Sleeping Pills (Z Drugs and Others)

The Z drugs—zolpidem, zaleplon, eszopiclone—are indicated for the short-term treatment of insomnia. These medications are not benzodiazepines, but they do act on the same receptors and though they have a somewhat different risk profile (reduced seizure risk with withdrawal, for example) they share many of the adverse effects of benzodiazepines such as drowsiness, memory impairment, reduced coordination, depression, and sleep disturbances. Benzodiazepines are also commonly prescribed for insomnia, namely temazepam and lorazepam. As noted, there are many adverse effects associated with use, with little long-term efficacy.

There is an increase in all of these effects with elderly and pediatric patients. Using any of the Z drugs, benzodiazepines, alcohol, or opiates in any combination increases the risks of impairment and overdose. It is easy to become dependent on these medications, and it can be difficult to return to normal unaided sleep when discontinuing use. There are safer medical alternatives as well as non-pharmacological options that can be explored.

When considering prescribing these medications for insomnia:

  • Avoid combinations of Z drugs, benzodiazepines, opioids, or stimulants
  • Use the lowest dose possible:
    • Avoid prescribing these for children and adolescents
    • Use cautiously and at the lowest doses in the elderly
  • Prescribe for only short intervals (7–10 days)
  • Consider alternatives:
    • Trazodone
    • Amitriptyline
    • Melatonin

Tramadol and Tapentadol

These are opiate-like analgesics used to treat moderate to severe pain. In addition to binding to mu opioid receptors, tramadol weakly inhibits norepinephrine and serotonin reuptake and tapentadol inhibits norepinephrine reuptake. Many of the risks associated with opioids are true for tramadol and tapentadol. Tramadol is now a Schedule IV drug and has been shown to increase the risk of precipitating a seizure. Both of these medications can cause physical and psychological dependency.

We recommend that tramadol be treated as other true opioids when evaluating risks and benefits of
opioid treatment.


Carisoprodol is a muscle relaxant with properties and risks similar to benzodiazepines including similar habit-forming properties. This medication should be used cautiously, if at all, especially in combination with opioids. It has been removed from the market in a number of countries worldwide, and the EU recommends it not be used for the treatment of low back pain. In patients experiencing severe pain from spasticity, consider alternatives such as tizanidine or baclofen.


Meperidine is a narcotic analgesic with sedative properties and is not recommended for outpatient treatment of acute or chronic pain. Additionally, meperidine is included in the 2015 AGS Beers Criteria as a potentially inappropriate medication to be avoided in patients 65 years and older because of potentially higher risk for delirium (neurotoxic metabolite), and lack of analgesia when taken orally. Furthermore, the American Pain Society does not recommend its use as an analgesic.

Long-Acting Opioids

Long-acting opiates consist of ER/LA formulations such as oxycodone, morphine ER, fentanyl patches, and methadone, among others.

Long-acting opiates carry the same risks as short-acting formulations. However, the risks of addiction, abuse, misuse, overdose and death are much greater, especially in opiate-naïve patients. For this reason, the use of long-acting opiates should be reserved for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative modalities (both pharmacologic and non-pharmacologic) have been maximally tried and subsequently failed.


Methadone has unique metabolic properties making it particularly dangerous to prescribe outside of a closely managed methadone clinic. Overdoses are greatly increased with methadone compared to other opioids. Most guidelines recommend dosing at fewer than 30 mg/day or not at all.

You will notice in the table below, as the dose of methadone increases, the potency of the drug in relation to other opioids increases in an exponential fashion. This table can assist in making safe medication switches from methadone to other opioids and vice versa.

Morphine Equivalents Methadone Factor
100 mg 4:1
100 – 300 mg 8:1
300 – 500 mg 12:1
500 – 1000 mg 15:1
1000 – 2000 mg 20:1
> 2000 mg 30:1


Gabapentin and pregabalin have a role in the treatment of neuropathic pain, but also have potential for misuse and abuse. These agents are perceived on the street as a substitute for most common illicit drugs. Overdoses have been fatal because of CNS depression, especially when combined with opioids, alcohol, or other CNS depressants.

Gabapentin and pregabalin are structurally related to GABA. They reduce the release of excitatory neurotransmitters as well as increase the effects of the dopaminergic reward system. This is responsible for the sedative and dissociative/psychedelic effects that can occur at higher doses. Pregabalin is a Schedule V controlled substance in the U.S. It may have a higher addiction potential than gabapentin resulting from its rapid absorption, faster onset of action, and a greater affinity for binding sites. The bioavailability of pregabalin does not change with higher doses, but bioavailability of gabapentin decreases by nearly 50% when the dose is increased from 900 mg/day to 3,600 mg/day. As a result, gabapentin doses greater than 1,800 mg/day don’t appear to provide additional neuropathic pain relief.

Gabapentin may help attenuate withdrawal symptoms from alcohol or opioids, and abusers will often “bridge” with gabapentin until they can obtain a supply of illicit drugs. However, it is important to note that individuals may also experience withdrawal symptoms from gabapentin itself. Consider alternatives such as tricyclics (TCAs) for neuropathic pain as an alternative to high-dose gabapentin.