Insomnia is defined as:
“Persistent difficulty with sleep initiation, duration, consolidation, or quality that occurs despite adequate opportunity and circumstances for sleep, and results in some form of daytime impairment.”
It is a very common problem that is estimated to occur in 5–10% of the general population, although some studies suggest that the rate is as high as 33% of the adults. In a 2014 survey in the United States asking about adults’ experience over the prior week, 45% of respondents reported having had difficulty falling asleep at least one night and 16% reported difficulty ≥5 nights; 52% reported having had difficulty staying asleep at least one night and 23% reported difficulty ≥5 nights; and 17% of adults reported having taken a prescription or over-the-counter medication for sleep at least once, with 10% reporting use for ≥5 nights.
Insomnia – CAM Treatment Options
Gabapentin (Neurontin) & Lyrica
Cognitive Behavior Therapy (CBT)
Meditation & Mindful Exercises
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Sleep is a state characterized by changes in the level of consciousness, unresponsiveness to the surrounding environment, and inactivity of voluntary muscles. Sleep restores people physically and psychologically, with recent research identifying sleep as the time during which metabolic toxins are eliminated from the brain.
The Physiology of Sleep
Sleep is divided by polysomnographic criteria into rapid eye movement (REM) sleep and non–rapid eye movement (NREM) sleep. NREM sleep amounts to approximately 75% to 80% of total sleep time, whereas REM sleep accounts for the remaining 20% to 25% of total sleep time. REM sleep is associated with dreaming, learning, and memory consolidation. Slow Wave Sleep (SWS) is also thought to be important in learning.
It is estimated that over 50% of the US population will suffer from a sleep disorder at some point in their life. The most common sleep disorder is insomnia and the prevalence of insomnia increases with age making this growing problem as our national average age becomes higher. Sleep apnea is the next most common sleep disorder. For those with chronic pain, sleep disruption is experienced in 50-80% of patients.
Sleep apnea is a common disorder that negatively impacts up to 20% of the population with an even greater frequency amongst patients with chronic pain. Untreated, sleep apnea leads to many medical complications including increased risk for heart attack, stroke, diabetes, high blood pressure, obesity, fatty liver… the list goes on. Of particular significance to patients taking opioids, untreated sleep apnea is a dangerous condition because when combined with the sedative, respiratory-depressant effects of opioids, the reduced oxygen levels associated with sleep apnea may lead to increased risk of death, heart attack or stroke. It is likely a major contributory factor in unintentional opioid related deaths.
See: Sleep Apnea
Insomnia is characterized by difficulty in initiating sleep and/or maintaining sleep, non-restorative sleep or poor-quality sleep. It is classified as short-term if it persists less than 3 months and chronic if it persists longer thnt 3 months and occurs at least three times per week. Sleep disturbances cause people to suffer from mental dysfunction and daytime sleepiness and can lead to various health and socioeconomic issues. People who suffer from insomnia for long time periods may also suffer from depression and experience a decreased quality of life. Patients with chronic pain are particularly victimized by insomnia.
Sleep remains one of the most poorly understood biological processes and effective solutions to insomnia often remain elusive. Worse still, “solutions” for sleep sometimes result in even worse outcomes as dependence on hypnotic medications such as the benzodiazepines (Valium, Xanax, Klonopin etc.) develop making them difficult to discontinue, even when they are not effective.
The search for sleep for those with chronic pain and insomnia is particularly challenging. Despite the lure of hypnotic medications as a solution, they are only recommended for short term use due to failure to maintain effectiveness over time, the development of dependence and associated withdrawal syndromes and their potentially dangerous medication interactions, especially with opioids. In the case of the benzodiazepines, the side effects can include frequent memory disorders, daytime drowsiness, falls, fractures, birth defects and increased risk for motor vehicle accidents.
Insomnia can be categorized as primary or secondary in which secondary insomnia is a result of a co-occuring medical condition(s) such as pain, mood disorders such as depression or anxiety or a separate sleep disorder. Given these insomnia subtypes, it can be difficult to distinguish between them due to overlapping symptoms and it is often difficult to assign causation to specific factors. Nevertheless, cotreatment of an underlying causative condition will likely facilitate resolution of both conditions.
Insomnia can also be categorized as difficulty falling asleep (sleep-onset insomnia), difficulty staying asleep (sleep-maintenance insomnia), early-morning awakenings coupled with an inability to return to sleep (terminal insomnia), and combined insomnia (more than one of these categories). Also, insomnia with objective short sleep duration (<6 hours) is another type. Different medications may be more or less effective for different categories, so it can be important to identify the symptom pattern when selecting a sleep medication.
Management of Insomnia – Overview
Current, Best Recommendations for Managing Insomnia
- Perform moderate, regular physical exercise, especially in the morning. Do not eat or exercise before retiring for sleep.
- Sleep Hygiene: Reduce all unnecessary light and sound from your sleep environment and avoid activities in the bed outside of sex and sleep.
- Take a warm bath with epsom salts in the evening hours before retiring.
- Practice a mindful exercise (meditation, prayer, music etc.) of preference for at least 20 minutes prior to retiring for sleep.
- Consider the use of a foam sleep wedge that safely and comfortably facilitates sleep positioning for optimal breathing that can reduce fatigue and improve energy (See below).
- Learn about certain foods that can contribute to swelling in the nasal passages and sinuses and interfere with optimal air exchange while sleeping – see our registered dietitian.
- Sleep Restriction: Sleep restriction therapy is a behavioral treatment for insomnia that works to decrease variability in the timing of sleep while increasing the depth of sleep. The goal is to shorten the amount of time spent in bed in order to consolidate sleep (See behavioral solutions below).
- When resorting to a hypnotic, start with magnesium supplements or epsom salt baths at bedtime then consider CAM alternatives first (see CAM Sleep).
- If a prescription hypnotic is indicated, try doxylamine or diphenhydramine first. Studies show no major difference in effectiveness versus benzodiazepines and related drugs. The main adverse effects of sedative antihistamines are daytime drowsiness/altered vigilance, and dry mouth. If used every night, however, these medications usually lose effectiveness.
- If a benzodiazepine is prescribed, avoid consistent use for more than two weeks.
Accurate’s Sleep Right Program
At Accurate Clinic we offer some simple but often overlooked approaches to improve sleep quality. Changing one’s sleep positioning by elevating the head is an effective means of improving air flow and oxygenation while asleep. Some people elevate the head of their bed but another simple alternative is the use of a foam sleep wedge that safely and comfortably facilitates sleep positioning that can reduce fatigue and improve energy. For the convenience of our patients we offer the foam wedge at an affordable price at Accurate Clinic.
To learn more about certain foods that can contribute to swelling in the nasal passages and sinuses and interfere with optimal air exchange while sleeping, make an appointment with our registered dietitian. Reducing congestion with simple dietary interventions can make a significant difference in your quality of sleep.
Behavioral Solutions for Insomnia
Experts agree that behavioral solutions for insomnia are the best, safest means for effective long term management. Behavioral solutions include sleep hygiene in which activity and environment are maintained in support of sleep including avoiding exercise and eating before retiring for sleep, turning of the TV and radio, keeping the lights dim and avoiding activities in the bed outside of sex and sleep. Additional behavioral approaches include deep relaxation techniques, self-hypnosis and cognitive behavioral techniques.
See: CBT, meditation and hypnosis
Cognitive Behavior Therapy – Insomnia (CBT-I)
Cognitive Behavior Therapy – Insomnia (CBT-I) combines cognitive and behavioral interventions. Cognitive interventions are aimed at sleep hygiene and changing patients’ beliefs and attitudes about sleep. Behavioral interventions are directed at stimulus control therapy to pair the bed with sleep, sleep restriction/compression to increase the drive to sleep and relaxation training to reduce hyperarousal.
Unfortunately, not all patients are able to obtain CBT-I because of a lack of availability of providers or cost constraints. CBT-I requires patients to make a considerable time commitment that they may be unable or unwilling to do. CBT-I also requires a substantial time investment of trained clinicians which may not be available. To facilitate access to CBT-I, digital courses are becoming available via the internet (digital CBT-I). Also, smart phone apps are also availabe, such as CBT-I Coach, to supplement but not replace clinician based treatment.
The goal is to shorten the amount of time spent in bed in order to consolidate sleep by decreasing variability in the timing of sleep while increasing the depth of sleep. Sleep restriction therapy is considered by many as the most effective sleep hygiene technique available. It is as effective as hypnotic medication, yet with a longer-lasting effects. It does require commitment to the process for success. It takes several weeks of maintaining your sleep schedule in order to see results. Initially, one may feel sleepier and experience more disrupted sleep but insomnia will improve gradually and the benefits will persist.
It should be noted that sleep restriction may exacerbate comorbidities including seizure disorders, severe obstructive sleep apnea, and untreated bipolar disorder, as well as individuals who are actively suicidal, or in patients with severe parasomnias such as sleep walking.
See: Sleep Restriction Therapy instructions
Medications for Sleep
Prescription medications for sleep include antidepressants, antihistamines, benzodiazepines, the “Z” drugs and others. Common examples of antidepressants effective for sleep include trazadone, amitriptyline (Elavil), doxepin, Remeron and others. Ramelteon (Rozerem), a prescription hypnotic medication that acts on melatonin receptors, has been shown to be helpful in insomnia.
Sleep Onset and/or Sleep Maintenance Insomnia
In 2017, the American Academy of Sleep Medicine (AASM) published a clinical practice guideline for treatment of insomnia in adults. The AASM makes suggestions about whether specific medications should be used for the treatment of sleep onset and/or sleep maintenance insomnia. Several medications recommended for treating both insomnia subtypes include certain benzodiazepines and the benzodiazepine receptor agonist Z-drugs such as Ambien.
Therapies recommended specifically for use in sleep onset insomnia include the BZD receptor agonist zaleplon (Sonata), the BZD triazolam, and the melatonin agonist ramelteon, whereas recommended therapies for sleep maintenance insomnia include suvorexant and doxepin.
All of the specific recommendations by the AASM are classified as “weak” because they are based on the degree of confidence in the availability and quality of data and other considerations including potential risks and patient preferences. The weak classification of these recommendations should not be misinterpreted as meaning that these sleep-promoting medications are not effective or appropriate for insomnia treatment, just that the existing data limits the degree of confidence in these recommendations, especially regarding subtypes of insomnia. Due to weak research evidence, trazodone and over-the-counter medications such as diphenhydramine (Benadryl), melatonin, L-tryptophan, and valerian are not recommended for treating either type of insomnia.
Changing from One Sleep Medication to Another
Abrupt changes in treatment with older-generation sleep medications can lead to rebound insomnia with worsened sleep. This is of practical concern because commonly a person with chronic insomnia whose medication treatment is no longer effective because of the devel- opment of physiological tolerance is rotated to a new sleeping medication.
A new medication (such as an suvorexant) may be prescribed, but the new medication may fail if the old one is abruptly discontinued because there is no cross-tolerance between the older medications (such as benzodiazepines and Z-drugs) and suvorexant. This failure may be misinterpreted as a medication failure due to ineffectiveness of the new medication instead of it actually being the result of abrupt discontinuation of the prior medication leading to rebound insomnia. A gradual tapering off of the old medication may help to avoid rebound insomnia, particularly when the older medication was taken frequently for months or years.
OTC antihistamines including doxylamine and diphenhydramine and prescription hydroxyzine and others showed no major difference in effectiveness versus benzodiazepines and related drugs. However they tend to build tolerance relatively quickly if used on consecutive nights. The main adverse effects of sedative antihistamines are daytime drowsiness, impaired thinking/memory and dry mouth.
The antidepressants are the most commonly used hypnotic medications outside of the benzodiazepines which have now gone out of favor for safety reasons. Trazadone is a common preferred choice and there is also some evidence that it can synergistically improve pain when taken with pregabalin (Lyrica).
Tricyclic antidepressants (TCAs)
The tricyclic antidepressants (TCAs) doxepin, nortriptyline and amitriptyline (Elavil) are commonly used. Doxepin is one of the few FDA approved drugs for insomnia at low dose (5mg) and is associated with fewer side effects than amitriptyline. Desipramine is less sedating than doxepin or amitriptyline and can be tried if these are too sedating, although desipramine can sometimes impair sleep. TCAs decrease sleep latency (time required to fall asleep), increase sleep efficiency and increase total sleep time.
Tricyclic antidepressants have pro-serotonergic, noradrenergic, dopaminergic and sodium channel blocking effects that likely responsible for their effiectiveness in both depression and pain, including neuropathic and central pain.
See: Neurobiology of Pain
SSRIs (Selective Serotonin Reuptake Inhibitors) & SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors)
The SSRIs such as fluoxetine (Prozac), citalopram (Celexa), sertraline (Zoloft), and paroxetine (Paxil) and SNRIs such as duloxetine (Cymbalta) and venlafaxine (Effexor) can be helpful in some patients but are not commonly used for insomnia. However, they can be especially helpful for sleep when the insomnia is secondary to anxiety and/or depression.
Mirtazapine is a very effective antidepressant with unique mechanisms of action, characterized by a rapid (as early as four days after initiation of treatment) and sustained improvement in depression symptoms with few side-effects. Mirtazapine shows significant benefit for insomnia, even in patients without depression, and is helpful for anxiety. It has a favorable safety profile for use in geriatric patients and has no cardiac toxicity.
Therapeutic Benefits of Mirtazapine (Remeron)
At doses 15-30 mg, mirtazapine reduces time required to fall sleep, improves total sleep time and sleep efficiency while decreasing frequency of awakenings. Interestingly, while it is effective at doses of 15-30 mg, it becomes less effective at higher doses.
Depression and Anxiety
As an antidepressant, mirtazapine is as effective as the tricyclic antidepressants and trazodone in patients with moderate-to-severe depression and causes fewer and less severe anticholinergic and cardiovascular side effects compared with the tricyclics. When compared with the SSRIs as well as the SNRIs, mirtazapine is equally effective but with a significantly earlier onset of action, with effects seen as early as 1 and 2 weeks after treatment initiation. Compared to patients taking SSRIs, patients have a 74% greater likelihood of achieving remission of depression during the first 2 weeks of therapy. This early improvement appears to be independent of mirtazapine’s sleep-improving properties and is a highly sensitive predictor of later stable response or remission.
Mirtazapine has been shown to be effective for geriatric depression, post–myocardial infarction depression, post-stroke depression and substance dependence with comorbid depression. In patients with alcohol dependence and comorbid depression, mirtazapine has shown significant improvement in both depression and alcohol craving.
A number of small studies have suggested that mirtazapine is effective in the treatment of patients with anxiety disorders including post-traumatic stress disorder (PTSD).
There are limited reports that mirtazapine may be effective for chronic pain including low back pain, fibromyalgia pain and tension-type headaches. A Cochrane review study published in 2018 did identify a statistically significant 30% improvenent in pain with fibromyalgia, suggesting this medication may be a good choice as a sleep medication in this population. Unfortunately, there are few studies available to allow for definitive pain benefit claims.
Mirtazapine also has other unique therapeutic benefits over other antidepressants including effectiveness for debilitating weight loss by improving appetite and reduction of post-operative nausea and vomiting. Mirtazapine may be a good option for patients with pain associated with low weight, agitation, anxiety, insomnia, nausea and drug- induced sexual dysfunction.
Dosing of Mirtazapine
The usual starting dosage is 15 mg, with a usual dosage range of 15-45 mg per day. Because of its sedative effect, it is usually recommended that mirtazapine be taken at bedtime. It is available in 15-mg and 30-mg scored tablets.
Side Effects of Mirtazapine
The most commonly reported side effect are mild and include sedation, dry mouth and increased appetite which can lead to significant weight gain. These side effects may be attributed in part to mirtazapine’s antihistaminic activity. Mirtazapine has been reported to have a lack of sexual side effects although studies provide conflicting results.
The side effect profile changes with the dosage. At low dosages, mirtazapine has a predominant effect on the histamine (H1) receptor, which is responsible for the increase in appetite, weight, and sedation. As one increases the dose, more noradrenergic and serotonin effects are noted which in turn counteract the effect on the histamine receptor and reduces sedation, often normalizing the appetite and reducing the possibility of weight gain associated with lower doses of mirtazapine. Therefore, based on the pharmacology of this medication, one can adjust the dose of mirtazapine to increase or decrease the likelihood of side effects in a manner that might optimize benefits.
Pharmacology of Mirtazapine
Mirtazapine is well absorbed and can be taken with or without food. It is extensively metabolized in the liver, and its metabolites are eliminated primarily in the urine (up to 75%) and in the feces. Mirtazapine has a half-life of 20–40 hours, which may increase by 30%–40% in patients with hepatic impairment. Mirtazapine has low protein binding and the drug’s clearance may decrease by 30%–50% in patients with moderate-to-severe renal impairment. Therefore, dosing of mirtazapine should be reduced, or avoided, in patients with significant liver or kidney disease. Over its usual dosage range, mirtazapine reaches peak plasma level approximately two hours after an oral dose and reaches a steady state in approximately five days.
Mirtazapine does not auto-induce, inhibit or induce hepatic isoenzymes and therefore has limited drug-drug interactions. However, mirtazapine should not be used within 14 days of the use of a monoamine oxidase inhibitor because of the possibility that a hypertensive crisis could be triggered.
Because mirtazapine has 5HT1A agonistic properties and blocks 5HT2 and 5HT3, it reduces the likelihood of side effects related to nonselective serotonin activation. Mirtazapine does have some histaminergic activity and blocks presynaptic alpha adrenergic receptors. However, it has virtually no anticholinergic, adrenergic, or typical serotonin reuptake inhibitor side effects and does not contribute to serotonin syndrome
Mirtazapine is tetracyclic antidepressant that increases serotonin and noradrenaline in the central nervous system (CNS). It is a type I histamine and serotonin type II & III receptors antagonisi. It enhances noradrenergic transmission via blockade of central α2-adrenoceptors and is a potent serotonin 5-HT2 and 5-HT3 antagonist, thereby increasing serotonergic stimulation via the 5-HT1 receptor. Mirtazapine has no significant affinity for dopamine receptors, low affinity for muscarinic cholinergic receptors, and no effect on monoamine reuptake.
Advantages of the Antidepressants
The advantages of the antidepressants include significant pain benefits in certain chronic pain syndromes, notably neuropathic pain syndromes and fibromyalgia. They also maintain their effectiveness well with limited tolerance. The antidepressants (both TCAs and SSRIs), however, are known to reduce REM sleep which can impair learning.
Side Effects of the Antidepressants
The side effects of the antidepressants, including excessive sedation, impaired thinking and dry mouth can be significant, limiting their usefulness. All antidepressants can sometimes trigger a worsening of depression when they are started, even leading to suicidal thoughts or behaviors. While this reaction is not common, it does occur especially in young adults and should be monitored for and the medication immediately discontinued if depression develops after starting. Weight gain and sexual dysfunction are also sometimes seen with antidepressants.
Suvorexant (Belsomra) is a relatively new medication for insomnia, the first of its kind in a novel pharmaceutical class of sleeping medications. This unique new class of medications works by a different mechanism than other sleep meds which offers many advantages over other currently available insomnia medications.
Even after continued use for 4 weeks, suvorexant is not associated with complex sleep-related behaviors (sleep walking) or next-day hangover effects such as cognitive or motor impairments, anterograde amnesia or rebound insomnia. Suvorexant appears to be safe in those with mild to moderated severity of obstructive sleep apnea when used at recommended doses.
For in-depth information, please click here: Suvorexant (Belsomra)
Gabapentinoids: Gabapentin (Neurontin) and Pregabalin (Lyrica)
Clinical observations and recent research confirms that gabapentin, and possibly pregabalin, can be effective for insomnia. Sleep studies indicate gabapentin normalizes stages of sleep, improves sleep efficiency and reduces spontaneous arousal in patients with primary insomnia (not due to other conditions). The use of gabapentin in normal subjects caused no disruption in sleep stages of significance.
Because nightime use of alcohol is known to disrupt sleep by causing increased awakenings and reduced SWS, a 2005 study looked at the use of gabapentin in subjects given a nightcap of alcohol as a model of disrupted sleep that might mimic other conditions associated with increased awakenings including stress and sleep apnea. In this study a single dose of 300-600 mg gabapentin one hour before bedtime improved sleep by decreasing awakenings and improving SWS in subjects who drank alcohol (4 ounces of 40% alcohol). No differences were seen in any of the subjective tests of drowsiness and performance.
Gabapentin was studied in alcoholics in treatment, when insomnia is a significant problem. After at least 4 weeks of abstinence, alcoholic patients with persistent insomnia reported significant sleep improvement during treatment with either gabapentin or trazodone. Although the overall sleep of each medication group improved significantly over time, patients who received gabapentin improved significantly more than did patients who received trazodone.
Another study that looked at the use of gabapentin in subjects with disrupted sleep evaluated a 500 mg dose of gabapentin taken 30 minutes before bedtime in subjects who went to bed 5 hours before their usual sleep time. In this model of disrupted sleep, (called sleep phase advance disruption), gabapentin showed significantly longer sleep duration and greater depth compared to placebo.
Studies also indicate that gabapentin and possibly pregabalin are effective in treating the insomnia associated with benzodiazepine (Xanax, Klonopin, Valium etc.) withdrawal.
Side Effects of the Gabapentinoids
The side effects of gabapentin and pregabalin include the potential for depression, rarely severe, drowsiness, impaired cognition, swelling of the extremities, weight gain. Gabapentin may offer fewer side effects compared with pregabalin but this varies from individual to individual.
See: Gabapentin (Neurontin) & Pregabalin (Lyrica),
Ramelteon (Rozerem) is a relatively new hypnotic that, like melatonin, acts on the melatonin receptors to facilitate sleep but it has a longer duration of action than melatonin. Recent research indicates melatonin to be effective for the insomnia related to fibromyalgia, suggesting that ramelteon may be a preferred choice for fibromyalgia patients. Studies also indicate that melatonin is effective in treating the insomnia associated with benzodiazepine (Xanax, Klonopin, Valium etc.) withdrawal. Additionally, melatonin has been shown to be effective for insomnia related to time zone change, but only when more than 2-3 time zones are involved.
The usual adult dose is 8 mg taken within 30 minutes of going to bed. Doses higher than 8 mg are not recommended. Taking it with or immediately after a high-fat meal should be avoided to get the best benefit.
Rozerem Safety Information
Because Rozerem is sedating, one should not drive or operate machinery after taking this medication. Side effects may also include dizziness, fatigue, nausea, and worsening insomnia.
As with many medications used for sleep, Rozerem may worsen depression or abnormal thoughts. Other possible side effects include hallucinations (rare) and nightmares. Patients taking Rozerem may experience somnambulism, which is inappropriate sleep activities including sleep walking, sleep driving, sleep eating or other behaviors in which there is no memory of the event upon awakening. If these symptoms occur, Rozerem should be discontinued. Somnambulism is also known to occur with the “Z” drugs (see below) used for sleep: Ambien, Sonata and Lunesta. There is a higher chance of these behaviors if one drinks alcohol with these sleep medications.
In patient 65 years of age or older, there appears to be no overall differences in safety or effectiveness compared with younger adults. Rozerem does not appear to suppress respiration and therefore appears safe in patients with COPD or sleep apnea, although definitive studies are not available. Rozerem may affect testosterone and prolactin. Consult your doctor if you experience changes in your period, libido, or problems with fertility.
No adjustment of Rozerem dosage is required in patients with renal impairment, including patients with severe renal impairment (creatinine clearance of ≤30 mL/min/1.73 m2) and patients who require chronic hemodialysis. Rozerem metabolism may be slowed in patients with liver disease resulting in greater and prolonged drug effects and therefore should be used with caution in patients with moderate liver impairment.
Rozerem Drug Interactions
Rozerem is metabolized by the liver enxymes Cyp1A2 (primarily), CYP3A4, CYP2C9 and therefore caution should be used when taking Rozerem with other medications that inhibit these enzymes including Luvox (Cyp1A2) and Fluconazole (CYP2C9).
Doxepin has been shown to increase blood levels of Rozerem so patients should be closely monitored when Rozerem is coadministered with doxepin. Alcohol causes additive psychomotor impairment; should not be used in combination.
Rozerem is a melatonin receptor agonist with both high affinity for melatonin MT1 and MT2 receptors and relative selectivity over the MT3 receptor. The activity of ramelteon at the MT1 and MT2 receptors is believed to contribute to its sleep- promoting properties, as these receptors, acted upon by endogenous melatonin, are thought to be involved in the maintenance of the circadian rhythm underlying the normal sleep-wake cycle.
Rozerem has no appreciable affinity for the GABA receptor complex or for receptors that bind neuropeptides, cytokines, serotonin, dopamine, noradrenaline, acetylcholine, or opiates. Ramelteon does not interfere with the activity of known endogenous enzymes.
The major metabolite of ramelteon, M-II, is pharmacologically active and has approximately one tenth and one fifth the binding affinity of the parent molecule for the MT1 and MT2 receptors, respectively. However, M-II circulates at higher concentrations than the parent producing 20- to 100-fold greater systemic exposure when compared to ramelteon. Similar to ramelteon, M-II does not interfere with the activity of known endogenous enzymes. All other known metabolites of ramelteon are inactive.
Although the total absorption of ramelteon is rapid and at least 84%, the absolute oral bioavailability is only 1.8% due to extensive first-pass metabolism. Repeated once daily dosing with ramelteon does not result in significant accumulation owing to the short elimination half-life of ramelteon (on average, approximately 1- 2.6 hours). The half-life of M-II is 2-5 hours and independent of dose.
When administered with a high-fat meal, the absorption of Rozerem is delayed, resulting in delayed onset of action and lower maximum blood levels which may reduce its effectiveness. It is therefore recommended that Rozerem not be taken with or immediately after a high-fat meal.
When benzodiazepine medications are used for sleep, it is best to limit them to intermittent and short-term use (< 2-3 weeks) as they are known to develop tolerance and dependence as well as to trigger abuse. While at one time immensely popular and frequently prescribed, the use of benzodiazepine have fallen out of favor over the last few years due to safety reasons. Long term use of benzodiazepines for greater than one year have been shown to often lose their effectiveness for sleep.
Benzodiazepines – Potential Concerns
Long term use of benzodiazepines has been associated with increased depression. Also, benzodiazepines offer particular danger to patients concomitantly taking opioids as evidenced by the marked, 10-fold increase incidence of unintentional opioid-related overdose deaths compared to opioid use without benzodiazepines. Benzodiazepines are now known to be associated with memory impairment with both short-term and long-term use as well as having the potential for birth defects including cleft palate. Finally, the high degree of physical dependence coupled with extended withdrawal syndromes and difficulty discontinuing have argued strongly against their long term use, defined as greater than 2-4 weeks.
Benzodiazepines have also been found to trigger addictive behavior in some individuals and those with problematic alcohol use and alcohol or sedative addiction are at particular risk.
In sleep studies, benzodiazepines have been shown to reduce REM sleep and Slow Wave Sleep (SWS) that are stages of sleep important for learning. These effects may be responsible for observations that the long term use of benzodiazepines is associated with impaired cognitive function and memory impairment. Recent research has also raised significant concern for the possibility that the use of benzodiazepines may contribute to the development of Alzheimer’s Disease although this risk is controversial.
Short-acting and Long-acting Benzodiazepines
Short-acting benzodiazepines used for sleep include temazepam (Restoril), flurazepam (Dalmane) and alprazolam (Xanax). Long-acting benzodiazepines commonly used for anxiety but sometime prescribed for sleep include diazepam (Valium), clonazepam (Klonopin) and lorazepam (Ativan).
Tapering Down or Off Benzodiazepines
When tapering down or off benzodiazepines or especially if they are discontinued abruptly, benzodiazepine-related insomnia can be very problematic. It is always best to taper down/off benzodiazepines slowly to minimize or avoid the insomnia and other withdrawal symptoms. As sleep aids for treating benzodiazepine-related insomnia, the use of gabapentin (Neurontin), pregabalin (Lyrica), melatonin and valerian root have been shown to be beneficial.
For more information, see: Benzodiazepines
Also see: Gabapentin (Neurontin) & Pregabalin (Lyrica), Melatonin
The “Z-drugs” include zolpidem (Ambien), eszopicione (Lunesta) and zalepione (Sonesta) and others. Chemically related to the benzodiazepines and also acting on benzodiazepine receptors, the “Z-drugs” share the potential risks associated with the benzodiazepines but appear to offer the advantages of less risk for addiction or abuse. Additionally, studies have also shown that they appear to sustain their effectiveness over the long term, exceeding 8 months without the development of tolerance or rebound. Unlike benzodiazepines (which reduce stage 3 and 4 sleep), the “Z-drugs” do not consistently alter sleep architecture, although high doses may reduce REM sleep.
Zolpidem is often prescribed for patients with sleep onset insomnia because it fast acting and has a relatively short half-life but it may not be as effective for sleep maintenance problems. However, zolpidem is also available as an extended-release formulation, which may be effective for both sleep onset and sleep maintenance.
Zolpidem (Ambien) – Potential Concerns
Numerous reports have been published regarding unusual side effects with zolpidem (Ambien) and rarely with the other “Z-drugs” that include various nocturnal activities with amnesia. These activities include sleepwalking but also more complex behaviors including sleep-eating, sleep-sex and sleep-driving have been reported without memory of the activites. These behaviors appear to be more common in women and if this side effect Ambien they should be discontinued immediately.
Ambien also has sedative effects that are potentially dangerous, like benzodiazepines, when taken with opioids including buprenorphine due to the potential for increased respiratory depression and accidental overdose. Caution should be employed when combining the Z-drugs, especially Ambien, with opioids so alternative hypnotics should be tried first when feasible.
Antipsychotic Medications (Seroquel) and Zyprexa)
Two of the newer, atypical antipsychotic medications, FDA-approved only for bipolar disorder and schizophrenia, Quetiapine (Seroquel) and Olanzapine (Zyprexa), are sometimes used off-label for treatment of insomnia. Self-reported outcomes and sleep studies suggest they are effective with increased total sleep time, slow wave restorative sleep, and decreasing sleep latency. At low doses, quetiapine primarily has antihistiminergic properties and is weakly pro-serotonergic . It has been known to decrease anxiety and enhance the effectiveness of antidepressant medications.
These medications may cause significant weight gain and cardiac conduction abnormalities, such as prolonged QT interval. Of additional and significant concern is their risk (low) of movement disorders, including tardive dyskinesia. Tardive dyskinesia is a very undesirable condition of uncontrollable movements of the mouth, tongue and/or neck that sometimes resembles a cow chewing its cud. It is an unpredictable side effect usually associated with only long term use, but not always, and one that does not always resolve when the drug is stopped. For this reason, the use of these medications for sleep should be weighed carefully for risks vs. benefits and in most cases avoided for use in uncomplicated insomnia, especially long-term.
Sleep – Overviews
- Mayo Clinic Discusses Healthy Sleeping Habits for Older Adults – 2019
- Healthy Sleep
- Sleep complaints: Whenever possible, avoid the use of sleeping pills. – PubMed – NCBI
Sleep – Why is Sleep Needed?
- Brain Basics: Understanding Sleep : National Institute of Neurological Disorders and Stroke (NINDS)
- Sleep Drives Metabolite Clearance from the Adult Brain – 2013
- Dopaminergic Neurogenetics of Sleep Disorders in Reward Deficiency Syndrome (RDS) – 2014
Sleep – Deficiency
Sleep – Strategies for Sleep
Sleep – Circadian rhythm sleep disorders, Shift Work
Sleep – Insomnia
- Pain-related Insomnia Versus Primary Insomnia
- Sleep disorders and depression
- Problem-Solving Therapy Compared to Cognitive Therapy for the Treatment of Insomnia
- Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults – An American Academy of Sleep Medicine Clinical Practice Guideline – 2017
- Lemborexant, A Dual Orexin Receptor Antagonist (DORA) for the Treatment of Insomnia Disorder – 2017
Sleep – Nightmares
- Nightmare disorder – Mayo Clinic
- Sleep terrors (night terrors) – Mayo Clinic
- Imagery rehearsal therapy – An emerging treatment for posttraumatic nightmares in veterans
- Putative dopamine agonist (KB220Z) attenuates lucid nightmares in PTSD patients – Role of enhanced brain reward functional connectivity and homeostasis redeeming joy – 2015
Sleep – Pain
- Sleep Disturbance and Chronic Pain
- Relationship among Chronic Pain, Opiates, and Sleep -Thesis
- sleep deprivation in patients with chronic neck and back pain
- The Effects of Sleep Deprivation on Pain Inhibition and Spontaneous Pain in Women
- Pain-related Insomnia Versus Primary Insomnia
- Sleep, Chronic Pain, and Inflammation- Integrative Approaches
Sleep – Sleep Studies (Polysomnograms – PSG)
Sleep – Opioids Effect on Sleep
- Relationship among Chronic Pain, Opiates, and Sleep -Thesis
- Sleep-Disordered Breathing and Chronic Opioid Therapy
- Opioid-induced respiratory depression: ABCB1 transporter pharmacogenetics. – PubMed – NCBI
Sleep – Natural and Herbal Preparations for Sleep
Natural and Herbal Preparations – Overview
- Updates on Nutraceutical Sleep Therapeutics and Investigational Research – 2015
- Herbal Insomnia Medications that Target GABAergic Systems – A Review of the Psychopharmacological Evidence – 2014
- Herbal triple combination: An effective alternative to benzodiazepines
- Efficacy and safety of a polyherbal sedative-hypnotic formulation compared to Ambien
Natural and Herbal Preparations – Melatonin
- Melatonin for the Treatment of Primary Sleep Disorders – 2013
- The effectiveness of melatonin for promoting healthy sleep – a rapid evidence assessment of the literature – 2014
- Insomnia associated with valerian and melatonin usage in the 2002 National Health Interview Survey. – 2007
- Ramelteon: MedlinePlus Drug Information
- Melatonin hypothesizing-that-putative-dopaminergic-melatonin-benzodiazepine-reward-circuitry-receptors – 2013
- Melatonin therapy in fibromyalgia. – PubMed – NCBI
Natural and Herbal Preparations – Valerian
- Valerian | University of Maryland Medical Center
- Valerian – No Evidence for Clinically Relevant Interactions 2014
- Can valerian improve the sleep of insomniacs after benzodiazepine withdrawal? – PubMed – NCBI
- Critical evaluation of the effect of valerian extract on sleep structure and sleep quality. – PubMed – NCBI
- Insomnia associated with valerian and melatonin usage in the 2002 National Health Interview Survey. – 2007
Sleep – Prescription Medications for Sleep
Rx Sleep Medications – Benzodiazepines
- Chronic benzodiazepine usage and withdrawal in insomnia patients. – PubMed – NCBI
- Correlates of benzodiazepine use in individuals with insomnia. – PubMed – NCBI
- Efficacy of two interventions on the discontinuation of benzodiazepines in long-term users: 36-month follow-up of a cluster randomised trial in pri… – PubMed – NCBI
- Benzodiazepine use and risk of Alzheimer’s disease – case-control study
Rx Sleep Medications – Doxepin
- Treatment-resistant insomnia treated with pregabalinEfficacy and Safety of Doxepin 3 and 6 mg in a 35-day Sleep Laboratory Trial in Adults with Chronic Primary Insomnia
- Doxepin – up-to-date – a review of its pharmacological properties and therapeutic efficacy with particular reference to depression
- Doxepin for insomnia: a systematic review of randomized placebo-controlled trials. – PubMed – NCBI
Rx Sleep Medications – Gabapentin (Neurontin)
- Gabapentin increases slow-wave sleep in normal adults – 2002
- Gabapentin improves sleep in the presence of alcohol. – PubMed – NCBI
- A Randomized, Double-Blind, Single-Dose, Placebo-Controlled, Multicenter, Polysomnographic Study of Gabapentin in Transient Insomnia Induced by Sleep Phase Advance – 2014
- Treatment effects of gabapentin for primary insomnia. – PubMed – NCBI
- An Open Pilot Study of Gabapentin vs. Trazodone to Treat Insomnia in Alcoholic Outpatients – 2003
Rx Sleep Medications – Pregabalin (Lyrica)
Rx Sleep Medications – Suvorexant (Belsomra)
- Belsomra Prescribing Information
- Kinetic properties of “dual” orexin receptor antagonists at OX1R and OX2R orexin receptors
- Orexin Receptor Antagonists as Emerging Treatments for Psychiatric Disorders – 2020
- An Update on Dual Orexin Receptor Antagonists and Their Potential Role in Insomnia Therapeutics – 2018
- single-use suvorexant for treating insomnia during overnight polysomnography in patients with suspected obstructive sleep apnea – a single-center experience – 2019
- Sleep disorders in the elderly – Diagnosis and management – 2016
- Adverse reaction with suvorexant for insomnia – acute worsening of depression with emergence of suicidal thoughts – 2017
- Insomnia in the Elderly – A Review – 2018
- Advances in the Treatment of Chronic Insomnia A Narrative Review of New Nonpharmacologic and Pharmacologic Therapies – 2021
- Suvorexant in insomnia – efficacy, safety and place in therapy – 2015
- Lifetime Prevalence Rates of Sleep Paralysis – A Systematic Review
- Profile of suvorexant in the management of insomnia – 2015
- Migraine and sleep disorders -a systematic review – 2020
- Research progress on the mechanism of orexin in pain regulation in different brain regions – 2020
- Orexinergic descending inhibitory pathway mediates linalool odor‐induced analgesia in mice – 2021
- The Insomnia-Addiction Positive Feedback Loop – Role of the Orexin System – 2021
Rx Sleep Medications – Lemborexant (Dayvigo)
Rx Sleep Medications – Mirtazapine (Remeron)
- The Use of Mirtazapine in a Patient with Chronic PainThe effect of mirtazapine in patients with chronic pain and concomitant depression. – 2006
- Efficacy of mirtazapine for the treatment of fibromyalgia without concomitant depression – 2016
- Mirtazapine for fibromyalgia in adults – 2018
- A Review of Therapeutic Uses of Mirtazapine in Psychiatric and Medical Conditions – 2013
- Mirtazapine: A Newer Antidepressant – American Family Physician – 1999
Rx Sleep Medications – Remaelton (Rozerem)
Rx Sleep Medications – Trazadone
- Trazodone: a review of its pharmacological properties … [Drugs. 1981] – PubMed – NCBI
- Cognitive, psychomotor and polysomnographic effects of trazodone in primary insomniacs
- An Open Pilot Study of Gabapentin vs. Trazodone to Treat Insomnia in Alcoholic Outpatients – 2003
Sleep Medications – “Z-Drugs”
- Hypnotic hazards – adverse effects of zolpidem and other z-drugs – 2008
- Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: meta-analysis of data submitted to the Food and Drug Administration – 2012
Sleep Medications – Zolpidem (Ambien)
- Zolpidem-Induced Sleepwalking, Sleep Related Eating Disorder
- Two Cases of Zolpidem-Associated Homicide
- Ambien (Zolpidem) Associated Homicide
- Ambien (Zolpidem)-Induced Sleepwalking, Sleep Related Eating Disorder
Sleep – Sleep Disorders
(see Sleep Apnea)
Periodic Limb Movement Disorder
- Periodic Limb Movement Disorder
- Periodic Limb Movement Disorder Causes and Treatments on MedicineNet.com
Restless Leg Syndrome
- Restless Legs Syndrome:Periodic Limb Movement Disorder : National Sleep Disorders Research Plan, 2003
- Sleepwalking – Mayo Clinic
- Seroquel (Quetiapine)-induced Sleep-related Eating Disorder-like Behavior
Emphasis on Education
Accurate Clinic promotes patient education as the foundation of it’s medical care. In Dr. Ehlenberger’s integrative approach to patient care, including conventional and complementary and alternative medical (CAM) treatments, he may encourage or provide advice about the use of supplements. However, the specifics of choice of supplement, dosing and duration of treatment should be individualized through discussion with Dr. Ehlenberger. The following information and reference articles are presented to provide the reader with some of the latest research to facilitate evidence-based, informed decisions regarding the use of conventional as well as CAM treatments.
For medical-legal reasons, access to these links is limited to patients enrolled in an Accurate Clinic medical program.
Should you wish more information regarding any of the subjects listed – or not listed – here, please contact Dr. Ehlenberger. He has literally thousands of published articles to share on hundreds of topics associated with pain management, weight loss, nutrition, addiction recovery and emergency medicine. It would take years for you to read them, as it did him.
For more information, please contact Accurate Clinic.
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