Using a “somniaxis” when diagnosing insomnia can help guide current pharmacologic treatment of this common but often hard-to-resolve disorder.

Chronic insomnia is a major public health problem affecting millions of individuals, along with their families and communities. Little is known about the mechanisms, causes, clinical course, comorbidities, and consequences of chronic insomnia.1

So begins the conclusion of the consensus of the June 2005 National Institutes of Health (NIH) Sleep Panel—and the NIH is not alone in being puzzled by insomnia. Review the available sleep literature and you will frequently encounter the “lack of understanding clause.” Yet approximately one third of Americans have at some point suffered from insomnia, and about a quarter of those are chronic insomniacs.2

In the past, physicians were hesitant to prescribe sleep medications, and the majority of prescriptions that were written were for benzodiazepines. Better treatments are now available.

Types of Insomnia
Although the International Classification of Sleep Disorders, Second Edition (ICSD-II), 2005 subclassifies insomnia into 11 entities (see Table 1 on page 40), there are really just three main types of insomnia: onset, wake-after-sleep-onset, and early awakening. These can be primary or secondary and acute or chronic. If secondary, a characterization of medical versus psychiatric is warranted. Any combination of the above is possible. Age is the most reliable proportionate correlate; anxiety and depression are the most common comorbidities.

Certain individuals are predisposed to sleeping less than others, some with consequences, others not. In those predisposed individuals who go on to experience insomnia symptoms, there are precipitating experiences that cause them to surpass a threshold from the preclinical to the clinical realm. However, as the precipitators subside, perpetuating circumstances—largely composed of maladaptive behaviors—tend to maintain insomnia, propelling it into the chronic phase.

Classifications of Insomnia
When diagnosing insomnia, the first step is to ask the question. I suggest it become the sixth vital sign, after pain and rated as a x/10 format, 10 being severe. If this has not been a regular part of a practice, the clinician initially may be surprised at how high a percentage of his or her patient population experiences insomnia.

There are currently three major classification systems for insomnia: the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV); ICSD-II (mentioned above); and the International Statistical Classification of Diseases and Related Health Problems (ICD-10). However, each can be too cumbersome, too noninclusive, or not treatment-oriented enough.

I propose using an axis system I call the “somniaxis” as a guide to the appropriate treatment selection or combination thereof (see Table 2 on page 40). Using this system, the first step is to determine if there is a reduction in the overall total sleep time, which can correlate with sleep quality (that is, sleep architecture). If the disorder does not reduce sleep quality or total sleep time, then it falls into the realm of dyssomnias or parasomnias, and it can then be treated in a step-by-step manner. If the insomnia is acute, then, by definition, it is self-limiting; and aside from improved sleep hygiene, it likely does not require treatment, unless it recurs frequently.

11 Types of Insomnia
Adjustment insomnia
Psychophysiologic insomnia
Paradoxical insomnia
Idiopathic insomnia
Insomnia due to mental disorder
Inadequate sleep hygiene
Behavioral insomnia of childhood
Insomnia due to drug or substance
Insomnia due to medical condition
Insomnia not due to substance or known physiological condition
Unspecified; physiological insomnia, unspecified

The next step is to determine if this is a primary or secondary issue. This may allow you to skip down to Axis IV. However, in no way does the presence of a primary insomnia or hyperarousal syndrome prevent comorbidities from existing, and these should be watched for and treated as appropriate. Primary-acute is rare. If on Axis III secondary comorbidities are identified as associated with the sleep disorders, they should be dealt with in conjunction with the insomnia as a more effective and probably swifter resolution of both can be obtained.

After this, the next step is to determine the type(s) of insomnia as this can help with the choice of treatment, be it behavioral or medicinal, shorter or longer acting, etc. Finally, determining whether the dysfunction is purely nocturnal (which is unusual) or if it affects daytime functioning can help guide the clinician to consider prescribing an adjunctive nonaddictive wake-promoting medication, such as modafinil. The longer-acting but not continuous-release nonbenzodiazepines that promote normal sleep architecture appear to be most effective, especially when used in conjunction with treatments of the comorbidities.

Managing Insomnia
Research indicates that nonpharmacological interventions often produce reliable and durable changes in the sleep patterns of patients with chronic insomnia.3 Combinations of behavioral and appropriate pharmacologic adjuncts may enhance these efforts.

In the past, insomniacs had several options, but few were good. Ethanol (EtOH), more commonly known as the “nightcap” of alcohol, is effective in reducing sleep latency. However, today we know that in most circumstances it also causes reduced REM and slow-wave sleep. In addition, there is increased early non-REM sleep and frequent wake-after-sleep-onset insomnia associated with alcohol. Plus, alcohol increases sleep apnea and restless legs syndrome (RLS), and it can be addictive.

Likewise, the first sleeping pills came with problems. Barbiturates, such as phenobarbital and meprobamate, like alcohol, can excessively impact nonspecific GABA (gamma-aminobutyric acid) activity in the central nervous system. Opiates, such as morphine and codeine, were initially hailed as magical wonder drugs that cured everything from the cough to pain to insomnia—that is, until the devastation from tolerance and addiction became evident.

Among the older sleep medications, benzodiazepines remain the most popular, constituting up to 73% of the prescriptions written for insomnia in the United States.4 Benzodiazepines can certainly reduce sleep latency and wake-after-sleep-onset insomnia, but they come with an increased risk of injury, including traffic accidents.

Because benzodiazepines are inexpensive, their use is often encouraged by insurance companies. Older patients and those with public insurance are more likely to receive these drugs than other people.4 The newer benzodiazepines, such as temazepam or triazolam, are somewhat improved, but they still have highly variable half-lives that can cause next-day carryover, sedation, and untoward effects. Remember that half-life correlates with metabolic blood levels—not with receptor activity.

In contrast, nonbenzodiazepines, such as zolpidem and zaleplon, have very short half-lives and shorten sleep latency. They therefore can be useful for insomniacs with the delayed-onset variety and for dyssomniacs with the delayed sleep phase syndrome-type. They show no significant improvement in sleep architecture (bias toward the Sleep Stages I and II) or in total sleep time. REM sleep may be reduced with higher doses of zolpidem,5 especially with continuous use. Eszopiclone, however, has a 6-hour half-life (9 hours in those older than 65), and thus can benefit total sleep time and reduce wake-after-sleep-onset insomnia with a more normalized sleep architecture, including slow-wave sleep and REM. It is the first nonbenzodiazepine that the US Food and Drug Administration has approved for long-term use. Not only was there sustained efficacy without tolerance or rebound,6 which is often seen with other medications, but there was actually a documented significant improvement in next-day functioning when researchers gave patients who took eszopiclone a Digit Symbol Substitution Test (DSST).6

There have been recent reports in The New York Times and broadcasts on CNN of what is termed the “zombie effect” with zolpidem. This is a constellation of symptoms that includes patients getting up in the middle of the night and performing complex tasks, such as cooking, eating, painting walls, waxing floors, and even driving, frequently being amnestic to such activities. A number of these cases have been linked to higher than normal doses of zolpidem or a combination of the drug with other substances, including alcohol. However, sleepwalking is a parasomnia with a possible genetic component that can affect up to 4% of adult males and about 3% of adult females.7-8As parasomnias may increase in individuals with sleep disorders in general, treated and untreated, prudence of judgment must be used in attributing causality.

Axis I Type: Insomnia, Dyssomnia, or Parasomnia
Axis II Primary or Secondary
IIa Acute versus Chronic
Axis III Associated Disorders
IIIa Psychiatric or Psychological versus Medical
Axis IV Onset, Wake-After-Sleep-Onset, or Early Awakening
Axis V Dysfunction: Day, Night, or Both

Still, it is concerning that reports such as these are linked more so to zolpidem than to other medications in the same drug class: the nonbenzodiazepines. One class effect that is important to acknowledge for all the nonbenzodiazepines is that higher doses can cause them to become less selective in which brain neurotransmitters they target and make their effects more like those of traditional benzodiazepines, which affect a range of chloride channel-dependent GABA-BZ receptors.9

Other Treatment Options
Antidepressants, such as tricyclics or trazodone, notoriously reduce REM sleep and disrupt slow-wave sleep. However, they do reduce sleep latency. Periodic limb-movement disorder (PLMD) and RLS may worsen with certain tricyclics. Trazodone can furthermore cause oversedation; alpha-adrenergic blockade, including orthostatic hypotension (low blood pressure upon standing); priapism (abnormal painful erection in men)10; and cardiac arrhythmias. Withdrawal of trazodone often results in REM rebound. Tricyclics can cause cardiac arrhythmias and significant anticholinergic (parasympathetic nerve-impulse-transmission inhibition) effects. Selective serotonin reuptake inhibitors (SSRIs) can produce alerting effects, as compared with the sedating effects of tricyclic antidepressants, and can, therefore, cause insomnia. Paroxetine decreases REM sleep, increases REM latency, and increases slow-wave sleep.11

Antiepileptics, such as tiagabine, have been shown to increase slow-wave sleep and REM sleep,12 and, more recently, have showed promise in improving quality total sleep time. However, the realization of the risk of induced seizures makes this choice less appealing.

Chronobiotics also impact sleep. Melatonin or ramelteon—the latter is 17 times as potent as melatonin, affecting the MT1 and MT2, but not the MT3, subtypes of receptors—aims to inhibit the alerting signals from the suprachiasmatic nucleus in the hypothalamus and may be useful in a few select cases of delayed sleep-phase syndrome or purely sleep-onset insomnia. However, in one study, no significant perceived improvement in overall total sleep time or number of awakenings could be substantiated in patients taking ramelteon.13

Antihistamines, such as diphenhydramine and hydroxyzine hydrochloride, also can induce early sleep onset in those select patients who have the onset variety of insomnia. They are generally short lasting due to their brief half-lives and do not rectify sleep architecture. Studies have shown that just like the antidepressant trazodone, antihistamines have only placebo-equivalent efficacy as a sleeping aid after the fourth to 14th day of use. Diphenhydramine is the most popularly used antihistamine sedative, but it is not H1-selective enough to counter the tuberomammillary nucleus’ stimulatory effect. A recent study showed modestly improved efficacy if combined with valerian root and hops dietary supplements.13

Sodium oxybate is a compound originally released for the treatment of cataplexy associated with narcolepsy. It is a GABA agonist and also binds directly to the more selective GHB-receptors. It has been used off-label for its amnestic sleep-promoting effect. The emergence of depression when patients are treated with sodium oxybate requires careful and immediate evaluation. Patients with a previous history of a depressive illness and/or suicide attempt should be monitored especially carefully for the emergence of depressive symptoms while taking sodium oxybate.

In treating insomnia, wake-promoting medications may sometimes also be used separately or conjunctively. Among these, modafinil shows improvement in the fatigue of excessive daytime sleepiness—often associated with narcolepsy, multiple sclerosis, Parkinson’s disease, or shift work14—and seems to improve slow-wave sleep and decrease sleep latency.15 It can be used safely and adjunctively for excessive daytime sleepiness and fatigue, especially in patients with insomnia, and can even counter daytime medication-induced sedation.

Nonpharmacologic Treatment
Cognitive behavioral therapy and interpersonal therapy have both been shown to be highly effective in insomnia reduction.16 In fact, cognitive behavioral therapy has shown the greatest efficacy of any single regimen for the longest duration. Part of the problem with nonpharmacologic treatments, however, is their lack of availability in many regions, as well as their expense. Often, the primary care setting is ill-equipped to provide such insomnia treatments, and the sleep specialty centers are more involved in dealing with narcolepsy and parasomnias than with insomnia. Thus, insomniacs are frequently referred to psychiatrists or psychologists.17

Our current American society is more vulnerable to sleep problems and depression due, in part, to the imposed stressors of the rat race, 24-hour businesses, and cities that never sleep. The advent of the use of electricity and artificial light sources has impacted our sleep patterns by altering our surrounding zeitgebers (external time givers). It is the physician’s responsibility to inquire about inadequate sleep and, once insomnia is identified, to treat it with the most rational approach. For acute sleeping problems, adjustments in sleep-hygiene patterns may suffice. However, for the most chronic insomnia, including both the primary and secondary types as identified in the “somniaxis,” some combination of a longer-acting nonbenzodiazepine drug with behavioral therapy seems to be the most effective treatment method available at this time. When necessary, concomitant use of an antidepressant, pain reliever, or wake-promoting compound may also be indicated.
Michael M. Candaras, MD, is director of the Neurology Associated of Western New York (NAWNY) and a neurologist at the Lake Shore Medical Specialty Clinic in Irving, NY.

Michael Candara’s article was adapted from a longer work. To read the full article, please click here.

1. National Institutes of Health. State-of-the-science conference statement: manifestations and management of chronic insomnia in adults. Available at: Accessed March 13, 2006.

2. Stoller MK. Economic effects of insomnia. Clin Ther. 1994;16: 873-897.

3. Morin CM, Culbert JP, Schwartz SM. Nonpharmacological interventions for insomnia: a meta-analysis of treatment efficacy. Am J Psychiatry. 1994;151:1172-1180.

4. Balkrishnan R, Rasu R, Rajagopalan R. Physician and patient determinants of pharmacologic treatment of sleep difficulties in outpatient settings in the United States. Sleep. 2005;28:715-719.

5. Samadder G. Pharmacology and sleep disorders. Sleep Review. 2001;2(3):16-20.

6. Rubens RP. Long-term Safety of Eszopiclone. Marlborough, Mass: Sepracor; 2005.

7. Hublin C. Prevalence and genetics of sleepwalking: a population-based twin study. Neurology. 1997;48:177-181.

8. Statement responding to recent media reports regarding appropriate use of Ambien (zolpidem tartrate) CIV. Bridgewater, NJ: Sanofi-Aventis; March 20, 2006.

9. Wieland HA, Luddens H, Seeburg PH. Molecular determinants in GABAA/BZ receptor subtypes. Adv Biochem Psychopharmacol. 1992;47:29-40.

10. Lippmann S, Mazour I, Shahab H. Insomnia: therapeutic approach. South Med J. 2001;94:866-873.

11. Oswald I, Adam K. Effects of paroxetine on human sleep. Br J Clin Pharmacol. 1986;22:97-99.

12. Placidi F, Diomedi M, Scalise A, Silvestri G, Marciani MG, Gigli GL. Effect of long-term treatment with gabapentin on nocturnal sleep in epilepsy. Epilepsia. 1997;38:S179-S180.

13. Silverman B. Takeda Rozerem:clinical significance debated in FDA review. In: McNeil DE, medical reviewer. The Pink Sheet Daily. January 23, 2006;18(14).

14. Happe S, Pirker W, Sauter C, et al. Successful treatment of excessive daytime sleepiness in Parkinson’s disease with modafinil. J Neurol. 2001;248:632-634.

15. Fry JM. Treatment modalities for narcolepsy. Neurology. 1998;50:S43-S48.

16. Thase ME. Which depressed patients will respond to interpersonal psychotherapy? The role of abnormal EEG sleep profiles. Am J Psychiatry. 1997;154:502-509.

17. Richardson GS. Managing insomnia in the primary care setting: raising the issues. Sleep. 2000;23:S9-S12.