Category:Schedule IV controlled substances

A Schedule IV controlled substance is a medicine that the United States Drug Enforcement Administration has placed in the fourth schedule of its Controlled Substances Act of 1970. Schedule IV substances have an accepted medical use, a lower abuse potential than the Schedule III medicines, and an abuse pattern that may lead to limited physical or psychological dependence relative to the higher schedules.

The prescribing convenience of a Schedule IV medicine approaches that of a non-controlled prescription. A Schedule IV prescription may be telephoned in to the pharmacy, may be refilled up to five times within six months of the original prescription date, and may be transmitted by fax without restriction. Most states require PDMP reporting of Schedule IV dispensing, and the controlled-substance registration requirement on the prescribing clinician remains the same as for the higher schedules, but the practical day-to-day differences from a non-controlled prescription are limited to those reporting and the absence of the refill-after-six-months allowance.

The medicines that populate Schedule IV are dominated by the benzodiazepines and the related "Z-drug" non-benzodiazepine hypnotics. The benzodiazepines (chlordiazepoxide, diazepam, lorazepam, alprazolam, clonazepam, midazolam, temazepam, and the longer list of clinically used agents) were introduced in 1960 with chlordiazepoxide and followed shortly by diazepam, both developed at Hoffmann-La Roche by Leo Sternbach on a screening programme that began with a discarded series of "useless" tricyclic compounds from his earlier work. Diazepam (Valium) became the most prescribed medicine in the world between 1969 and 1982. The class produced rapid and reliable anxiolysis and sedation, but with a tolerance and dependence pattern that emerged over the following decade and led, in the 1980s, to the recognition of benzodiazepine withdrawal syndrome and to a substantial tightening of prescribing practice. The Z-drug hypnotics (zolpidem (Ambien, Sanofi, 1992), zaleplon, eszopiclone) were developed in the late 1980s and 1990s as selective alpha-1-subunit GABA-A agonists with hypnotic but reduced anxiolytic and muscle-relaxant action; they share Schedule IV with the benzodiazepines.

The Schedule IV tier also includes the wakefulness-promoting medicine modafinil (Provigil, Cephalon, 1998) and the related armodafinil; the anti-obesity medicines phentermine (a sympathomimetic stimulant with substantially lower abuse potential than the Schedule II amphetamines), diethylpropion, and the older phendimetrazine (Schedule III rather than IV); tramadol, the atypical opioid that was unscheduled at U.S. introduction in 1995 and was moved to Schedule IV by the DEA in 2014 in response to accumulating evidence of dependence and overdose; and the GABA-receptor partial agonist suvorexant (an orexin-receptor antagonist for insomnia) along with the related lemborexant and daridorexant. Selected anticonvulsants used principally for benzodiazepine indications (carisoprodol, the muscle relaxant prodrug of meprobamate, was moved to Schedule IV in 2012) round out the category.

The benzodiazepine class deserves particular clinical attention given its size and its overdose profile. Concurrent prescription of a benzodiazepine and an opioid is associated with a substantial excess of fatal respiratory depression compared to either alone, a finding that is reflected in the FDA boxed warning that has been on these medicines since 2016 and in the contemporary guidelines that recommend against routine co-prescription except in carefully considered circumstances. The benzodiazepines and Z-drugs are also implicated in falls and fracture in elderly patients, in cognitive impairment that may not fully reverse on discontinuation, in motor-vehicle collision risk, and in disinhibition phenomena. The contemporary practice has moved toward shorter courses, lower doses, taper rather than abrupt discontinuation when long use is to be stopped, and increasing use of non-benzodiazepine alternatives for anxiety (the SSRIs and SNRIs for chronic anxiety, propranolol for performance anxiety, the new gepants and antihistamines for situational use).

Not exhaustive; see DEA Schedule IV for the comprehensive list.

• Benzodiazepines (anxiolytic, hypnotic, anticonvulsant, muscle relaxant): alprazolam (Xanax), lorazepam (Ativan), clonazepam (Klonopin), diazepam (Valium), midazolam (Versed), temazepam (Restoril), oxazepam, chlordiazepoxide (Librium, the original of the class), flurazepam, triazolam, estazolam, quazepam
• Z-drug hypnotics: zolpidem (Ambien), eszopiclone (Lunesta), zaleplon (Sonata)
• Wakefulness-promoting medicines: modafinil (Provigil), armodafinil (Nuvigil)
• Atypical opioid analgesics (less abuse potential than the Schedule II opioids): tramadol (rescheduled to Schedule IV in 2014); butorphanol; pentazocine
• Anti-obesity sympathomimetics: phentermine, diethylpropion
• Other: carisoprodol (Soma, the meprobamate prodrug muscle relaxant), suvorexant and the related orexin antagonists lemborexant and daridorexant (insomnia)

The boundary of this category is "medicine placed in Schedule IV of the U.S. Controlled Substances Act." The U.S. designation is federal; many of these medicines have different international classification. Of historical interest, several medicines have moved between the federal schedules over time: tramadol from unscheduled to Schedule IV in 2014, hydrocodone combination products from Schedule III to Schedule II in 2014, carisoprodol from unscheduled to Schedule IV in 2012, propoxyphene (Darvon, Darvocet) from Schedule IV to fully withdrawn in 2010. The schedule of an individual medicine is therefore not necessarily a permanent feature of its regulatory status.

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.