From the Editor

Insomnia is a troubling and under-treated problem

OBG Manag. 2011 November;23(11):6-9

References

1. Krystal AD. Insomnia in women. Clin Cornerstone. 2003;5(3):42-50.

2. Bolge SC, Balkrishnan R, Kannan H, Seal B, Drake CL. Burden associated with chronic sleep maintenance insomnia characterized by nighttime awakenings among women with menopausal symptoms. Menopause. 2010;17(1):80-86.

3. Ensrud KE, Stone KL, Blackwell TL, et al. Frequency and severity of hot flashes and sleep disturbance in postmenopausal women with hot flashes. Menopause. 2009;16(2):286-292.

4. Schiff I, Regestein Q, Tulchinsky D, Ryan KJ. Effects of estrogens on sleep and psychological state of hypogonadal women. JAMA. 1979;242(22):2405-2407.

5. Lo HS, Yang CM, Lo HG, Lee CY, Ting H, Tzang BS. Treatment effects of gabapentin for primary insomnia. Clin Neuropharmacol. 2010;33(2):84-90.

6. Vollmer KO, Anhut H, Thomann O, Wagner F, Jahnchen D. Pharmacokinetic model and absolute bioavailability of the new anticonvulsant gabapentin. Adv Epileptol. 1989;17:209-211.

7. Guttuso T, Jr, Kurlan R, McDermott MP, Kieburtz K. Gabapentin’s effect on hot flashes in postmenopausal women: a randomized controlled trial. Obstet Gynecol. 2003;101(2):337-345.

8. Butt DA, Lock M, Lewis JE, Ross S, Moineddin R. Gabapentin for the treatment of menopausal hot flashes: a randomized controlled clinical trial. Menopause. 2008;15(2):310-318.

9. Aguirre W, Chedraul P, Mendoza J, Ruilova I. Gabapentin vs. low-dose transdermal estradiol for treating postmenopausal women with hot flushes. Gynecol Endocrinol. 2010;26(5):333-337.

10. Walsh JK, Krystal AD, Amato DA, et al. Nightly treatment of primary insomnia with eszopiclone for six months: effect on sleep, quality of life and work limitations. Sleep. 2007;30(8):959-968.

11. Soares CN, Joffe H, Rubens R, Caron J, Roth T, Cohen L. Eszopiclone in patients with insomnia during perimenopause and early postmenopause: a randomized controlled trial. Obstet Gynecol. 2006;108(6):1402-1410.

12. Freedman RR, Roehrs TA. Sleep disturbance in menopause. Menopause. 2007;14(5):826-829.

13. Brown JP, Gallicchio L, Flaws JA, Tracy JK. Relations among menopausal symptoms sleep disturbance and depressive symptoms in midlife. Maturitas. 2009;62(2):184-189.

14. Buysse DJ. Insomnia, depression and aging. Assessing sleep and mood interactions in older adults. Geriatrics. 2004;59(2):47-51.

15. Joffe H, Petrillo L, Viguera A, et al. Eszopiclone improves insomnia and depressive and anxious symptoms in perimenopausal and postmenopausal women with hot flashes: a randomized double-blinded, placebo-controlled crossover trial. Am J Obstet Gynecol. 2010;202(2):171. e1-11.

Because gabapentin reaches it peak serum level 2 to 3 hours after ingestion of an oral dose, it is best to recommend that your patient take the drug a few hours before going to bed.⁶ Gabapentin has a half-life of 5 to 7 hours, allowing a single dose taken near bedtime to last throughout the night.

For cooling hot flushes. In addition to being effective for the treatment of insomnia, gabapentin has been reported, as I noted, to alleviate hot flushes. Dosages required to achieve this effect are greater than what is typically prescribed for insomnia:

In two clinical trials^7,8 in which gabapentin was evaluated for treating hot flushes, researchers reported that a dose of 300 mg, three times daily, reduced hot flushes better than placebo did.
In a third clinical trial, gabapentin was prescribed as a single, 600-mg dose at bedtime. Investigators reported that gabapentin reduced hot flushes almost as well as low-dosage transdermal estradiol.⁹

Eszopiclone

This drug (sold as Lunesta) is a non-benzodiazepine gamma-aminobutyric acid (GABA) type A-receptor agonist that is FDA-approved for treating both sleep-onset and sleep-maintenance insomnia. A typical starting dosage is 2 mg at night, increased to 3 mg as needed. Note: If your patient is simultaneously taking a drug that inhibits the cytochrome P₄₅₀ 3A4 (CYP3A4) enzyme system (e.g., ritonavir and other protease inhibitors, ketoconazole, verapamil, dilitiazem, fluconazole), begin the dosage of eszopiclone at 1 mg nightly and do not increase it!

For comparison, consider the half-life of four of the most commonly prescribed sleep medicines:

eszopiclone, 5 to 7 hours
zolpidem (Ambien), 1.5 to 2.4 hours
extended-release zolpidem (Ambien CR), 1.5 to 2.4 hours (although the active drug is released from its matrix over a longer duration)
zaleplon (Sonata), 1 hour.

Because eszopiclone and extended-release zolpidem have the longest-lasting effects, they are most likely to maintain sleep throughout the night.

The most common side effects of eszopiclone are a persistent metallic taste, somnolence, headache, dizziness, and unpleasant dreams.

Eszopiclone (as well as extended-release zolpidem) is approved for long-term use. Non-benzodiazepine GABA_A agonists such as eszopiclone are not considered addictive.

Notable research. In a 6-month trial, eszopiclone, 3 mg nightly, was associated with improvements in sleep, quality of life, and work performance, compared with placebo.¹⁰ In a trial of more than 400 perimenopausal women who had symptoms of insomnia, eszopiclone, 3 mg nightly for 4 weeks, improved sleep onset, sleep maintenance, sleep duration, sleep quality, and daytime functioning, also compared to placebo.¹¹ Eszopiclone also improved depressive symptoms as recorded by the Montgomery-Åsberg Depression Rating Scale.¹¹

The latter finding is significant. Investigators have reported that insomnia and mood disturbances, such as depression and anxiety, exhibit an association in some mid-life women.^12,13 The two problems may influence each other: Insomnia increases the risk of daytime mood disturbance while emotional distress increases the chance that a woman will experience insomnia.¹⁴

In a study, perimenopausal and postmenopausal women who experienced the combination of hot flashes, insomnia, and mild depression with or without anxiety were randomized to eszopiclone, 3 mg nightly for 11 weeks, or to placebo pill.¹⁵ Compared with placebo, eszopiclone alleviated insomnia, nocturnal (but not daytime) hot flushes, and symptoms of depression and anxiety and improved quality of life.

Note: During nights that follow cessation, for any reason, of eszopiclone treatment, sleep latency and episodes of wakefulness may increase.

“… and in the morning wake … new-created”

Literature is filled to overflowing with reflections on the nature of sleep. D. H. Lawrence depicted it as a profound restorative in the poem “Shadows.” Here is an excerpt:

And if tonight my soul may find her peace in sleep, and sink in good oblivion, and in the morning wake like a new-opened flower then I have been dipped again in God, and new-created.

As I said: How appreciative your patients will be if you can help them feel like a “new-opened flower,” come morning!

INSTANT POLL

What are your clinical pearls for treating women who complain of symptoms of insomnia?