, S., S. It is also marketed as a combination drug with levomenthol under the brand name Doxure.

Approx.

Oral doxepin is approved for the treatment of depression and sleep-supporting insomnia, and topical forms are FDA-approved for the short-term treatment of certain itchy skin conditions. While in Australia and the United Kingdom, the only licensed indicator (s) is the treatment of underlying depression and eczema pruritus, respectively.

Research

Antihistamine

As of 2017, there was no good evidence that topical doxepin was useful for the treatment of localized neuropathic pain.Cidoxepine is being developed by Elorac, Inc. for the treatment of chronic urticaria (hives). As of 2017, it is in phase II clinical trials for this indicator. The drug has also been investigated for the treatment of allergic rhinitis, atopic dermatitis and contact dermatitis, but these symptoms have been reversed.

Headache

Doxepin is being developed by Winston Pharmaceuticals in an intranasal form for the treatment of headache. As of August 2015, it was in phase II clinical trials for this indicator.

External relations

90,000 🏥 16 Antidepressants that cause weight gain 2021

Overview

Weight gain is a possible side effect of many antidepressants. Although each person responds differently to antidepressant treatment, the following antidepressants may be more likely to cause weight gain during your treatment.

AdvertisementAdvertisement

TCA

1. Tricyclic antidepressants

Tricyclic antidepressants, also known as cyclic antidepressants or TCAs, can cause weight gain.These medicines include:

• amitriptyline (Elavil)
• amoxapine
• desipramine (norpramine)
• doxepin (adapin)
• imipramine (tofranil-PM)
• nortriptyline (Pamelor)
• protriptyline (Vivactil)
• trimipramine (Surmontil)

TCAs were among the first drugs approved for the treatment of depression. They are not prescribed as often because newer treatments have fewer side effects.Weight gain was a common reason people discontinued treatment with these types of antidepressants, according to a 1984 study.

However, TCAs may be effective in people who do not respond to other types of antidepressants despite unwanted side effects.

More details: Tricyclic antidepressants “

MAOIs

2. Certain monoamine oxidase inhibitors (MAOIs)

Monoamine oxidase inhibitors (MAOIs) were the first class of antidepressants to be developed.MAOIs that cause weight gain include:

• phenelzine (Nardil)
• isocarboxazid (Marplan)
• tranylcypromine (Parnate)

Because of certain side effects and safety concerns, MAOIs are most often prescribed when other antidepressants are not working. Of the three MAOIs listed above, phenelzine is most likely to lead to weight gain, according to a 1988 review.

On the other hand, a newer formulation of the MAOI known as selegiline (Emsam) has been shown to actually result in weight loss during treatment.Emsam is a transdermal medication that is applied to the skin with a patch.

AdvertisementAdvertisementAdvertisement

SSRI

3. Long-term use of some selective serotonin reuptake inhibitors (SSRIs)

SSRIs are the most commonly prescribed class of depressive drugs. Long-term use of the following SSRIs can lead to weight gain:

• paroxetine (Paxil, Pekseva, Brissel)
• sertraline (Zoloft)
• fluoxetine (Prozac)
• citalopram (Seleka)

Although some SSRIs are initially associated with weight loss, long-term use of SSRIs is primarily associated with weight gain.Long term use is considered a treatment that lasts longer than six months.

Of the SSRIs listed above, paroxetine is most commonly associated with weight gain with both long-term and short-term use.

Atypical antidepressants

4. Some atypical antidepressants

Mirtazapine (Remeron) is a noradrenergic-type antagonist, which is a typical atypical antidepressant. The drug has been repeatedly demonstrated to be more likely to increase weight and increase appetite than other drugs.However, mirtazapine is less likely to cause people to gain weight compared to TCAs.

However, mirtazapine does not have the same number of other side effects as other antidepressants. Other side effects it can cause include:

• nausea
• vomiting
• sexual dysfunction

Advertising Advertise

Less weight

Antidepressants that do not cause weight gain

Other antidepressants were associated with less weight gain as a side effect.These antidepressants include:

• escitalopram (Lexapro, Cipralex), SSRI
• duloxetine (Cymbalta), another SSRI
• buproprion (Wellbutrin, Forfivo and Aplenzin), atypical antidepressant
• nefazodone (Serzone), serotonin antagonist and reuptake inhibitor
• venlafaxine (Effexor) and venlafaxine ER (Effexor XR), which are serotonin and norepinephrine reuptake inhibitors (SNRI)
• desvenlafaxine (Pristiq), SNRI
• levomilnacipran (Fetzima), other SNRI
• vilazodone (Viibryd), serotonergic antidepressant
• Virtsoxetine (Trintellix), atypical antidepressant
• Selegiline (Emsam), a new MAOI that you apply to your skin, which can lead to fewer side effects than MAOIs taken by mouth

Weight gain is also less likely to occur with the following SSRIs when used for less than six months:

• sertraline (Zoloft)
• fluoxetine (Prozac)
• citalopram (Celexa)

Some antidepressants can even lead to weight loss.For example, duloxetine and bupropion have been reported to cause weight loss in some people.

Learn more: List of Depression Drugs »

Advertising

Takeout

Removal

Not everyone on an antidepressant gains weight. Some people do lose a few pounds. Experts emphasize that concerns about weight gain should not influence antidepressant choice for most people. There are other side effects and factors to consider when choosing an antidepressant.

If you do gain weight while taking an antidepressant, the drug may not actually be the direct cause of your weight gain. An improved mood while taking an antidepressant, for example, can increase appetite, leading to weight gain.

Do not stop taking this medicine right away, even if you gain some weight. You will need to work with your doctor to find an antidepressant that helps with your symptoms of depression and does not lead to unwanted side effects.This may take a little patience. Your doctor may also give you some advice on how to prevent weight gain with antidepressant therapy.

90,000 How can certain antidepressants affect your weight?

Weight gain is one of the potential side effects of antidepressants.It is estimated that about 25% of people taking these drugs experience weight gain.

You will be interested in: Antidepressants: main types and applications

Although responses to specific antidepressants vary between individuals, some antidepressants are more likely to cause weight gain than others.

Antidepressants and weight

Experts do not fully understand why antidepressants lead to weight gain.One theory is that antidepressants can affect a person’s metabolism. In addition, depression itself can lead to severe weight loss, so relieving symptoms of this condition can restore appetite and cause weight gain.

Antidepressants affect serotonin, a neurotransmitter that regulates mood and controls appetite. These changes can also increase your cravings for carbohydrate-rich foods such as bread, pasta, and sweets.

Weight gain while taking antidepressants may also indicate that the drug is not effective in controlling the symptoms of the condition, in particular the weight gain caused by depression itself.

Antidepressants that can lead to weight gain

You will be interested in: How to stop using antidepressants without harming the body?

The following antidepressants are more likely to cause weight gain:

• Tricyclic antidepressants (TCAs): Also known as cyclic antidepressants, tricyclic antidepressants are among the earliest forms of antidepressants. TCAs are less commonly prescribed than current forms of antidepressants because they can cause more side effects, including weight gain.However, TCAs may be effective in people who are not suitable for other treatments. Examples of TCAs are amitriptyline, amoxapine, desipramine, doxepin, imipramine, nortriptyline, and protriptyline.
• Monoamine oxidase inhibitors (MAOIs): MAOIs are another early class of antidepressants. While they work quite effectively, they tend to cause weight gain and other adverse reactions. In addition, this type of drug can cause an increase in blood pressure when other drugs are used.MAOIs include isocarboxazid, phenelzine, and tranylcypromine.
• Selective serotonin reuptake inhibitors (SSRIs): The most commonly used form of antidepressant, SSRI, has been associated with short-term weight loss and long-term weight gain. Selective serotonin reuptake inhibitors include citalopram, fluoxetine, paroxetine, and sertraline.

Other types of antidepressants

You will be interested in: Antidepressants during pregnancy – danger to the fetus?

Not all antidepressants cause weight gain, and some cause less weight gain than other commonly prescribed medications.