Drug Update: Primary Insomnia

OB/GYN News, August 1, 2000 by Timothy F. Kirn

Insomnia strikes 30%-40% of American adults annually and 10% have insomnia that is chronic or severe.

Behavioral therapy is the first step recommended by some experts. But for patients whose primary insomnia has lasted for more than 4 weeks, drug therapy is the most common treatment. Drug therapy works faster; behavioral therapy produces more durable results. Combining the two may work even better but not dramatically so.

The benzodiazepine receptor agonists (BRAs) are considered the top drug class. The other drugs listed here are alternatives that can be used for selected patients or after several BRAs have proved ineffective or are not tolerated.

Primary insomnia is diagnosed mainly by exclusion. Insomnia can be secondary to several physical and psychological conditions that must be ruled out before starting drug therapy Experts have five rules for treating patients with drugs for insomnia: Use the lowest effective dose, limit drug use to 2-4 days a week, use drug therapy for a maximum of 4 weeks, discontinue the drug gradually and watch for rebound insomnia.

BRAs are not recommended for pregnant or breast-feeding women. Patients with hepatic or renal insufficiency may have an increased risk of sedative side effects from drugs in this class. The dose of BRAs should be halved for elderly patients. Among the non-BRAs, amitriptyline should not be used in women who are pregnant or breast-feeding. Doxepin and the listed antihistamines also should be avoided in breastfeeding women.

HYPNOTIC AGENTS

The class of hypnotic agents is largely composed of benzodiazepine receptor agonists. BRAs differ in their elimination half-lives. Some experts say that the drugs with short half-lives--zaleplon, zolpidem, and triazolam--are best for patients who have trouble falling asleep, while the intermediate half-life BRAs--estazolam, oxazepam, and temazepam--are best for patients who have trouble staying asleep. The BRAs with longer half-lives-clonazepam, flurazepam, and quazepam--are considered by some experts to be best used when daytime anxiolytic activity is desirable; in addition, these drugs may cause less rebound insomnia. But other experts say that the efficacy of all BRAs is similar. Rule out sleep apnea before prescribing a BRA because it may depress respiration.

DRUG            DOSE          COST/DAY [*]
zaleplon        10-20 mg      $2.12 (10 mg)
  (Sonata)
triazolam       0.125-0.25 mg $0.64 (0.125 mg)
zolpidem        5-10 mg       $1.74 (5 mg)
  (Ambien)
estazolam       1-2 mg        $0.89 (1 mg)
oxazepam        15-30 mg      $0.79 (15 mg)
temazepam       15-30 mg      $0.46 (15 mg)
clonazepam      0.5-2 mg      $0.72 (0.5 mg)
quazepam        7.5-15 mg     $2.32 (7.5 mg)
  (Doral)
flurazepam      15-30 mg      $0.31 (15 mg)
clorazepate     3.75-15 mg    $1.19 (3.75 mg)
chloral hydrate 500 mg-2 g    $0.20 (500 mg)
DRUG            COMMENT [+]
zaleplon        The newest BRA and insomnia drug on the market
  (Sonata)      and the shortest-acting one. May give patients
                better control and may be particularly useful
                when nighttime awakenings are periodic. Along
                with zolpidem, appear to disrupt sleep patterns
                less than other drugs in class, but this has not
                been proved.
triazolam       BRA with a short half-life. Reported to be
                associated with amnesia.
zolpidem        BRA with a short half-life.
  (Ambien)
estazolam       BRA with an intermediate half-life.
oxazepam        BRA with an intermediate half-life.
temazepam       BRA with an intermediate half-life.
clonazepam      BRA with a long half-life. Use cautiously in the
                elderly because long half-life may trigger falls.
quazepam        BRA with a long half-life.
  (Doral)
flurazepam      BRA with a long half-life.
clorazepate     BRA labeled for anxiety disorders; not approved
                insomnia. Also used to treat restless legs
                syndrome.
chloral hydrate Not a BRA. Generally not recommended because of
                its narrow therapeutic range and the potential
                for abuse.
                              ANTIDEPRESSANTS
               Drugs in this class may be preferred for some
              patients because these agents do not act via a
              benzodiazepine receptor and therefore have less
               abuse potential. Antidepressants are also an
               option for patients who do not respond to the
                                hypnotics.
DRUG            DOSE      COST/DAY [*]
trazodone       50-150 mg $0.47 (50 mg)
amitriptyline   10 mg     $0.12
ANTIHISTAMINES
diphenhydramine 25-50 mg  $0.08 (25 mg)
MELATONIN
melatonin       2 mg      $0.14
DRUG            COMMENT [+]
trazodone       Trazodone is often preferred in this class
                because it is not a tricyclic antidepressant
                and therefore has no anticholinergic side
                effects or potential for cardiac toxicity. Can
                cause priapism or orthostatic hypotension.
amitriptyline   A tricyclic antidepressant; the lethal-dose-
                to-effective-dose ratio is worse for tricyclics
                than for benzodiazepines. This sedating
                antidepressant can also increase the risk of
                falls in elderly patients; therefore, start with
                a low dose. A similar tricyclic is doxepin
                (Sinequan).
ANTIHISTAMINES
diphenhydramine Antihistamines are safe but only minimally
                effective. Generally not recommended because
                they may reduce sleep quality and produce
                residual drowsiness. Causes anticholinergic side
                effects. Sold without a prescription. A similar
                over-the-counter antihistamine is doxylamine
                (Unisom Sleep Tabs). Experts say there is no
                important difference between diphenhydramine
                and doxylamine.
MELATONIN
melatonin       Usually used to treat jet lag or by people with
                swing-shift fatigue. Holds promise for treating
                insomnia, but the best dose for this indication
                is unknown. Results of clinical trials for the
                treatment of insomnia had conflicting results for
                efficacy. Mechanism of action is unknown. No
                serious adverse effects have been reported with
                short-term use. Sold over the counter.
(*.)Cost is based on the average wholesale price
for a 100-unit container of the generic formula-
tion, unless otherwise indicated, in the 2000 Red Book.
(+.)The comments reflect the viewpoints and
expertise of the following sources:
Dr. Karl Doghramji, director, Sleep Disorders
Center, Thomas Jefferson University Hospital, Philadelphia.
Thomas Roth, Ph.D., chief, Sleep Disorders and
Research Center, Henry Ford Hospital, Detroit.
Dr. John W. Winkelman, medical director, Sleep
Health Center, Brigham and Women's Hospital, Boston.