First of all, sorry for the wall of text, when I'm a bit anxious I tend to research and write. It's great for work but it takes a brave person to read everything.
Oh, the DEA definitely knows that Alprazolam has great abuse potential. Back when the DEA decided to open Notice and Commentary for rescheduling Opioid/APAP drugs from Schedule III to II I (
https://www.federalregister.gov/articles...edule#h-13) actually had some legitimate concerns regarding some of my clients - they lived in very rural areas, had issues with transport and access to doctors, and the lack of refills really would screw them in many ways, so of course I, as well as quite a few people, sent in comments to the DEA in regards to such concerns.
The DEA did respond very well (albeit not in the way we hoped). They did the whole analysis and cited what they're looking for and not looking for. I don't agree with their rationale but I understand their mission does not cover what we were arguing.
DEA does an 8 factor review pursuant to 21 USC 811©. To save you time this is the list:
© Factors determinative of control or removal from schedules
In making any finding under subsection (a) of this section or under subsection (b) of section 812 of this title, the Attorney General shall consider the following factors with respect to each drug or other substance proposed to be controlled or removed from the schedules:
(1) Its actual or relative potential for abuse.
(2) Scientific evidence of its pharmacological effect, if known.
(3) The state of current scientific knowledge regarding the drug or other substance.
(4) Its history and current pattern of abuse.
(5) The scope, duration, and significance of abuse.
(6) What, if any, risk there is to the public health.
(7) Its psychic or physiological dependence liability.
(8) Whether the substance is an immediate precursor of a substance already controlled under this subchapter.
Of course, not all the terms are defined, but here's what they said:
"(a) Individuals are taking the drug or other substance in amounts sufficient to create a hazard to their health or to the safety of other individuals or to the community; or
(b) There is a significant diversion of the drug or other substance from legitimate drug channels; or
© Individuals are taking the drug or other substance on their own initiative rather than on the basis of medical advice from a practitioner licensed by law to administer such drugs; or
(d) The drug is so related in its action to a drug or other substance already listed as having a potential for abuse to make it likely that it will have the same potential for abuse as such substance, thus making it reasonable to assume that there may be significant diversions from legitimate channels, significant use contrary to or without medical advice, or that it has a substantial capability of creating hazards to the health of the user or to the safety of the community.
The DEA considered the HHS's evaluation and all other relevant data, including data related to the above mentioned criteria, and finds that:Show citation box
(a) Individuals are using HCPs in amounts sufficient to create a hazard to their health, to the safety of other individuals, or to the community."
I think Alprazolam (As well as several other benzos) certainly fir the profile here. While Alprazolam itself does not pose much of a danger of overdose, its mixing certainly does. There's anecdotal evidence that there's significant diversion and use outside of medical advice. They are not necessarily related to a higher scheduled substance - argument for Methaqualone in effects but chemically certainly dissimlar, We know of its potential for abuse and history and pattern of abuse, there's plenty of scientific literature on it, and abuse is both significant and poses a risk to public health certainly. Its dependence potential is very high on its own and certainly from this analysis the case can be made that it should be scheduled higher.
In fact the DEA itself recognizes regularly that Alprazolam is regualrly diverted and gets people high similar to Schedule III substances.
"Still later in his testimony, when no question was pending, the DI proceeded to state that even aside from the Suboxone prescriptions, the 241 prescriptions at issue were suspicious because they were for oxycodone and alprazolam, which are highly abused drugs. "
https://www.federalregister.gov/articles...-and-order
"In the second human abuse potential study, perampanel produced subjective responses similar to or greater than those produced by alprazolam (Schedule IV) and ketamine (Schedule III). Perampanel (8, 24, and 36 mg), ketamine (Schedule III) (100 mg), alprazolam (Schedule IV) (1.5 and 3 mg), and placebo were administered to 34 subjects who were current recreational poly-drug users with histories of CNS depressant and psychedelic drug use. The effects of perampanel (24 and 36 mg) on the drug-liking Visual Analogue Scale (VAS) were higher than that of alprazolam (Schedule IV) (1.5 and 3 mg) and similar to ketamine (Schedule III) (100 mg). For the Addiction Research Center Inventory Morphine-Benzedrine Group (ARCI MBG) (euphoria) measure, the responses produced by perampanel (24 and 36 mg) were comparable to those produced by alprazolam (Schedule IV) (3 mg) and ketamine (Schedule III) (100 mg), indicating that perampanel produces euphoria comparable to that produced by alprazolam (Schedule IV) and ketamine (Schedule III). The rates reported for euphoria AEs were 37 percent for the 8 mg dose and 46 percent for the 24 and 36 mg doses of perampanel. The rates reported for euphoria AEs for 3 mg alprazolam (Schedule IV) and 100 mg ketamine (Schedule III), were 13 percent and 89 percent, respectively.
For the measure of feeling “high†on a VAS, perampanel (24 and 36 mg) produced responses that were comparable to those for ketamine (Schedule III) (100 mg) and alprazolam (Schedule IV) (1.5 and 3 mg). Perampanel (36 mg) was long-acting for the sedation and “high†effects. They lasted at least 22 hours. It was demonstrated that perampanel causedNMDA-antagonist specific effects, such as “floating,†“spaced out,†“detached,†and “feeling happy,†that were similar to those of ketamine (Schedule III) and greater than those of alprazolam (Schedule IV) (1.5 and 3 mg). The duration of these effects was longer for perampanel (24 and 36 mg) than for ketamine (Schedule III) (100 mg): 24 to 48 hours compared to 3 hours, respectively. The measures of “sedation,†“confused,†“slowed down,†“attention span,†and “clear crisp vision†following doses of 24 and 36 mg perampanel were similar to, or greater than, alprazolam (Schedule IV), and greater than ketamine (Schedule III). The duration of effects of higher doses of perampanel on the majority of measures was longer than for 3 mg alprazolam (Schedule IV) and 100 mg ketamine (Schedule III)."
https://www.federalregister.gov/articles...hedule-iii
"The “abuse frequency ratio,†calculated as the ratio of nonmedical use related annual emergency department visits (as reported in DAWN) to the total number of annual prescriptions for pregabalin is less than that for the Schedule IV drug, alprazolam. Further, because ezogabine has abuse-related human and animal data in its NDA file similar to data generated for pregabalin, ezogabine is likely to have an abuse potential similar to pregabalin. The “abuse frequency ratios†for pregabalin range from 29 to 47, while those for alprazolam are approximately three to six times higher, ranging from 160 to 235. Thus, pregabalin was placed into Schedule V based both on abuse-related human and animal data submitted in its NDA and by epidemiological data which justified placement relative to drugs in Schedule IV. Given that ezogabine has abuse-related human and animal data in its NDA file similar to the data generated by pregabalin, it is likely that ezogabine will have an abuse potential similar to this Schedule V drug."
https://www.federalregister.gov/articles...schedule-v
However, at the same time, the DEA indicates (16 years ago, btw) that benzos were not used for recreational purposes. "The petitioner asserts that “common household painkillers†and benzodiazepines produce more ED visits than marijuana and that marijuana users are no more likely to be seen in EDsthan other chronic drug users. DAWN data do not confirm the petitioner's assertions. For 1999, the estimated rate of mentions of selected drugs per 100,000 population is 69.4 for cocaine, 35.8 for marijuana/hashish, 34.7 for heroin/morphine, 17.5 for alprazolam/diazepam/lorazepam, and 16.9 for aspirin/acetaminophen. The estimated rate of mentions of marijuana/hashish per 100,000 population is similar to that of heroin/morphine, but approximately twice that of aspirin/acetaminophen and that of alprazolam/diazepam/ lorazepam. However, marijuana estimated rate of mentions/100,000 population is approximately half that of cocaine.
These drugs are easily distinguished by the motivation for their use. In 1999, marijuana/hashish mentions were related to episodes in which the motive for drug intake was primarily dependence (34.2%) followed by recreational use (28%), suicide (11.5%) and other psychic effects (8.1%). DAWN defines “psychic effects†as a conscious action to use a drug to improve or enhance any physical, emotional, or social situation or condition. The use of a drug for experimentation or to enhance a social situation, as well as the use of drugs to enhance or improve any mental, emotional, or physical state, is reported to DAWN under this category. Examples of the latter include anxiety, stay awake, help to study, weight control, reduce pain and to induce sleep. A different pattern is observed for tranquilizers (alprazolam/diazepam/lorazepam) and aspirin/acetamipnophen. Alprazolam/diazepam/lorazepam mentions were primarily related to episodes where the motive for drug intake was primarily suicide (approximately 58%), followed by dependence (approximately 17%), other psychic effects (approximately 11%), and recreational use (approximately 5%). For the use of aspirin/acetaminophen the primary motive of the episode was suicide (80%), other psychic effects (9%) and recreational use (2%)."
https://www.federalregister.gov/articles...f-petition
Hell, citizens regularly comment and write to the FDA about Alprazolam. Here's one from June 15.
http://www.regulations.gov/#!documentDet...-0091-0122
The response:
"FDA has reviewed the evidence and information provided in the Petition and we do not  agree that it warrants the labeling change you seek, nor does it support your contention that such a labeling change would prevent physical dependency and withdrawal symptoms. The Petition is focused on the use of benzodiazepines to treat anxiety disorders, many of which are chronic  in nature. These disorders often have a relapsing course and may need frequent, regular treatment.  For example, some benzodiazepines are indicated for the treatment of generalized anxiety disorder (GAD) and panic disorder, both of which are chronic conditions and can be treated for up to 8 months with benzodiazepines.
In addition, a review of the literature supports chronic use of many benzodiazepines in the treatment of GAD, panic disorder, and social anxiety disorder.In light of their effective use in controlling the symptoms ofthese chronic conditions, FDA believes it would be clinically inappropriate and overly restrictive to recommend a maximum duration of use for benzodiazepines of 2 to 4 weeks as the Petition requests.
We also disagree with your characterization of the current language in benzodiazepine labeling regarding duration of use as "vague and undefined." The labeling for all benzodiazepine products contains language noting that the product has not been studied  for long-term use and that physicians should periodically reevaluate the long-term utility  of the drug for each individual patient.
FDA believes that these statements in the labeling are sufficient to alert physicians to be vigilant in monitoring their patients who  take benzodiazepines for extended periods of time.  After consideration of the information provided in your Petition, the Agency continues to believe that the current labeling for each benzodiazepine product contains the essential scientific information needed for the safe and effective use of that drug to help prevent physical dependency  and withdrawal symptoms and, as such, the addition of the information you request to be added to the labeling is not warranted to address these particular issues.  In addition, the Petition provides no evidence that "2 to 4 weeks" is the appropriate duration of use to
prevent physical dependency and withdrawal symptoms for all benzodiazepine products."
Frankly, looking at publications from the DEA, FDA, and everyone else, it seems that the rationale why Alp or any other benzos are Schedule IV instead of anything else seems to be the following:
1) It's been like this for ages and we can't change it now
2) It's not as problematic as the Schedule IIIs we have now
3) The WHO seems to be ok with it being Schedule III
4) Individual doctors should know better and it's not really our problem
I actually don't think anything will get moved to Schedule III. The DEA is focused on Meth and Opioids right now. The FDA, looking at their denial letter from the citizen peition to Ms. Robin, clearly has some misconceptions as to the nature of how benzodiazepines in general are being prescribed and what withdrawals are like (I had a 5 year 4mg a day Xanax script, I kicked it CT and had a seizure and withdrawals lasted a year, so statements like
"FDA continues to believe that long-term use ofbenzodiazepines may be appropriate for
some patients who suffer from chronic conditions for which these drugs are indicated.
We disagree with your contention that, generally, benzodiazepines "[are] not meant for
use for more than two to four weeks" or else patients will become physically dependent
and experience withdrawal. For the reasons discussed above, your request is denied. "
and
"In response to the claims in the Petition regarding protracted withdrawal, FDA conducted
an independent literature review. According to our research, the literature does not
support the existence of a "protracted" benzodiazepine withdrawal syndrome. One study
The labeling for Ativan (lorazepam) states, "[Withdrawal] Symptoms reported following
discontinuation ofbenzodiazepines include headache, anxiety, tension, depression, insomnia,
restlessness, confusion, irritability, sweating, rebound phenomena, dysphoria, dizziness, derealization,
depersonalization, hyperacusis, numbness/tingling of extremities, hypersensitivity to light, noise, and
physical contact/perceptual changes, involuntary movements, nausea, vomiting, diarrhea, loss of
appetite, hallucinations/delirium, convulsions/seizures, tremor, abdominal cramps, myalgia, agitation,
palpitations, tachycardia, panic attacks, vertigo, hyperreflexia, short-term memory loss, and
hyperthermia. Withdrawal symptoms (e.g. rebound insomnia) can appear following cessation of
recommended doses after as little as one week of therapy."
The labeling for Serax (oxazepam) states, "Withdrawal symptoms, similar in character to those noted
with barbiturates and alcohol (convulsions, tremor, abdominal and muscle cramps, vomiting, and
sweating), have occurred following abrupt discontinuation of oxazepam."
The labeling for Librium (chlordiazepoxide) states, "Withdrawal symptoms, similar in character to
those noted with barbiturates and alcohol (convulsions, tremor, abdominal and muscle cramps,
vomiting and sweating), have occurred following abrupt discontinuance of chlordiazepoxide."
by Kaplan states that withdrawal symptoms usually disappear over a few weeks.
Another study by Shader says that the withdrawal syndrome is generally mild and always
self-limited and that, after withdrawal is complete, patients recover completely without
residual sequelae. Shader concludes that, "there is no reliable evidence to support the
existence of post withdrawal syndrome. Experimental neuropharmacologic studies
document that all the side-effects of benzodiazepines, whether behavioral or
neurochemical, disappear within several days or weeks after the drug is eliminated. The
weight of evidence indicates that any new symptoms that persist for more than two
months after the last dose of a benzodiazepine either are part of the premorbid condition
or have appeared by coincidence or as a consequence of the natural history of the
underlying illness."
Yet another study by Mattilla-Evenden et al. found that the
symptoms reported as evidence of benzodiazepine-induced psychiatric morbidity seemed
in most cases to have been a feature of pre-existing psychopathology that became more
manifest after discontinuation of benzodiazepine treatment.
Based on our review of the literature, FDA cannot conclude that a "protracted"
withdrawal syndrome results from use of benzodiazepine products. Therefore, adding a
warning regarding a "protracted" withdrawal syndrome to the labeling for each
benzodiazepine would not be appropriate and your request is denied.
Are crazy and laughable, but if that's where we are, I don't think we'll be going anywhere anytime soon, unfortunately.
![[Image: SyAa0qj.png]](https://i.imgur.com/SyAa0qj.png)
