INSOMNIA/FIBROMYALGIA
From the 13th Annual Psychopharmacology Update, presented by the University of Nevada School of Medicine and the
Nevada Psychiatric Association
| PHARMACOTHERAPY FOR INSOMNIA —W. Vaughn McCall, MD, MS, Professor and Chair, Department of Psychiatry
and Behavioral Medicine, and Medical Director, Sleep Center, Wake Forest University School of Medicine, Winston-Salem,
NC
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| Sleep conditions not requiring treatment with hypnotics: pain (opioid not required to reduce pain to level that
allows sleep; try acetaminophen or nonsteroidal anti-inflammatory drugs first); poorly compensated chronic obstructive
pulmonary disease (treat with oxygen); menopausal and perimenopausal sleep disturbances (refer to specialist for
hormone replacement therapy, which has been shown in studies to improve sleep in menopausal and perimenopausal
women)
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| Pharmacologic treatment of insomnia secondary to depression: most research on insomnia does not address
its treatment in mental disorders; subjectively, psychiatric patients report improvement in sleep with tricyclic
antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), venlafaxine, nefazodone, and trazodone;
however, polysomnography (PSG) in sleep laboratory often shows no objective improvement with these medications
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| “Pseudo” hypnotics: until recently, treatment of insomnia often involved drugs not approved by Food and Drug Administration
(FDA) for such use; trazodone—most commonly used “pseudo”hypnotic, but no data to support this; in
study, 100 mg of trazodone comparable to 10 mg of zolpidem in effect on sleep and sleep duration for 1 wk, but by wk 2,
trazodone similar to placebo; amitriptyline—no data; doxepin—in small study, 25 to 50 mg of doxepin superior to placebo
over 4 wk; PSG showed improvement in total sleep time, sleep efficiency and quality, and ability to work during
daytime; mirtazapine—no placebo-controlled randomized clinical trials in chronic insomnia; associated with prolonged
motor reaction times next day and with impaired actual (not simulated) driving performance; quetiapine—no randomized
controlled trials in insomnia; in study that involved good sleepers, larger doses associated with periodic limb movements
(PLM); olanzapine—no randomized controlled trials in insomnia; clonazepam—no randomized controlled trials
in primary insomnia; in 2 studies, clonazepam added to antidepressant; in first study, clonazepam provided advantage for
up to 3 wk, but in second study, it merged with placebo after 3 wk; hydroxyzine—no placebo-controlled trials in insomnia;
alprazolam—no randomized placebo-controlled trials in insomnia; lorazepam—2 trials in medical/surgical conditions;
one trial showed taking lorazepam night before surgery helped patients sleep better than with placebo; other trial
showed that small does of lorazepam better than placebo for one night for patients in noisy hospital ward; in other trials,
lorazepam use in chronic insomnia effective for up to 18 nights, but next day patients had reduced scores on psychomotor
tests
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| Approved hypnotics: include benzodiazepines, nonbenzodiazepine benzodiazepine receptor agonists, and melatonin
receptor agonists
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| Benzodiazepines: electroencephalography (EEG) in sleep laboratory shows benzodiazepines increase sleep by 30
to 40 min/night, but, subjectively, patients think sleep increased much longer; dose and half-life of benzodiazepines
explain most effects; drugs with longer half-lives prolong period of sleep, but may have residual side effects next
day; increasing dose “is usually a losing strategy,” especially for drugs with shorter half-lives
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| Clinical pearl: educate patients to have realistic expectations of sleep; advise them of age-appropriate norms for
sleep (“even if you’re not an insomniac, most 50- or 60-yr-olds don’t sleep like they did when they were 20; we’re
not [going] to turn you into a 20-yr-old again”)
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| Nonbenzodiazepine benzodiazepine receptor agonists: most trials include only patients with primary insomnia,
few or none with psychiatric disorders; zolpidem (Ambien)—continuous-release (CR) formulation reduces time
to fall asleep or to return to sleep when patients awakened in fourth or fifth hour of night; has open-ended duration
of use; eszopiclone (Lunesta)—patients shown to fall asleep faster than those on placebo for 6 mo of trial, so also
has open-ended duration of use; also shown that patients had fewer minutes awake in middle of night; in trials in
geriatric patients, those who received eszopiclone showed decrease in daytime napping; in depression study, patients
on fluoxetine randomized to adjuvant eszopiclone or placebo; those who received eszopiclone had reduction
in daytime symptoms of depression (benefit continued for 14 days after eszopiclone discontinued)
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| Melatonin receptor agonist: ramelteon (Rozerem) reduces sleep latency; no evidence of increase in total time of
sleep; shown that efficacy continues for ≥6 mo, so also has open-ended duration of use
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| Alternative strategies for using hypnotics: bolus therapy—depression study showed that if hypnotic used every
night for 8 wk and then withdrawn, efficacy continued; intermittent use—in study, patients with primary insomnia
instructed to use zolpidem 3 to 5 nights/wk for 12 wk; at end of study, “the patients were not paying a penalty
for going on and off the pill”; efficacy seen in time to fall asleep, waking after sleep onset, and total sleep time; middle-of-night
dosing —patient who falls asleep and then awakens in middle of night, can take zaleplon (Sonata) if ≥4
hr left in night; in sleep laboratory, patients allowed to sleep for 4 hr, then awakened, stimulated until fully awake,
randomized to zaleplon, zolpidem, or placebo, and allowed to sleep another 3 hr; next morning, little separation between
those who got zaleplon or placebo (both groups equally awake); however, those who got zolpidem very
sleepy; based on this data, zaleplon only medication approved for middle-of-night dosing
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| Limitations of hypnotics: Michigan study showed that people in nursing homes with untreated insomnia had
higher rates of falling than those taking hypnotics; adverse events include motor vehicle accidents, memory impairment,
tolerance and/or dependence, abuse, and respiratory depression; safety data show ramelteon has no abuse potential
and no residual effects next day
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| Conclusions: evidence base weak for using nonapproved medications as “pseudo” hypnotics; nonbenzodiazepine
hypnotics can be distinguished based on purpose of use; for intermittent use, data support zolpidem; for after-bedtime
use, zaleplon; long-term use for sleep onset, zolpidem CR, eszopiclone, and ramelteon; long-term use for
sleep maintenance, zolpidem CR and eszopiclone; use in secondary insomnia (such as that due to depression),
zolpidem CR and eszopiclone; preferred use in those at high risk for addiction, ramelteon
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| EMERGING TREATMENTS FOR FIBROMYALGIA —Barry Eliot Cole, MD, MPA, Executive Director, American
Society of Pain Educators, and Vice-President for Medical and Scientific Services, Aventine Health Sciences, Montclair,
NJ
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| What is fibromyalgia? not disorder of muscles, bones, joints, tendons, and ligaments; “it has something to do with
the way muscles respond to pressure”; associated with neurochemical and neuroendocrinologic changes, including
elevated levels of substance P in cerebrospinal fluid, impaired secretion of growth hormone, hyperactivity of sympathetic
nervous system, overactive neurons that produce corticotropin-releasing hormone, and multiple neuroendocrine
disturbances; pathophysiology appears to have correlation with low-level spinal cord impingement (which
cannot be seen on magnetic resonance image [MRI] when patient in anatomically neutral position); role of dopamine
in central nervous system unclear
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| Patient’s perspective: “it virtually hurts everywhere”; much more common in women than in men; change of climate
does not help; many tender points; patients have sleep disturbances, consistently reporting nonrestorative
sleep (sleep studies show changes in sleep architecture, often loss of delta-wave sleep); constant stiffness, aching,
and awakening with feeling of soreness
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| Management of fibromyalgia: not exclusively pharmacologic; nonpharmacologic modalities include aerobic exercise,
cognitive behavioral therapy, patient education, strength training, acupuncture, biofeedback, balneotherapy,
and hypnotherapy; “the best shot we’ve got for fibromyalgia is to be as clever and creative as our minds will let us;
to think about everything nonpharmacologic, everything pharmacologic”; some suggest low glycemic index diet,
but no evidence to support this approach
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| Tricyclic antidepressants (TCAs): have been used since 1980s to promote sleep, based on theory that patients
who get good night’s sleep do better next day; no TCAs approved by FDA, but some (eg, amitriptyline, nortriptyline,
cyclobenzaprine [“spin-off” of TCAs]) used off-label
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| Other medication classes: serotonin-norepinephrine reuptake inhibitors (SNRIs)—none approved by FDA, but duloxetine
“actively and aggressively pursuing” FDA approval; venlafaxine might work, but no data; milnacipran not
approved in United States as SNRI antidepressant (rumored that manufacturer seeking fibromyalgia indication);
anticonvulsants—“rich literature” but only pregabalin approved; analgesics—tramadol “a mediocre opioid and a
really good SNRI”; over short term, analgesic may work as weak opioid, but over long term, SNRI effects more
significant; no manufacturers currently pursuing label specifically for fibromyalgia; controlled-release opioids currently
used for moderate-to-severe pain
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| Newer treatments for fibromyalgia: in most clinical trials, 0 to 10 pain scale used (0 being no pain at all and 10
being “worst pain you could ever imagine”); all pain scales linear, ie, progression from 4 to 8 means doubling of
pain intensity, and from 8 to 4 means halving of pain intensity; other measures include Visual Analog Pain Scale
(VAPS), Medical Outcomes Study (MOS), Multidimensional Assessment of Fatigue (MAF), Hospital Anxiety and
Depression Scale (HADS), Short Form 36 Health Survey (SF-36), Patient Global Impression of Change (PGIC),
and Fibromyalgia Impact Questionnaire (FIQ); FDA currently accepts 30% reduction in pain or 30% of patients experiencing
improvement as evidence of efficacy, but urging drug manufacturers to increase criterion to 50%
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 | Pregabalin: only medication currently approved by FDA for treatment of fibromyalgia; 14-wk trial of fixed-dose
pregabalin showed significant improvement in pain; studies showed 450 mg/day most effective dose; dose >600
mg/day not well tolerated; significant number of patients achieved >50% reduction in pain, but many patients
perceived benefits in areas other than pain, including decrease in tenderness of tender points and increased optimism;
in 6-mo trial, no participants experienced complete loss of therapeutic response (although some loss of effect
over time reported)
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| Duloxetine: manufacturer currently seeking FDA approval for fibromyalgia; 2 studies showed mixed results; in first
study (which included men as well as women), “the men screwed up the data” (not enough men to power study,
and their consistency not as good as that of women); second trial women only; in both studies, women did better
in total FIQ scores vs only pain scores; looking only at women, clear distinction between duloxetine and placebo
seen in 1 to 2 wk, with little difference between 60-mg/day and 120-mg/day doses
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| Milnacipran: no FDA-approved indications; literature sparse; phase 2 and ongoing phase 3 trials suggest that milnacipran
“is probably going to be a pretty good, effective treatment”; tested doses range from 50 mg/day to 200 mg/day
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| Sodium oxybate: referred to as GHB (γ-hydroxybutyrate) when used as recreational drug (not FDA-approved); as
sodium oxybate, used to improve stage IV sleep; despite embargo on release of information (new manufacturer),
speaker has learned that in trials, 20% of patients had 50% improvement at dose of 4 g/day (seemed statistically
better than 6 g/day )
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| Pramipexole: dopamine agonist that appears specific for D3 receptors; more robust effect on restless leg syndrome
(RLS) than ropinirole; since 1999, reports that people with fibromyalgia and RLS who used dopamine agonists
saw improvement in both conditions; statistically significant clinical improvement seen in study of pramipexole
(1.55 mg/day) in 166 patients for average of 4 mo (range 2-12 mo); studies ongoing
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| Conclusions: 30% decrease on Brief Pain Inventory seen with gabapentin (not approved by FDA); 30% improvement
on VAPS shown with sodium oxybate; pharmacologic strategies that appear effective include using anticonvulsants
that have calcium channel mechanism, SNRIs, medications that promote sleep, and perhaps dopamine
agonists; effective nonpharmacologic strategies include daily aerobic exercise and cognitive behavioral therapy; fibromyalgia
complex condition and requires multidisciplinary approach
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Suggested Reading
Cohrs S et al: Sleep-promoting properties of quetiapine in healthy subjects. Psychopharmacology (Berl) 174:421,
2004; Crofford LJ, Clauw DJ: Fibromyalgia: where are we a decade after the American College of Rheumatology
classification criteria were developed? Arthritis Rheum 46:1136, 2002; Dempsey J: Milnacipran for fibromyalgia.
Issues Emerg Health Technol Feb:1, 2008; Goldenberg DL et al: Management of fibromyalgia syndrome.
JAMA 292:2388, 2004; Gracely RH et al: Functional magnetic resonance imaging evidence of augmented pain
processing in fibromyalgia. Arthritis Rheum 46:1333, 2002; Hajak G et al: Doxepin in the treatment of primary insomnia:
a placebo-controlled, double-blind, polysomnographic study. J Clin Psychiatry 62:453, 2001; Henriksson
KG: Fibromyalgia—from syndrome to disease. Overview of pathogenetic mechanisms. J Rehabil Med
41(Suppl):89, 2003; Hindmarch I et al: A double-blind study in healthy volunteers to assess the effects on sleep of
pregabalin compared with alprazolam and placebo. Sleep 28:187, 2005; Krystal A et al: Evaluation of eszopiclone
discontinuation after cotherapy with fluoxetine for insomnia with coexisting depression. J Clin Sleep Med 3:48, 2007;
Lemon M: A new option for the treatment of fibromyalgia. S D Med 61:17, 2008; Londborg PD et al: Short-term
cotherapy with clonazepam and fluoxetine: anxiety, sleep disturbance and core symptoms of depression. J Affect Disord
61:73, 2000; Mendelson WB et al: The treatment of chronic insomnia: drug indications, chronic use and abuse
liability. Summary of a 2001 New Clinical Drug Evaluation Unit meeting symposium. Sleep Med Rev 8:7, 2004; Ridout
F et al: A placebo controlled investigation into the effects of paroxetine and mirtazapine on measures related to
car driving performance. Hum Psychopharmacol 18:261, 2003; Roizenblatt S et al: Alpha sleep characteristics in
fibromyalgia. Arthritis Rheum 44:222, 2001; Rooks DS: Talking to patients with fibromyalgia about physical activity
and exercise. Curr Opin Rheumatol 20:208, 2008; Saletu-Zyhlarz GM et al: Insomnia related to dysthymia: polysomnographic
and psychometric comparison with normal controls and acute therapeutic trials with trazodone. Neuropsychobiology
44:139, 2001; Sharpley AL et al: Olanzapine increases slow-wave sleep and sleep continuity in
SSRI-resistant depressed patients. J Clin Psychiatry 66:450, 2005; Sigal LH et al: 18 tender points and the “18-
wheeler” sign: clues to the diagnosis of fibromyalgia. JAMA 279:434, 1998; Smith WT et al: Summit Research
Network. Is extended clonazepam cotherapy of fluoxetine effective for outpatients with major depression? J Affect
Disord 70:251, 2002; Staud R, Rodriguez ME: Mechanisms of disease: pain in fibromyalgia syndrome. Nat Clin
Pract Rheumatol 2:90, 2006.
Educational Objectives
| The goal of this program is to improve the management of insomnia and fibromyalgia. After hearing and assimilating
this program, the clinician will be better able to:
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| 1. Cite the evidence supporting or not supporting the off-label use of prescribed medications for the treatment of
insomnia.
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| 2. List the hypnotic agents approved by the Food and Drug Administration for the treatment of insomnia, and describe
the differences among them.
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| 3. Describe the essential features of fibromyalgia.
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| 4. Discuss treatment considerations in fibromyalgia.
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| 5. Identify medications with demonstrated efficacy in the treatment of fibromyalgia.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts
of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health
care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. McCall
is on the Speakers’ Bureaus of Sepracor and Sanofi, and receives research support from and serves as scientific advisor
to Sepracor, Sanofi, and Takeda. Dr. Cole is a consultant to Eli Lilly, Reckett-Benkisser, ProEthic Pharma, and
Nektar; is on the Speakers’ Bureau of Eli Lilly; and is a full-time employee (Vice-President for Medical and Scientific
Services) at Aventine Health Sciences. Both speakers discussed off-label use of medications. The planning committee
reported nothing to disclose.
Acknowledgments
Drs. McCall and Cole were recorded at the 13th Annual Psychopharmacology Update, held February 21-23, 2008, in
Las Vegas, NV, and sponsored by the University of Nevada School of Medicine and the Nevada Psychiatric Association.
The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of
this program.
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