The Dangers of Combining Sleeping Pills With Other Medication

Insomnia affects about a third of all Americans and an even higher percentage of elderly people.

Many people are prescribed sleep­ing pills to treat insomnia. But sleep­ing pills should be considered a last resort only used when other measures have failed to relieve insomnia.

Among the many ways to com­bat insomnia are limiting caffeine after noon, reducing alcohol intake, avoiding naps, practicing relaxation techniques, sticking to a regular sleep schedule, using sound machines if you sleep in a noisy place, and not using the bed for activities other than sleeping or sex. (See the article on alternatives to sleeping pills in Worst Pills, Best Pills News, July 2010.)

Those who are taking sleeping pills should be aware of other medica­tions that can increase the effect of sleeping pills. Excessive sedation at night due to drug interactions could increase the risk of falls, should the person get up in the night for some reason. Moreover, excessive sedation causing respiratory depression could be dangerous for people with certain disorders, such as lung disease.

How do drugs interact with sleeping pills?

Most people are aware that tak­ing sleeping pills with other sedative drugs can cause additional sedative effects. Many drugs have sedative side effects, and one should therefore be cautious about combining them with sleeping pills.

In addition, many drugs that are not necessarily sedating can increase the effect of sleeping pills by inhibit­ing the metabolism of sleeping pills. This is the type of interaction that we will discuss below.

Benzodiazepine and non-benzodiazepine sleeping pills

Benzodiazepine sleeping pills have been used for many years to treat insomnia, but they have been largely replaced by nonbenzodiazepines. FDA-approved benzodiazepines for insomnia include estazolam (PROSOM), flurazepam (DAL­MANE), quazepam (DORAL), temazepam (RESTORIL) and triazo­lam (HALCION). All of these ben­zodiazepines (except temazepam) are metabolized by the enzyme CYP3A4, and their effect can be substantially increased when they are used with inhibitors of CYP3A4 (see Table 2).

Nonbenzodiazepine sleeping pills include eszopiclone (LUNESTA), zaleplon (SONATA) and zolpidem (AMBIEN). These agents also are metabolized by CYP3A4, and the drugs in Table 2 would be expected to interact, resulting in increased sedative effects. (The interactions of zaleplon are not as well studied as the other two, but the effects are probably similar.)

Melatonin-type drugs

Ramelteon (ROZEREM) induces sleep by stimulating melatonin re­ceptors, and it has different interac­tions from the sleeping pills listed below. Ramelteon is metabolized primarily by the enzyme CYP1A2, and inhibitors of this enzyme can dramatically increase ramelteon blood levels. For example, the potent CYP1A2 inhibitor, fluvoxamine (LUVOX), produced a 190-fold in­crease in ramelteon blood levels. For a list of other CYP1A2 inhibitors, see Table 3.

What You Can Do

The best way to avoid drug inter­actions with sleeping pills is to avoid taking sleeping pills. But if you are taking them, here are some recom­mendations:

• If you are taking one of the sleeping pills that is metabolized by CYP3A4 (Table 1), be aware that concurrent use of drugs that inhibit CYP3A4 (Table 2) may increase the sedative effect of the sleeping pill. Every case is dif­ferent, so discuss this with your prescriber to come up with a suitable solution. Keep in mind that newly marketed drugs also may inhibit CYP3A4, so the list may grow with time. Avoid a drug interaction by not mixing any of the drugs in tables 1 and 2 with each other.
• If you are taking ramelteon, it is best to completely avoid taking CYP1A2 inhibitors (Table 3). The magnitude of the interaction is potentially so large that it would best to avoid taking these combi­nations.

Table 1. Benzodiazepine and Nonbenzodiazepine Sleeping Pills

* Do Not Use on WorstPills.org
** Limited Use on WorstPills.org

Table 2. Drugs That Increase the Effects of Benzodiazepine and Non-benzodiazepine Sleeping Pills

* Do Not Use on WorstPills.org
** Limited Use on WorstPills.org
*** Last Choice on WorstPills.org

Table 3. Drugs That Increase the Effect of Melatonin-Type Drugs (ramelteon, Rozermen)

* Do Not Use on WorstPills.org
** Limited Use on WorstPills.org