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#1 fishinghat

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Posted 03 August 2016 - 05:56 PM

Part 1

Benzo Notes

Usage data

https://www.ncbi.nlm...pubmed/25517224
In 2008, approximately 5.2% of US adults aged 18 to 80 years used benzodiazepines. The percentage who used benzodiazepines increased with age from 2.6% (18-35 years) to 5.4% (36-50 years) to 7.4% (51-64 years) to 8.7% (65-80 years). Benzodiazepine use was nearly twice as prevalent in women as men. The proportion of benzodiazepine use that was long term (> 120 days) increased with age from 14.7% (18-35 years) to 31.4% (65-80 years), while the proportion that received a benzodiazepine prescription from a psychiatrist decreased with age from 15.0% (18-35 years) to 5.7% (65-80 years). In all age groups, roughly one-quarter of individuals receiving benzodiazepine involved long-acting benzodiazepine use.

https://www.ncbi.nlm...pubmed/25613443
Estimates of the number of benzodiazepine-dependent persons in Germany range from 128 000 to 1.6 million.

Use benzodiazepines for only 4 weeks or less to minimize risk of addiction.

https://www.ncbi.nlm...les/PMC4318457/
Dependency problems with benzodiazepines have been a familiar phenomenon for
about 40 years for this reason, pharmaceutical companies and the German Federal Institute for Drugs and Medical Devices (BfArM) have restricted the standard period of use to 2–4 weeks since the 1980s. According to the current law on prescriptions of medical drugs, hypnotics and tranquillizers can be prescribed for period can be extended if sound reasons exist.

http://www.smw.ch/co...smw-2011-13277/
Within weeks of chronic use, tolerance to the pharmacological effects can develop and withdrawal becomes apparent once the drug is no longer available, which are both conditions indicative of benzodiazepine dependence.
Withdrawal symptoms are observed following discontinuation or abrupt reduction of BDZs dosage, even after a relatively short treatment period (three to four weeks). Such physiological symptoms are the main signs of physical dependence. The most frequent are insomnia, gastric problems, tremors, agitation, fearfulness and muscle spasms. Less frequently observed are irritability, sweating, depersonalisation, hypersensitivity to stimuli, depression, suicidal behaviour, psychosis, seizures and delirium tremens. Over-rapid withdrawal from BDZs also increases the severity of the symptoms. Slow and gradual reduction of dosage customised to the individual accompanied by psychological support are the most effective way of managing withdrawal. Complete withdrawal can require four weeks to several years.

National Health Committee. Guidelines for assessing and treating anxiety disorders. Wellington (New Zealand): National Health Committee; 1998.
Recommend restricting their use to no more than 3–4 weeks

https://www.ncbi.nlm...pubmed/17535048
Recommend restricting their use to no more than 3–4 weeks

https://www.ncbi.nlm...t1-ndt-11-1885/
Review of research listing proper use of benzos.
In general, compounds with higher potency and a shorter half-life are associated with a greater likelihood of developing withdrawal syndromes and dependence.
A significant risk of dependence is recognized in some patients receiving treatment for longer than one month, and health professionals should be aware of this when considering the relative treatment benefits and risks.

https://www.ncbi.nlm...pubmed/16639148
Benzodiazepine dependence could be prevented by adherence to recommendations for short-term prescribing (2-4 weeks only when possible).

Clinical Guideline 22 (amended). Anxiety: management of anxiety (panic disorder, with or without agoraphobia, and generalised anxiety disorder) in adults in primary, secondary and community care" (PDF). National Institute for Health and Clinical Excellence. 2007. pp. 23–25. Retrieved 2009-08-08.
According to National Institute for Health and Clinical Excellence (NICE), benzodiazepines can be used in the immediate management of GAD, if necessary. However, they should not usually be given for longer than 2–4 weeks. The only medications NICE recommends for the longer term management of GAD are antidepressants.

McIntosh A, Cohen A, Turnbull N, et al. (2004). "Clinical guidelines and evidence review for panic disorder and generalised anxiety disorder" (PDF). National Collaborating Centre for Primary Care. Retrieved 2009-06-16.
Barbui C, Cipriani A (2009). "Proposal for the inclusion in the WHO Model List of Essential Medicines of a selective serotonin-reuptake inhibitor for Generalised Anxiety Disorder" (PDF). WHO Collaborating Centre for Research and Training in Mental Health. Retrieved 2009-06-23.
Based on the findings of placebo-controlled studies, they do not recommend use of benzodiazepines beyond two to four weeks, as tolerance and physical dependence develop rapidly, with withdrawal symptoms including rebound anxiety occurring after six weeks or more of use.

https://www.ncbi.nlm...pubmed/25613443
Benzodiazepines are generally highly effective when first given, but they should generally be given only for strict indications and for a limited time. If these drugs still need to be given beyond the short term, timely referral to a specialist is indicated, and possibly also contact with the addiction aid system.

http://www.rcpsych.a...diazepines.aspx
Royal College of Psychiatrists
How long should I take a benzodiazepine for?
Up to 4 weeks - no longer. This should really be just to give other (often psychological) treatments a chance to work.

Limited effectiveness/Long-term use and Addiction

http://www.ncbi.nlm....pubmed/16933543
The Canadian Psychiatric Association (CPA) recommends benzodiazepines alprazolam, bromazepam, lorazepam, and diazepam only as a second-line choice, if the treatment with two different antidepressants was unsuccessful. Although they are second-line agents, benzodiazepines can be used for a limited time to relieve severe anxiety and agitation. CPA guidelines note that after 4–6 weeks the effect of benzodiazepines may decrease to the level of placebo, and that benzodiazepines are less effective than antidepressants in alleviating ruminative worry, the core symptom of GAD. However, in some cases, a prolonged treatment with benzodiazepines as the add-on to an antidepressant may be justified.

https://www.ncbi.nlm...pubmed/16639148
Tolerance to anti-anxiety effects develops more slowly with little evidence of continued effectiveness beyond four to six months of continued use.

Curran, H. V.; Collins, R.; Fletcher, S.; Kee, S. C. Y.; Woods, B.; Iliffe, S. (2003-10-01). "Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life". Psychological Medicine 33 (7): 1223–1237. doi:10.1017/s0033291703008213. ISSN 0033-2917. PMID 14580077.
"Holbrook AM. %282004%29. Treating insomnia. - PubMed - NCBI". www.ncbi.nlm.nih.gov. PMID 25282004. Retrieved 2015-12-10.
Poyares, Dalva; Guilleminault, Christian; Ohayon, Maurice M.; Tufik, Sergio (2004-06-01). "Chronic benzodiazepine usage and withdrawal in insomnia patients". Journal of Psychiatric Research 38 (3): 327–334. doi:10.1016/j.jpsychires.2003.10.003. ISSN 0022-3956. PMID 15003439.
Friedman MJ (1998). "Pharmacotherapy for posttraumatic stress disorder: a status report". Clinical Neurosciences Supplement 52: S115–S121.
Heather N, Bowie A, Ashton H, McAvoy B, Spencer I, Brodie J, Giddings D (2004). "Randomised controlled trial of two brief interventions against long-term benzodiazepine use: outcome of intervention". Addiction Research and Theory 12 (2): 141–154. doi:10.1080/1606635310001634528.
Bandelow, Borwin; Zohar, Joseph; Hollander, Eric; Kasper, Siegfried; Möller, Hans-Jürgen; Zohar, Joseph; Hollander, Eric; Kasper, Siegfried (2008-01-01). "World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders HYPERLINK "http://www.ncbi.nlm....ubmed/18949648"HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/18949648" The World Journal of Biological Psychiatry 9 (4): 248–312. doi:10.1080/15622970802465807. ISSN 1562-2975. PMID 18949648.
Ashton, Heather (2005-05-01). "The diagnosis and management of benzodiazepine dependence". Current Opinion in Psychiatry 18 (3): 249–255. doi:10.1097/01.yco.0000165594.60434.84. ISSN 0951-7367. PMID 16639148.
Morin, Charles M.; Bélanger, Lynda; Bastien, Célyne; Vallières, Annie (2005-01-01). "Long-term outcome after discontinuation of benzodiazepines for insomnia: a survival analysis of relapse". Behaviour Research and Therapy 43 (1): 1–14. doi:10.1016/j.brat.2003.12.002. ISSN 0005-7967. PMID 15531349.
Michelini S, Cassano GB, Frare F, et al. (2016). "Long-term use of benzodiazepines: tolerance, dependence and clinical problems in anxiety and mood disorders.". Pharmacopsychiatry 29: 127–134
http://www.ncbi.nlm....pubmed/24434093

Several studies (listed above) have confirmed that long-term benzodiazepines are not significantly different from placebo for sleep or anxiety. This may explain why patients commonly increase doses over time and many eventually take more than one type of benzodiazepine after the first loses effectiveness.

https://www.ncbi.nlm...pubmed/15078112
Discontinuation of benzodiazepines or abrupt reduction of the dose, even after a relatively short course of treatment (three to four weeks), may result in two groups of symptoms—rebound and withdrawal. Rebound symptoms are the return of the symptoms for which the patient was treated but worse than before. Withdrawal symptoms are the new symptoms that occur when the benzodiazepine is stopped. They are the main sign of physical dependence.

https://www.ncbi.nlm...pubmed/26164054
While benzodizapines may have short-term benefits for anxiety, sleep and agitation in some patients, long-term (i.e., greater than 2–4 weeks) use can result in a worsening of the very symptoms the medications are meant to treat.

https://www.ncbi.nlm...pubmed/26545257
The relative proportion of long-term BZD users in adult BZD users ranged from 6% to 76% (mean 24%) The estimates were higher in studies only on the elderly (47%). Long-term use involved typically steady treatment with low BZD doses. However, in elderly patients long-term BZD use and exceeding recommended doses was relatively common. Several characteristics associated with long-term use were found.

https://www.ncbi.nlm.../pubmed/2222129
Patients who were able to remain free of benzodiazepines for at least 5 weeks obtained lower levels of anxiety than before benzodiazepine discontinuation.
 


#2 fishinghat

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Posted 03 August 2016 - 05:59 PM

Part 2

 

Effects of long-term use.

Alzheimer's Disease

https://www.ncbi.nlm...pubmed/26011780
During the 4-year follow-up, we found that 45% of individuals with Alzheimer's Disease (AD) and 38% of individuals without AD used BZDRs. The prevalence of long-term (≥ 180 days) BZDR use was more common among individuals with AD (30%) than individuals without AD (26%). The high prevalence of long-term BZDR use among individuals with AD is especially a cause for concern because long-term use may further impair cognition and may be associated with serious adverse events.

https://www.ncbi.nlm...pubmed/25208536
No association for Alzheimer's disease was found for a cumulative dose <91 prescribed daily doses. The strength of association increased with exposure density 1.32 for 91-180 prescribed daily doses and 1.84 for >180 prescribed daily doses). Benzodiazepine use is associated with an increased risk of Alzheimer's disease. The stronger association observed for long term exposures reinforces the suspicion of a possible direct association, even if benzodiazepine use might also be an early marker of a condition associated with an increased risk of dementia. Unwarranted long term use of these drugs should be considered as a public health concern.

https://www.ncbi.nlm...pubmed/25491057
Taking benzodiazepine is associated with an increased risk of Alzheimer disease

Cancer Risk

https://www.ncbi.nlm...pubmed/25674736
Clonazepam was associated with a higher risk for cancers. Moreover, specific cancer risk among BZDs use was observed significantly increased 98% for brain, 25% for colorectal, and 10% for lung, as compared with non-BZDs use. Diazepam, chlordiazepoxide, medazepam, nitrazepam, and oxazepam are safe among BZDs use for cancer risk.

https://www.ncbi.nlm...pubmed/24314718
In this population-based study, we found a significant increase in the risk of benign brain tumor development in a cohort of long-term (>2 months) BZD users.

https://www.ncbi.nlm...pubmed/23043261
BZRD use was not associated with an overall increase in cancer risk.

Dementia

https://www.ncbi.nlm...pubmed/25691075
Out of the ten studies retrieved, nine reported an increased risk of dementia in benzodiazepine users. The risk increased with cumulative dose and treatment duration and when long-acting molecules were used. Even if the causal nature of this association remains unproved, the reviewed material provides arguments for evoking a causal link. Further research would be necessary to elucidate the mechanism of this effect, if any, to evaluate the risk of exposure in younger population and the influence of risk factors such as depression. In any case, the body of evidence seems sufficient for avoiding prescriptions or renewals that are not fully justified and indiscriminate long-term use.

https://www.ncbi.nlm...pubmed/26016483
The risk of dementia increased by 22% for every additional 20 defined daily dose per year. Long-term benzodiazepine users have an increased risk of dementia compared with never users.

https://www.ncbi.nlm...les/PMC4737849/
The risk of dementia is slightly higher in people with minimal exposure to benzodiazepines but not with the highest level of exposure. These results do not support a causal association between benzodiazepine use and dementia.

https://www.ncbi.nlm...les/PMC3460255/
In this prospective population based study, new use of benzodiazepines was associated with increased risk of dementia. The result was robust in pooled analyses across cohorts of new users of benzodiazepines throughout the study and in a complementary case-control study.

Memory/Cognative Function

https://www.ncbi.nlm...pubmed/21494764
In the course of the 10 year-follow-up, 3.9% of subjects were defined as occasional users of benzodiazepine and 7.5% as long-term users. The analysis revealed a significant alteration of long-term memory in women whereas there was no significant association in men.

https://www.ncbi.nlm...pubmed/22705064
Chronic use of benzodiazepine was significantly associated with a lower latent cognitive level, but no association was found between chronic use and an acceleration of cognitive decline, neither on the latent cognitive process, nor on specific neuropsychological tests. Our results suggest that chronic benzodiazepine use is associated with poorer cognitive performance but not with accelerated cognitive decline with age.

https://www.ncbi.nlm.../pubmed/7639085
This study confirmed earlier observations of neuropsychological deficits in long-term benzodiazepine-using patients and demonstrated that these changes (decrease in general intelligence and of nonverbal memory) are at least partly reversible (within a year) by discontinuing drug intake.

Sleep

https://www.ncbi.nlm...pubmed/23692988
Our findings do not support long-term effectiveness of BZDs; long-term users slept more poorly than nonusers and were even more outspoken in users of long-acting BZDs.

Tasman A; Kay J; Lieberman JA, eds. (2008). Psychiatry (3rd ed.). Chichester, England: John Wiley & Sons. pp. 1186–1200, 2603–2615. ISBN 978-0470065716.
Disrupting REM sleep by inhibiting deep stage sleep

https://www.ncbi.nlm...pubmed/20963787
Long-term benzodiazepine users were more likely to report poor sleep quality.

https://www.ncbi.nlm...pubmed/26547856
Melatonin ineffective in helping sleep during benzo withdrawal.

https://www.ncbi.nlm...pubmed/22704915
Benzodiazepines may be efficient in reducing symptoms in the short term, but evidence from this long temporal follow-up study indicates limited positive influences in the long term.

https://www.ncbi.nlm...pubmed/25145751
Sleep quality in chronic BZD/Z users significantly decreased over 1 year and was significantly worse than in nonusers at the end of this period. This study suggests that using BZD/Zs chronically does not maintain or improve sleep quality.

https://www.ncbi.nlm...pubmed/15003439
Benzos decrease REM sleep.

Elderly

https://www.ncbi.nlm...pubmed/15001721
Jackson SG, Jansen P, Mangoni A (22 May 2009). Prescribing for Elderly Patients
The long-term effects of benzodiazepines and benzodiazepine dependence in the elderly can resemble dementia, depression, or anxiety syndromes, and progressively worsens over time. Adverse effects on cognition can be mistaken for the effects of old age. The benefits of withdrawal include improved cognition, alertness, mobility, reduced risk incontinence, and a reduced risk of falls and fractures. The success of gradual-tapering benzodiazepines is as great in the elderly as in younger people. Benzodiazepines should be prescribed to the elderly only with caution and only for a short period at low doses.

https://www.ncbi.nlm...pubmed/16639148
McIntosh A, Semple D, Smyth R, Burns J, Darjee R (2005). "Depressants". Oxford Handbook of Psychiatry (1st ed.). Oxford University Press. p. 540. ISBN 0-19-852783-7.
American Geriatrics Society 2012 Beers Criteria Update Expert Panel (2012). "American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults" (PDF)
The elderly are at an increased risk of suffering from both short- and long-term adverse effects, and as a result, all benzodiazepines are listed in the Beers List of inappropriate medications for older adults.

https://www.ncbi.nlm...pubmed/26545257
The relative proportion of long-term BZD users in adult BZD users ranged from 6% to 76% (mean 24%) The estimates were higher in studies only on the elderly (47%). Long-term use involved typically steady treatment with low BZD doses. However, in elderly patients long-term BZD use and exceeding recommended doses was relatively common. Several characteristics associated with long-term use were found.

https://www.ncbi.nlm...les/PMC1934057/
Patients achieved withdrawal or reduced their dose by at least 50% after 6 and 12 months.

Seizures

https://www.ncbi.nlm...pubmed/21815323
Since the first report of benzodiazepine withdrawal seizure in 1961, many case reports have followed. Withdrawal seizures have occurred with short, medium, and long halflife benzodiazepine, if discontinued abruptly. Withdrawal seizures usually occur in patients who have been taking these medications for long periods of time and at high doses. Seizures have also been reported with less than 15 days of use and at therapeutic dosage. Almost all the withdrawal seizures reported were grand mal seizures. The severity of seizures range from a single episode to coma and death. Benzodiazepine dose tapering can be done faster in a hospital setting in high-dose abusers, but must be done more slowly in the outpatient setting in therapeutic dosage users.
Many many other articles also address this issue.
 


#3 fishinghat

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Posted 03 August 2016 - 06:03 PM

Part 3

From the manufacturer drug inserts

https://dailymed.nlm...8f-880eced0239f

Xanax (generic name is alprazolam) (Pfizer)

Warnings (Pfizer)
"Even after relatively shortterm use at the doses recommended for the treatment of transient anxiety and anxiety disorder (ie, 0.75 to 4.0 mg per day), there is some risk of dependence. Spontaneous reporting system data suggest that the risk of dependence and its severity appear to be greater in patients treated with doses greater than 4 mg/day and for long periods (more than 12 weeks). "
"Seizures attributable to XANAX were seen after drug discontinuance or dose reduction in 8 of 1980 patients with panic disorder or in patients participating in clinical trials where doses of XANAX greater than 4 mg/day for over 3 months were permitted. The duration of use in the above 8 cases ranged from 4 to 22 weeks. There have been occasional voluntary reports of patients developing seizures while apparently tapering gradually from XANAX. The risk of seizure seems to be greatest 24–72 hours after discontinuation."

Adverse Reactions

"It is suggested that the daily dosage of XANAX be decreased by no more than 0.5 mg every three days. Some patients may benefit from an even slower dosage reduction. In a controlled postmarketing discontinuation study of panic disorder patients which compared this recommended taper schedule with a slower taper schedule, no difference was observed between the groups in the proportion of patients who tapered to zero dose; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome."

Drug Abuse and Dependence

"When necessary, immediate management of withdrawal symptoms requires re-institution of treatment at doses of XANAX sufficient to suppress symptoms."

Also from Pfizer;
"Demonstrations of the effectiveness of XANAX by systematic clinical study are limited to 4 months duration for anxiety disorder and 4 to 10 weeks duration for panic disorder; however, patients with panic disorder have been treated on an open basis for up to 8 months without apparent loss of benefit. The physician should periodically reassess the usefulness of the drug for the individual patient."
"Withdrawal reactions may occur when dosage reduction occurs for any reason. This includes purposeful tapering, but also inadvertent reduction of dose (eg, the patient forgets, the patient is admitted to a hospital). Therefore, the dosage of XANAX should be reduced or discontinued gradually."
"There have been reports of failure of other benzodiazepines to fully suppress these withdrawal symptoms. These failures have been attributed to incomplete cross-tolerance but may also reflect the use of an inadequate dosing regimen of the substituted benzodiazepine or the effects of concomitant medications."

https://dailymed.nlm...0a-41a0946f956c

Valium (generic name is diazepam) (Genentech)

Drug Abuse and Dependence
"Diazepam is subject to Schedule IV control under the Controlled Substances Act of 1970. Abuse and dependence of benzodiazepines have been reported. Addiction-prone individuals (such as drug addicts or alcoholics) should be under careful surveillance when receiving diazepam or other psychotropic agents because of the predisposition of such patients to habituation and dependence. Once physical dependence to benzodiazepines has developed, termination of treatment will be accompanied by withdrawal symptoms. The risk is more pronounced in patients on long-term therapy."
"Since the risk of withdrawal phenomena and rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage be decreased gradually."

No additional information on the Genentech website.

https://dailymed.nlm...b6-30936715d73b

Klonopin (generic name is clonazepam) (Genentech)

Drug Abuse and Dependence
"After extended therapy, abrupt discontinuation should generally be avoided and a gradual dosage tapering schedule followed."
"Following the short-term treatment of patients with panic disorder, patients were gradually withdrawn during a 7-week downward-titration (discontinuance) period."

Dosage and Administration
"There is no body of evidence available to answer the question of how long the patient treated with clonazepam should remain on it. Therefore, the physician who elects to use Klonopin for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient."
"Treatment should be discontinued gradually, with a decrease of 0.125 mg bid every 3 days, until the drug is completely withdrawn."

No additional information on the Genentech website.

Ativan (generic name is lorazepam) (Valeant Pharmaceuticals)

Indication and usage

"Ativan (lorazepam) is indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety or anxiety associated with depressive symptoms.The effectiveness of Ativan (lorazepam) in long-term use, that is, more than 4 months, has not been assessed by systematic clinical studies."

Warnings
"The dependence potential is reduced when lorazepam is used at the appropriate dose for short-term treatment."
"In general, benzodiazepines should be prescribed for short periods only (e.g., 2 to 4 weeks). Extension of the treatment period should not take place without reevaluation of the need for continued therapy. Continuous long-term use of product is not recommended. Withdrawal symptoms (e.g., rebound insomnia) can appear following cessation of recommended doses after as little as one week of therapy. Abrupt discontinuation of product should be avoided and a gradual dosage-tapering schedule followed after extended therapy."

No additional information on the Valeant Pharmaceuticals website.


#4 fishinghat

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Posted 03 August 2016 - 06:06 PM

Part 4

Effects of Discontinuation/Withdrawal

Guina, Jeffrey; Rossetter, Sarah R.; DeRHODES, Bethany J.; Nahhas, Ramzi W.; Welton, Randon S. (2015-07-01). "Benzodiazepines for PTSD: A Systematic Review and Meta-Analysis". Journal of Psychiatric Practice 21 (4): 281–303. doi:10.1097/PRA.0000000000000091. ISSN 1538-1145. PMID 26164054.
Michelini S, Cassano GB, Frare F, et al. (2016). "Long-term use of benzodiazepines: tolerance, dependence and clinical problems in anxiety and mood disorders.". Pharmacopsychiatry 29: 127–134
Gelpin, E.; Bonne, O.; Peri, T.; Brandes, D.; Shalev, A. Y. (1996-09-01). "Treatment of recent trauma survivors with benzodiazepines: a prospective study". The Journal of Clinical Psychiatry 57 (9): 390–394. ISSN 0160-6689. PMID 9746445.
Rosen, Craig S.; Greenbaum, Mark A.; Schnurr, Paula P.; Holmes, Tyson H.; Brennan, Penny L.; Friedman, Matthew J. (2013-12-01). "Do benzodiazepines reduce the effectiveness of exposure therapy for posttraumatic stress disorder?". The Journal of Clinical Psychiatry 74 (12): 1241–1248. doi:10.4088/JCP.13m08592. ISSN 1555-2101. PMID 24434093.
Wilhelm, F. H.; Roth, W. T. (1997-09-01). "Acute and delayed effects of alprazolam on flight phobics during exposure". Behaviour Research and Therapy 35 (9): 831–841. doi:10.1016/s0005-7967(97)00033-8. ISSN 0005-7967. PMID 9299803.
Matar, Michael A.; Zohar, Joseph; Kaplan, Zeev; Cohen, Hagit (2009-04-01). "Alprazolam treatment immediately after stress exposure interferes with the normal HPA-stress response and increases vulnerability to subsequent stress in an animal model of PTSD". European Neuropsychopharmacology 19 (4): 283–295. doi:10.1016/j.euroneuro.2008.12.004. ISSN 1873-7862. PMID 19167197.
Curran, H. V.; Collins, R.; Fletcher, S.; Kee, S. C. Y.; Woods, B.; Iliffe, S. (2003-10-01). "Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life". Psychological Medicine 33 (7): 1223–1237. doi:10.1017/s0033291703008213. ISSN 0033-2917. PMID 14580077.
Pary R, Lewis S (2008). "Prescribing benzodiazepines in clinical practice". Resident and Staff Physician 54 (1): 8–17.

Withdrawal symptoms or rebound symptoms in between doses mimicking or exacerbating underlying anxiety or sleep disorders, inhibiting the benefits of psychotherapy by inhibiting memory consolidation and reducing fear extinction, and reducing coping with trauma/stress and increasing vulnerability to future stress. Anxiety, insomnia and irritability may be temporarily exacerbated during withdrawal, but psychiatric symptoms after discontinuation are usually less than even while taking benzodiazepines. Fortunately, for those with benzodiazepine-induced problems, functioning significantly improves within 1 year of discontinuation.

https://www.ncbi.nlm...pubmed/16639148
https://www.ncbi.nlm...pubmed/19062773
Royal Pharmaceutical Society of Great Britain (2009). British National Formulary (BNF 57). BMJ Group and RPS Publishing. ISBN 978-0-85369-845-6.
Opinion as to the time needed to complete withdrawal ranges from four weeks to several years. A goal of less than six months has been suggested, but due to factors such as dosage and type of benzodiazepine, reasons for prescription, lifestyle, personality, environmental stresses, and amount of available support, a year or more may be needed to withdraw.

https://www.ncbi.nlm...les/PMC2943829/
Based on collective findings in this benzodiazepine withdrawal-anxiety model, we propose a functional model illustrating the changes in glutamate receptor populations at excitatory synapses during benzodiazepine withdrawal.
(Physically alters GABA receptor shape and function during withdrawal.)

https://www.ncbi.nlm.../pubmed/1675688
Protracted withdrawal syndromes from benzodiazepines.
Benzodiazepines can give rise not only to slowly reversible functional changes in the central nervous system, but may also occasionally cause structural neuronal damage.

http://www.ncbi.nlm....pubmed/25466558
This occurred independently of neuronal activity and intracellular calcium and involved GABA(A)R–gephyrin interactions, suggesting that the changes in GABA(A)R diffusion depend on conformational changes of the receptor.

https://www.ncbi.nlm...pubmed/20935233
Similar to above.

http://www.ncbi.nlm....les/PMC3494928/
Chronic BZ treatment results in allosteric uncoupling of the GABA and BZ binding sites, suggesting changes in receptor subunit composition and/or receptor function (reviewed in ref. 7). Chronic dosing of animals with BZ leads to a reduction in GABAAR synaptic inhibition (8\l "–10) and produces diverse changes in GABAAR transcripts across the brain (7). Direct comparison and interpretation of these and other studies assessing mRNA levels has been challenging due to differences in treatment paradigm (time and dose), brain regions assessed, and the BZ ligand used. Radioligand binding studies have reported mixed results, ranging from decreases to no change in CNS BZ binding sites, likely due to methodological limitations in assessing subtype-specific GABAAR changes.
(Multiple references to changes in the receptors)

https://www.ncbi.nlm...pubmed/15219633
Impaired hypothalamic-pituitary-adrenocortical (HPA) system is related to severity of benzodiazepine withdrawal in patients.

https://www.ncbi.nlm...pubmed/20140603
BDNF plasma levels decrease during benzodiazepine withdrawal in patients suffering from comorbidity of depressive disorder and benzodiazepine dependence.

https://www.ncbi.nlm...pubmed/17132385
Patients achieved withdrawal or reduced their dose by at least 50% after 6 and 12 months. Abstinence and withdrawal symptoms were also measured.

https://www.ncbi.nlm.../pubmed/7439058
Among the benzodiazepines, lorazepam seems to have a particularly high addiction potential.

https://www.ncbi.nlm.../pubmed/2880872

https://www.ncbi.nlm.../pubmed/3676860
Specificity and intensity of BDZ withdrawal symptoms were the same for those dependent upon high doses of BDZs and those dependent upon low doses, but a protracted withdrawal was only observed in low-dose BDZ-dependent patients.

http://www.ncbi.nlm..../pubmed/9063050
Protracted benzodiazepine withdrawal syndrome mimicking psychotic depression.


Withdrawal Notes

http://www.benzosupp...ey_contents.htm
See..
http://www.benzosupp...instatement.htm
29% had to go over the ORIGINAL DOSE to stabilize or could not reach a dose high enough to stabilize.

Updosing during withdrawal
http://www.benzosupp...g/up_dosing.htm
24% said it was unsuccessful.

Ashton, H. (1984). Benzodiazepine withdrawal: An unfinished story. British Medical Journal, 288, 1135-1140.
Ashton, H. (1987). Benzodiazepine withdrawal: Outcome in 50 patients. British Journal of Addiction, 82, 665-671.
These symptoms have often been temporarily alleviated by a moderate increase in dosage or the addition of another benzodiazepine, but eventually re-emerge during further chronic use and only disappear after the benzodiazepine is stopped.

http://www.smchealth...per08-12-13.pdf
If symptoms to bad stabilize dose or go up in dose for 1-2 weeks.

https://www.ncbi.nlm...d00117-0138.pdf
Small "extra dose" on any day they feel a special need for
extra help. This helps them to feel in control.

http://www.btpinfo.o...benzodiazepines
Never abruptly stop any benzodiazepine or Z drug. The shock caused by such an abrupt withdrawal is so severe that even after resumption of your drug at the previous dose, it may take weeks or months to "stabilise", and in some cases, you may never stabilise from a cold turkey withdrawal until after you have completed your reduction.


Withdrawal

Suicide
http://www.ncbi.nlm....les/PMC2047018/
Two recent studies have examined the role of benzodiazepines on actual or attempted suicide. A study examining elderly suicides in Sweden found that between 1992 and 1996, benzodiazepine hypnotics dominated drug-poisoning suicides (216 of 548, 39%) in those aged over 65 years.4 During the same time frame, a population-based cohort study in Canada found a significant association between suicide attempts and benzodiazepine usage (odds ratio = 6.2). While disinhibition and paradoxical reactions inducing suicidal impulses were considered, the authors believed that confounding by the original indication was a more likely explanation.5 Neither study reported withdrawal symptoms as a factor, although both advised examining for depression and restrictive prescribing for groups at risk of suicide.


#5 fishinghat

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Posted 03 August 2016 - 06:13 PM

Part 5

Withdrawal Treatment

https://riordanclini...ical-rationale/
Benzodiazepine withdrawal treatment. GABA, Vitamin C and niacin.

Flumazenil

https://www.ncbi.nlm...pubmed/14578014
FLU (iv injection) immediately reversed BZD effects on balance task and significantly reduced withdrawal symptoms in comparison with oxazepam and placebo on both self-reported and observer-rated withdrawal scales. The partial agonist also reduced craving scores during the detoxification procedure. In addition, during oxazepam tapering, group B patients experienced paradoxical symptoms that were not apparent in FLU patients. Patients treated with FLU showed a significantly lower relapse rates on days 15, 23 and 30 after the detoxification week. Our data provide further evidence of FLUs ability to counteract BZD effects, control BZD withdrawal and normalize BZD receptor function.

https://www.ncbi.nlm...les/PMC4014019/
Preliminary data suggest that continuous intravenous or subcutaneous flumazenil infusion for 4 days significantly reduces acute benzodiazepine withdrawal sequelae.

https://www.ncbi.nlm...pubmed/26096314
The most common AEs (adverse events) in the flumazenil group were agitation and gastrointestinal symptoms, whereas the most common SAEs (significant adverse events)were supraventricular arrhythmia and convulsions.

https://www.ncbi.nlm...pubmed/27166362
This paper reports the data related to 214 subjects addicted to high doses of benzodiazepine and treated with the FLU-SSI method between 2012 and 2014. This technique is less invasive and requires less nursing intervention than intravenous infusion. Our data support FLU-SSI as a possible efficient strategy for the treatment of patients with long-term, high-dose benzodiazepine addiction

https://www.ncbi.nlm...pubmed/22596209
This small proof-of-concept study indicates that subcutaneous flumazenil infusion has excellent tolerability, efficacy and improvement on measures of psychological distress.

Cyamemazine (antihistamine)

https://www.ncbi.nlm...pubmed/22421069
Therefore, the anxiolytic efficacy of cyamemazine in benzodiazepine withdrawal can be due to a 5-HT(2AR) antagonistic activity at the cortical level.
cyamemazine vs. bromazepam
https://www.ncbi.nlm...pubmed/16243418
28 patients (total 618) in the cyamemazine group and 18 in the bromazepam group had an adverse event, including anxiety, insomnia, dry mouth and somnolence. No extra-pyramidal symptoms were reported. In conclusion, cyamemazine was comparable to bromazepam in ensuring successful benzodiazepine withdrawal and in controlling the acute benzodiazepine withdrawal syndrome. Cyamemazine may be useful to facilitate benzodiazepine withdrawal in those patients where bromazepam substitution is not appropriate.

Pregabalin (Lyrica)

"Common side effects include: sleepiness, confusion, trouble with memory, poor coordination, dry mouth, problem with vision, and weight gain.[6] Potentially serious side effects include angioedema, drug misuse, and an increased suicide risk.[6] It is moderately addictive both physically and psychologically.[1]"
Wiki

https://www.ncbi.nlm...pubmed/24532157
Our findings suggest that successful treatment of long-term BDZ use with PGB is associated with a substantial, though only partial, recovery of BDZ-compromised neuropsychological functioning, at least at a 2-month follow-up.

https://www.ncbi.nlm...pubmed/21334859
The success rates did not differ according to either the benzodiazepine of abuse or the presence of other substance use disorders. Significant and clinically relevant improvements were observed in withdrawal and anxiety symptoms, as well as in patients' functioning. At week 12, tolerability was rated as good or excellent by 90% and 83% of the clinicians and patients, respectively. Our results suggest that pregabalin is an efficacious and well-tolerated adjunctive treatment for benzodiazepine withdrawal.

https://www.ncbi.nlm...pubmed/22568872
Available evidence suggests that monotherapy with pregabalin, within the dosage range of 150 - 600 mg/d, is a promising "novel" option for the safe and efficacious relapse prevention of both AD and BD. However, its efficacy as monotherapy in the acute treatment of AD withdrawal syndrome is still controversial.

https://www.ncbi.nlm...pubmed/22545971
Between 15% and 29% of the patients were able to stop using benzodiazepines after starting pregabalin or gabapentin treatment. Psychiatric patients who started pregabalin were able to reduce the amount of benzodiazepines used by 48%, compared to only 14% among starters of gabapentin. This study shows that some patients reduced their use of benzodiazepines substantially after starting pregabalin.

Gabapentin

"Serious side effects may include an increased risk of suicide, aggressive behaviour, and drug reaction with eosinophilia and systemic symptoms.[4] It is unclear if it is safe during pregnancy or breastfeeding.[8] Lower doses should be used in people with kidney problems. Gabapentin does not affect the activity of the inhibitory neurotransmitter γ-aminobutyric acid (GABA); how it works is unclear.[4}"
Wiki

Possible links to pancreatic and other cancers (below)
http://clinicaltrial...how/NCT01138124
http://www.bioportfo...ancer-gprd.html
http://clinicaltrial...how/NCT01236053
http://www.ncbi.nlm....les/PMC3314779/

https://www.ncbi.nlm...pubmed/22545971
Between 15% and 29% of the patients were able to stop using benzodiazepines after starting pregabalin or gabapentin treatment. Psychiatric patients who started pregabalin were able to reduce the amount of benzodiazepines used by 48%, compared to only 14% among starters of gabapentin. This study shows that some patients reduced their use of benzodiazepines substantially after starting pregabalin.

Afobazole (fabomotizole)

Clinical trials have shown fabomotizole to be well tolerated and reasonably effective for the treatment of anxiety. Fabomotizole has found little clinical use outside Russia and has not been evaluated by the FDA.
https://www.ncbi.nlm...pubmed/25076752
Afobazole (5.0 mg/kg, i.p.) effectively (i) ameliorated withdrawal-induced anxiety, returning behavioral pattern in the elevated plus maze test up to levels comparable to that in vehicle-treated animals, and (ii) increased withdrawal-reduced dopamine level (+23.8%, p < 0.05) in striatum. It is suggested that afobazole, due to its multitarget receptor action, can be useful in the diazepam withdrawal-induced anxiety blockade through modulation of dopaminergic system activity.
nitric oxide synthase inhibitors

https://www.ncbi.nlm...pubmed/21857078
Administration of the non-selective NO synthase inhibitors N(G)-nitro-L-arginine (L-NOARG) and N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME) significantly attenuated the withdrawal syndrome (i.e., pentetrazole-induced seizures) in diazepam-dependent mice. L-NOARG significantly suppressed hypermotility in clonazepam-dependent rats and inhibited the decrease in body weight observed after 12 h of withdrawal in chlordiazepoxide- and clonazepam-dependent rats. Moreover, a clear propensity of L-NOARG to protect benzodiazepine-dependent rats against audiogenic seizures was observed

Phenobarbital

Side effects include a decreased level of consciousness along with a decreased effort to breathe. There is concern about both abuse and withdrawal following long term use. It may also increase the risk of suicide. It is pregnancy category B or D in the United States and category D in Australia.
Wiki

Many research articles have been written on its withdrawal.

https://www.ncbi.nlm.../pubmed/1575069
https://www.ncbi.nlm.../pubmed/2147093
https://www.ncbi.nlm...pubmed/22285834
We reviewed the medical records of 310 patients treated with a 3-day fixed-dose phenobarbital taper for benzodiazepine dependence over a 5-year period between 2004 and 2009. We recorded the incidence of seizures, falls, delirium, and emergency department (ED) visits or readmission to our institution within 30 days as markers for safety; we also recorded how many patients had doses held because of sedation. The taper was well tolerated, although one quarter of the patients had at least one dose held because of sedation. There were no seizures, falls, or injuries reported. Six percent had a readmission, and 7% had an ED visit at our institution within 30 days of discharge, but only 3 patients required readmission for withdrawal symptoms. Overall, this protocol appears to be safe and effective.

βCCT

βCCT, an antagonist selective for α1GABAA receptors.

https://www.ncbi.nlm...pubmed/23149168
Acute challenge with either flumazenil (10mg/kg) or βCCt (1.25, 5 and 20 mg/kg) alleviated the diazepam withdrawal-induced anxiety. Moreover, both antagonists induced an anxiolytic-like response close, though not identical, to that seen with acute administration of diazepam. These findings imply that the mechanism by which antagonism at GABA(A) receptors may reverse the withdrawal-induced anxiety involves the α(1) subunit and prompt further studies aimed at linking the changes in behavior with possible adaptive changes in subunit expression and function of GABA(A) receptors.

https://www.ncbi.nlm...pubmed/24695241
In conclusion, the current study suggests that the role of α1-containing GABAA receptors in mediating the development of physical dependence may vary based on the effect being studied and duration of protracted treatment. Moreover, the present data supports previous findings that the lack of activity at α1-containing GABAA receptors is not sufficient to eliminate physical dependence liability of ligands of the benzodiazepine type.

https://www.ncbi.nlm...les/PMC4066304/
Variable effectiveness.

GB-115 dipeptide

https://www.ncbi.nlm...pubmed/22238979
It is established that, in 24-48 h following BZ withdrawal, GB-115 dipeptide administered in doses of 0.1 and 0.5 mg/kg, i.p., produced an anxiolytic effect in all animals, which was manifested by increasing the stay time and number of entries in EPM. In the striatum of outbred rats, GB-115 increased DOPAC (+25%) and DA (+31.6%) levels that were decreased during diazepam withdrawal syndrome. The obtained results showed the GB-115 efficiency in attenuating the anxiety caused by BZ withdrawal.

Captodiamine

Captodiame, also known as captodiamine, is an antihistamine sold under the trade names Covatine, Covatix, and Suvren which is used as a sedative and anxiolytic. It is a derivative of diphenhydramine.
Wiki

https://www.ncbi.nlm...pine withdrawal
Analysis of the primary study criterion revealed a statistically significant difference (p < 0.0001) in the emergence of withdrawal symptoms between the two groups in favour of captodiamine at two, six and eight weeks following initiation of therapy. These results were supported by significant beneficial effects of captodiamine on the majority of secondary outcome measures. The switch to captodiamine was associated with an improvement in vigilance, which may be an advantage for the overall safety of the anxiolytic treatment, for example with regard to road safety. Discontinuation of captodiamine was not associated with the emergence of rebound anxiety.

Dothiepin (a tricyclic antidepressant not available in the USA)

https://www.ncbi.nlm.../pubmed/8730942
Not significant efficacy.

Varied treatments evaluated

https://www.ncbi.nlm...pubmed/16856084
Results support the policy of gradual rather than abrupt withdrawal of benzodiazepine. Progressive withdrawal (over 10 weeks) appeared preferable if compared to abrupt since the number of drop-outs was less important and the procedure judged more favourable by the participants. Short half-life benzodiazepine, associated with higher drop-out rates, did not have higher withdrawal symptoms scores. Switching from short half-life benzodiazepine to long half-life benzodiazepine before gradual taper withdrawal did not receive much support from this review. The role of propanolol in benzodiazepine withdrawal was unclear; adding tricyclic antidepressant (dothiepin) decreased the intensity of withdrawal symptoms but did not increase the rate of benzodiazepine abstinence at the end of the trial. Buspirone and Progesterone failed to suppress any benzodiazepine symptoms. Carbamazepine might have promise as an adjunctive medication for benzodiazepine withdrawal, particularly in patients receiving benzodiazepines in daily dosages of 20 mg/d or more of diazepam (or equivalents).

Buspirone

https://www.ncbi.nlm.../pubmed/2880872
It was concluded that buspirone does not help benzodiazepine withdrawal and does not suppress benzodiazepine withdrawal symptoms.

https://www.ncbi.nlm...pubmed/11097963
The success rate of the taper in this study was significantly higher for patients who received imipramine (82.6%), and nonsignificantly higher for patients who received buspirone (67.9%), than for patients who received placebo (37.5%). The imipramine effect remained highly significant even after the analysis adjusted for three other independent predictors of taper success: benzodiazepine dose, level of anxious symptoms at baseline, and duration of benzodiazepine therapy.

https://www.ncbi.nlm.../pubmed/2878622
This finding supports preclinical studies indicating that buspirone has no clinically significant benzodiazepine receptor activity.

https://www.ncbi.nlm.../pubmed/2211568
Buspirone and alprazolam may be used together safely, and buspirone may be started early in the alprazolam tapering process. Thirty-six patients received placebo t.i.d. and 36 received buspirone 5 mg. t.i.d. Findings included significantly greater anxiety (as measured by the Hamilton Rating Scale for Anxiety) in the placebo group and significantly reduced manifestations of abstinence (as measured by the Abstinence Rating Scale) in the buspirone group

https://www.ncbi.nlm...pubmed/22298398
Buspirone-treated patients tended to have lower anxiety levels than placebo-treated patients.

https://www.ncbi.nlm.../pubmed/2885432
Failure of buspirone to protect against lorazepam withdrawal symptoms.

Tianeptine and Carbamazepine

https://www.ncbi.nlm...pubmed/12647454
It appears from this study that both drugs (carbamazepine and tianeptine) are comparable, safe and efficient in treating benzodiazepine withdrawal symptoms.

Carbamazepine

Common side effects include nausea and drowsiness. Serious side effects may include skin rashes, decreased bone marrow function, suicidal thoughts, or confusion. It should not be used in those with a history of bone marrow problems. Use during pregnancy may cause harm to the baby; however stopping it in pregnant women with seizures is not recommended. Its use during breastfeeding is not recommended. Care should be taken in those with either kidney or liver problems.
Wiki

https://www.ncbi.nlm.../pubmed/9005346
Compared with a gradual tapering off of benzodiazepines, abrupt withdrawal plus CBZ medication seems to be better tolerated

https://www.ncbi.nlm.../pubmed/1297907
Thirty-six outpatients aged > or = 60 yrs suffering from general anxiety disorders and benzodiazepine abuse underwent gradual discontinuation of benzodiazepine therapy in two groups, one treated with carbamazepine and one with placebo. The carbamazepine-treated group demonstrated a lower incidence of withdrawal symptoms rated according to the Physician Withdrawal Check List

https://www.ncbi.nlm.../pubmed/2929759
All patients tolerated rapid discontinuation well and none developed significant withdrawal symptoms.

https://www.ncbi.nlm.../pubmed/2021297
The results of this pilot investigation suggest that carbamazepine might have promise as an adjunctive drug therapy for the benzodiazepine withdrawal syndrome, particularly in patients receiving benzodiazepines in daily dosages of 20 mg/d or greater of diazepam equivalents.

https://www.ncbi.nlm.../pubmed/1854420
These geriatric patients experienced no major withdrawal symptoms, but mild symptoms were common. There was no correlation between dose or duration of alprazolam use and extent of withdrawal symptoms. We recommend use of this treatment regimen in a hospital setting only, where close monitoring can occur.

https://www.ncbi.nlm.../pubmed/1686406
Fundamental withdrawal symptoms (like hypersensitivity to sensory stimuli, abnormal perception of movement, depersonalisation or derealisation) were also less severe in the group treated with CBZ compared with the group not receiving that treatment. These findings support the results of previous reports indicating a therapeutical effect of CBZ in BZD withdrawal.
Widely used by detox centers.

Topiramate (Topomate)

People taking topiramate should be aware of the following risks:
⦁ Avoid activities requiring mental alertness and coordination until drug effects are realized.
⦁ Topiramate may impair heat regulation, especially in children. Use caution with activities leading to an increased core temperature, such as strenuous exercise, exposure to extreme heat, or dehydration.
⦁ Topiramate may cause visual field defects.
⦁ Topiramate may decrease effectiveness of estrogen-containing oral contraceptives.
⦁ Taking topiramate in the 1st trimester of pregnancy may increase risk of cleft lip/cleft palate in infant.
⦁ As is the case for all antiepileptic drugs, it is advisable not to suddenly discontinue topiramate as there is a theoretical risk of rebound seizures.
Wiki

There is an extensive list of side effects on Wiki and the FDA websites. Too numerous to list here.

https://www.ncbi.nlm...pubmed/12858324
A case is presented of a rapid benzodiazepine-withdrawal treated successfully with topiramate.

https://www.ncbi.nlm...pubmed/17071548
In our case of a patient with recurrent major depressive disorder, subthreshold anxiety disorder and addiction to alprazolam, topiramate appears to be efficient and safe in alprazolam withdrawal.

Alpidem

Clinical trial to obtain US FDA approval were halted in 1992 and the drug never received FDA approval. It was withdrawn from the French market by 1994 and is not approved for marketing anywhere in the world.. In 1995, Alpidem was withdrawn from the market in most of the world following reports of severe liver damage.

https://www.ncbi.nlm.../pubmed/8097214
It was concluded that alpidem is not helpful in helping patients withdrawing from a benzodiazepine withdrawal perhaps because of partial agonist properties

https://www.ncbi.nlm...pubmed/19698430
A severe WS was diagnosed in 11.1% of the patients in the alpidem group and in 31.6% of the placebo group. If not having been withdrawn from the market, alpidem could have been useful for the prevention of BZ withdrawal syndrome.

Valproate

https://www.ncbi.nlm...pubmed/22915484
Non-fatal and fatal liver failure associated with valproic acid.

Many research articles om serious side effects, some fatal for this drug.

Placebo

https://www.ncbi.nlm...pubmed/11205424
Thus, females had the highest base-line ratings and were the only group that showed a significant reduction in symptom ratings after placebo injections on the first occasion. Gender differences were also found for systolic and diastolic blood pressure.

Progesterone

is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species.
This drug has its own severe withdrawal.

https://www.ncbi.nlm.../pubmed/7604143
There was no progesterone versus placebo difference in the severity of taper withdrawal.

https://www.ncbi.nlm.../pubmed/9000261
The principal finding of the present work is that the intensity of diazepam withdrawal syndrome was significantly reduced by acute administration of progesterone

Clonidine

https://www.ncbi.nlm.../pubmed/2872826
The intensity, severity, and duration of the abstinence syndrome were not altered by clonidine at a dose sufficient to markedly reduce blood pressure and plasma free 3-methoxy-4-hydroxyphenylglycol.

https://www.ncbi.nlm.../pubmed/8577798
Finally, low doses of clonidine (0.03 mg/kg, i.p.) were shown to have anxiolytic properties and to reverse the anxiogenic effects of lorazepam on withdrawal.

Ipsapirone

https://www.ncbi.nlm.../pubmed/1676531
Ipsapirone causing true potentiation of BZ withdrawal

Not approved by the FDA yet.

Propranolol (Beta-Blocker)

https://www.ncbi.nlm.../pubmed/1971767
Those in the propranolol group suffered more severe symptoms.

https://www.ncbi.nlm.../pubmed/7910743
This paper describes pharmacological treatments that can reverse the anxiogenic response detected in animal tests when rats are withdrawn from chronic treatment with diazepam. Concurrent treatment with the calcium channel antagonist verapamil prevented this withdrawal response and the benzodiazepine-receptor antagonist flumazenil reversed the anxiogenic response and restored the system to a drug-naive state. Other treatments that reversed the anxiogenic response were the GABAB agonist baclofen, the 5-HT1A receptor agonist buspirone, and the 5-HT3 receptor antagonist (R,S)-zacopride (GABA = gamma-aminobutyric acid; 5-HT = 5-hydroxytryptamine). Both the enantiomers of zacopride contributed to this reversal. These behavioural reversals are interpreted in the light of biochemical studies showing increased 45Ca2+ flux and [3H]5-HT release from the hippocampus, during benzodiazepine withdrawal .

Hydroxyzine (Atarax) (antihistamine)

https://www.ncbi.nlm...les/PMC3598901/
Benzo use was reduced by 25% every 2 to 4 weeks.
25 mg Hydroxyzine/day.

https://www.ncbi.nlm.../pubmed/9417395
The patients had to be long term consumers (at least 3 months) of 2 mg daily of lorazepam and were withdrawn using transiently an antihistaminic anxiolytic (hydroxyzine or placebo TAD) according to 6 different procedures defining 6 parallel groups: hydroxyzine 50 mg, abrupt or progressive withdrawal; hydroxyzine 25 mg, abrupt or progressive withdrawal; placebo, abrupt or progressive withdrawal. Following this 4 week-period of withdrawal, the patients were without any treatment for a post-study follow up 2 month-period.
After a one-month period of withdrawal (under placebo or hydroxyzine) followed by a 2 month-period without any treatment, 75% patients were totally free of any drug and their level of anxiety was significantly decreased
Levels of anxiety were significantly improved in hydroxyzine 50 mg group and in hydroxyzine 25 mg group but not in placebo group. Withdrawal symptoms between D0 and D28 were improved only in hydroxyzine 50 mg group and the number of side effects was significantly improved in both the hydroxyzine (25 et 50 mg) groups but not in placebo group.
When a patient is engaged to be withdrawn from of a lorazepam long term treatment, it can therefore be proposed as a support a transient prescription of hydroxyzine 25 mg TAD to markedly anxious patients and of hydroxyzine 50 mg TAD to patients presenting a withdrawal symptomatology.

https://www.ncbi.nlm...pubmed/18379511
The study aimed at investigating of efficacy of hydroxyzine (atarax) as a substitutive drug used in case of benzodiazepine tranquilizers (BDT) withdrawal in patients who received BDT for more than 3 months. Fifty-nine patients with protracted chronic anxiety-phobic disorders were divided into 2 groups: in the first (main) one, BDT were withdrawn at once with the following assignment of substitutive therapy with atarax and in the second (control) group the withdrawal was continuous during 14 days with the simultaneous assignment of a substitutive placebo therapy. In the first group (resumed the BDT therapy because of worsening of their state 23,3% patients finished their participation in the study ahead of time as compared to 65,6% of those in the control group. The Hamilton Anxiety Scale scores were more reduced in the main group than in the control one. The results obtained suggest that atarax is worth to be used as a substitutive drug for BDT.

 


#6 fishinghat

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Posted 03 August 2016 - 06:18 PM

Part 6

Z Drugs

Definition - Z-drugs are a group of nonbenzodiazepine drugs with effects similar to benzodiazepines, which are used in the treatment of insomnia, and most of whose names start with the letter "Z". Some Z-drugs may have advantages over benzodiazepines. (Wiki)

Eszopiclone (Lunesta) (Zopiclone )
Zaleplon (Sonata).
Zolpidem (Ambien)

Benzodiazepines and Z Drugs

https://www1.ghc.org...benzo-zdrug.pdf
Benzodiazepine and Z-Drug Safety Guideline
This guidance document is an excellent over view of these two drug groups. It explains how the Z-Drugs act just like benzos, a little less effective on anxiety and a little more effective on sleep. They are just as addictive, severe withdrawal and because their action is the same as benzos they should not be taken with benzos as it increases the rate of addictiveness and severity of withdrawal.

https://www.ncbi.nlm...pubmed/25474727
The risk to develop BZD/z-drugs dependence is significantly associated with psychiatric history and with the quantity of BZD/z-drugs that is taken.

https://www.ncbi.nlm...pubmed/24774720
Dependence on benzodiazepines (BZDs) or Z-drugs (zolpidem, zopicline and zaleplon) is a common clinical phenomenon.

https://www.ncbi.nlm...pubmed/18505619
There were no significant differences in patients' perceptions of efficacy or side-effects reported by those on Z drugs compared to patients taking benzodiazepines. Side-effects were commonly reported, which may have contributed to a high proportion of responders, particularly patients on Z drugs who were wishing to stop, or who had previously tried to stop taking this medication. Reported prescribing practices were often at variance with the licence for short-term use.
About half of those with sleep problems seek medical help, which often involves a prescription of hypnotic drugs including benzodiazepines like temazepam, or Z drugs such as zopiclone, zolpidem, or zaleplon. Most hypnotic prescribing takes place in primary care, and drug treatments may be inappropriately prescribed for 4 weeks or longer in up to 50% of new prescriptions.
No significant differences between Z drugs and benzodiazepines were found in respect of perceived benefits or adverse effects, including withdrawal or dependence.

https://www.nice.org...522015122913515
Guidance document from NICE (National Institute for Health and Care Excellence, UK)on the use of Benzos and Z-drugs.
"There is no firm evidence of differences in the effects of zaleplon, zolpidem, zopiclone and the shorter-acting benzodiazepines."
"If treatment with one of these hypnotic medicines does not work, the doctor should not prescribe one of the others."
A drug used to induce sleep is described as a 'hypnotic'.

The Summary of Product Characteristics (SPC) specifies that treatment (with Zaleplon) should be as short as possible with a maximum duration of 2 weeks. The SPC states that the duration of treatment (with Zolpidem) should usually vary from a few days to 2 weeks with a maximum of 4 weeks, including tapering off where appropriate. The SPC also states that the duration of treatment (with Zopiclone) should be 2–5 days for transient insomnia and 2–3 weeks for short-term insomnia.

http://www.nhsgrampi...zo_649_1014.pdf
In practice short-term prescribing should be limited to a maximum of two weeks as signs of psychological and physical dependence can develop if prescribed for longer periods.

*Z- drugs which include zaleplon, zolpidem and zopiclone are non benzodiazepine hypnotics, they carry the same risks and dependence problems as benzodiazepines.

Z drugs are indicated only for the short term management of severe insomnia that interferes with normal daily life, and should be prescribed for short periods of time only (up to two to four weeks for Zopiclone, Zolpidem and up to two weeks for Zaleplon).[2], [3]

There is no justification for prescribing more than one benzodiazepine or Z-drug concurrently, except during the period of conversion.

If the patient is struggling with symptoms of withdrawal, halt the reduction and maintain the current dose until symptoms improve. Increases in dose are to be discouraged.

http://www.setrust.h...and_Z_Drugs.pdf
There is no significant difference in adverse effects between benzodiazepines and zopiclone and not enough data to choose one over the other. There is no significant difference in sleep latency between benzodiazepines and zopiclone. The risk of hip fracture is as likely with z drugs as with other benzodiazepines.

They offer no clinically significant advantages over benzodiazepines

Only use for the short-term treatment of severe anxiety or insomnia (anxiety maximum of 4 weeks, insomnia maximum of 10 nights)

Ambien (Zolpidem)

https://dailymed.nlm...96-8702a28e6e76
Note - The following is from the drug insert supplied with Ambien (Manu; Sanofi-aventis) and is an example of a typical drug insert for Z-Drugs. See above website for inserts from other Z-drugs and manufacturers.

"Sleep-driving" and other complex behaviors while not fully awake. Risk increases with dose and use with other CNS depressants and alcohol. Immediately evaluate any new onset behavioral changes.

Depression: Worsening of depression or, suicidal thinking may occur. Prescribe the least amount of tablets feasible to avoid intentional overdose.

Withdrawal effects: Symptoms may occur with rapid dose reduction or discontinuation
Observed reactions include anaphylaxis and angioedema.

Additive effects occur with concomitant use of other CNS depressants (e.g. benzodiazepines, opioids, tricyclic antidepressants, alcohol), including daytime use. Downward dose adjustment of AMBIEN CR and concomitant CNS depressants should be considered.

Abnormal thinking and behavior changes have been reported in patients treated with sedative/hypnotics, including AMBIEN CR. Some of these changes included decreased inhibition (e.g. aggressiveness and extroversion that seemed out of character), bizarre behavior, agitation and depersonalization. Visual and auditory hallucinations have been reported.

Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with "sleep-driving", patients usually do not remember these events. Amnesia, anxiety and other neuro-psychiatric symptoms may also occur.

In primarily depressed patients treated with sedative-hypnotics, worsening of depression, and suicidal thoughts and actions (including completed suicides), have been reported. Suicidal tendencies may be present in such patients and protective measures may be required.

Zolpidem can cause drowsiness and a decreased level of consciousness, which may lead to falls and consequently to severe injuries. Severe injuries such as hip fractures and intracranial hemorrhage have been reported.

Data from a clinical study in which selective serotonin reuptake inhibitor- (SSRI-) treated patients were given zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n=95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction.

Zolpidem tartrate is classified as a Schedule IV controlled substance by federal regulation.

https://www.ncbi.nlm...pubmed/14519173
Zolpidem and zopiclone can cause dependence.

https://www.ncbi.nlm...pubmed/24531568
We found that subchronic zolpidem and diazepam administration produced ...increased anxiety-like behaviors 1 day after drug termination.

https://www.ncbi.nlm...pubmed/26776243
This study demonstrated a significant association between using zolpidem and suicide or suicide attempt in people with or without comorbid psychiatric illnesses.

https://www.ncbi.nlm...pubmed/22444504
In 83.5% of cases, psychoactive substances other than zolpidem were detected, most commonly antidepressants (46.2%), benzodiazepines (35.2%), opioids (26.4%), and alcohol (39.6%). In summary, zolpidem was a factor contributing to death in a large proportion of cases, predominately involving drug toxicity and suicide.

https://www.ncbi.nlm...pubmed/24931450
Results revealed medium effect sizes for zopiclone and zolpidem on measures of verbal memory. An additional medium effect size was observed for zolpidem on attention. Finally, smaller effect sizes were observed for zolpidem speed of processing and for zopiclone on working memory. It is clear from these data that the use of a single dose of the z-drugs in healthy adults as measured in the morning following the exposure does produce a specific rather than a generalized negative effect on cognitive function. However, there were only enough studies to evaluate the individual cognitive effects of the zolpidem and zopiclone medications; the specific effects of zaleplon and eszopiclone cannot be ascertained because only one study met the inclusion and exclusion criteria for the review.

https://www.ncbi.nlm...les/PMC3906775/
This case showed that zolpidem can exert abuse capability, euphoric mood, tolerance, and withdrawal syndrome.

http://www.benzo.org.uk/ashtonad.htm
Do not change type or dose of antidepressants while withdrawing from a benzo. Wait for 4 weeks or more after withdrawal complete to change.
 


#7 gail

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Posted 03 August 2016 - 06:41 PM

Many thanks Fisherman!

Quite a job you did. Interesting material for us users of Benzos!

#8 TryinginFL

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Posted 03 August 2016 - 06:48 PM

Thanks so much, FH!

 

It will take me quite a while to read through all of that - that was quite a job there...


#9 gail

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Posted 04 August 2016 - 10:19 AM

Just bringing the topic back up!

#10 fishinghat

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Posted 05 August 2016 - 12:18 PM

Also;

Lunesta

“Lunesta is now available in a generic form in the United States as of May 2014. On May 15, 2014 US FDA asked for lowering starting dose of drug Eszopiclone (Lunesta) from 2 Mg to 1 Mg after it was observed in a study that even after 8 hours after taking drug in night, some patients were not able to cope up with their next-day activities like driving and other activities that require full alertness.”


Lunesta is slightly effective in the treatment of insomnia where difficulty in falling asleep is the primary complaint. Kirsch et al. found the benefit over placebo to be of questionable clinical significance. Although the drug effect and the placebo response were rather small and of questionable clinical importance, the two together produce a reasonably large clinical response.


Use of benzodiazepines and similar benzodiazepine-like drugs such as eszopiclone may lead to physical and psychological dependence.

Tolerance may develop after repeated use of benzodiazepines and benzodiazepine-like drugs for a few weeks. Lunesta was studied for up to 6 months in a group of patients which showed no signs of tolerance or dependence in a study funded and carried out by Sepracor.


Lunesta acts on benzodiazepine binding site situated on GABAA neurons as an agonist.


In a 2009 article in the New England Journal of Medicine, "Lost in Transmission — FDA Drug Information That Never Reaches Clinicians", it was reported that the largest of three Lunesta trials found that compared to placebo Lunesta "was superior to placebo" while it only shortened initial time falling asleep by 15 minutes on average. "Clinicians who are interested in the drug’s efficacy cannot find efficacy information in the label: it states only that Lunesta is superior to placebo. The FDA’s medical review provides efficacy data, albeit not until page 306 of the 403-page document. In the longest, largest phase 3 trial, patients in the Lunesta group reported falling asleep an average of 15 minutes faster and sleeping an average of 37 minutes longer than those in the placebo group. However, on average, Lunesta patients still met criteria for insomnia and reported no clinically meaningful improvement in next-day alertness or functioning."[19]
All of the above from Wikipedia

http://www.ncbi.nlm....pubmed/24882900

http://www.ncbi.nlm....pubmed/23251857
Lunesta less effective in patients with depression and anxiety
http://www.ncbi.nlm....pubmed/23198272
Lunesta induced psychosis.

http://www.ncbi.nlm....pubmed/23126273
Sleepiness extends to daytime.

http://www.ncbi.nlm....pubmed/23063301
Effectiveness

http://www.ncbi.nlm....pubmed/22731653
Helps with sleep with those with psych disorders.

http://www.ncbi.nlm....pubmed/21540024
stimulates the hypothalamo-pituitary-adrenal axis

http://www.ncbi.nlm....pubmed/21367352
Effective on PTSD patients.

http://www.ncbi.nlm....pubmed/20408925
Makes anti-depressants more effective.

http://www.ncbi.nlm....pubmed/20153782
Effects on REM sleep.

#11 gail

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Posted 05 August 2016 - 04:07 PM

Anything on Trazodone 50 mg for sleep?
Adverse effects? Withdrawal?

#12 TryinginFL

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Posted 05 August 2016 - 04:25 PM

Hope nothing bad on the T...

 

Have been taking 50mg for years..


#13 fishinghat

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Posted 05 August 2016 - 06:41 PM

Will get you something but that is a fairly low dose. Most tricyclics have been linked to specific types of heart issues (irregular rythyms...). I will get back to you.


#14 gail

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Posted 07 August 2016 - 10:06 AM

Oops, here we are again.

Tricyclic, I did not know this!
I wonder if it is still prescribed at a higher dosage for depression. Will check this while my brain is functioning...

#15 fishinghat

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Posted 07 August 2016 - 01:47 PM

I am just starting to look at the info on trazadone and should get it posted in a few days.  But I did find this on Wiki....

Trazodone (sold under many brand names worldwide[1]) is an antidepressant of the serotonin antagonist and reuptake inhibitor (SARI) class. It is a phenylpiperazine compound. Trazodone also has anti-anxiety (anxiolytic) and sleep-inducing (hypnotic) effects.[5] Its side-effect profile and potential toxicity are considerably different from those of the original antidepressants (i.e., the monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs)).[6]

 

It is NOT a tricyclic. That is what happens when a man of my age goes by memory. ;o;


#16 fishinghat

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Posted 07 August 2016 - 04:19 PM

My bad, my bad, my bad.  Foot into mouth up to knee.


#17 fishinghat

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Posted 08 August 2016 - 10:47 AM

Trazodone

https://www.ncbi.nlm...pubmed/25920951
Antidepressant-induced galactorrhea and increases in prolactin levels have rarely been reported. Trazodone can potentiate the serotonergic activity of citalopram. To our knowledge, no cases of galactorrhea associated with use of trazodone have been reported to date.

https://www.ncbi.nlm...les/PMC4418332/
These findings suggest that trazodone could be effective therapy for patients with OSA (obstructive sleep apnea) without worsening hypoxemia.

https://www.ncbi.nlm...pubmed/26017199
Trazodone and omeprazole interaction causing frequent second-degree Mobitz type 1 atrioventricular (AV) block (Wenckebach phenomenon) and syncope: a case report and literature review.
A 54-year-old man who was a former smoker, with dyslipidemia, coronary artery disease, and anxiety disorder developed lightheadedness and syncope the morning of admission. He was taking trazodone 50 mg daily, omeprazole 20 mg daily, and simvastatin 20 mg at bedtime. He doubled the dose of trazodone 50 mg on the night prior to presentation to calm his anxiety. An electrocardiogram revealed sinus rhythm at 60 beats per minute and second-degree Mobitz type 1 atrioventricular (AV) block with 5:4 AV conduction. Results of basic metabolic panel, thyroid-stimulating hormone, and chest radiograph were normal. A transthoracic echocardiogram revealed aortic valve sclerosis. We tested for Lyme disease given his history of hunting in the woods 8 months prior to presentation, but the titer was negative. Trazodone and omeprazole were discontinued. By the 3rd day of medication discontinuation, all symptoms had resolved and the frequency of second-degree AV Mobitz type 1 AV block had decreased to once per hour.

https://www.ncbi.nlm...pubmed/26088119
Although trazodone is approved and marketed in most countries worldwide for the sole treatment of Major Depressive Disorder, the use for this medication is very common for many other conditions, such as primary or secondary insomnia, Generalised Anxiety Disorder, Panic Disorder, Post-Traumatic Stress Disorder and Obsessive- Compulsive Disorder. Other, not officially approved, uses of trazodone include: the treatment of bulimia, benzodiazepine and/or alcohol dependence or abuse, fibromyalgia, degenerative diseases of the central nervous system such as dementia and other organic disorders, schizophrenia, chronic pain, and diabetic neuropathy. In addition, due to its 5HT2A receptor antagonistic action, trazodone may be used to prevent the occurrence of initial and long-term side effects of SSRI, such as anxiety, insomnia and sexual dysfunction.

https://www.ncbi.nlm...pubmed/26174731
It is very effective in the treatment of depression, in anxiety and insomnia. Its known side effects mainly occur with prolonged use of daily doses of 150-200 mg. The ability to enhance drowsiness may be associated with some risk in elderly patients. This

clinical case illustrates an acute extrapyramidal event (movement disorders, like tardives) induced by a low dose of trazodone.

https://www.ncbi.nlm...pubmed/25376160
Prolonged-release trazodone was more effective than placebo in MDD and was well tolerated.

https://www.ncbi.nlm...pubmed/24023050
The bioactive intermediate metabolites of trazodone might cause hepatotoxicity (Liver toxicity).

https://www.ncbi.nlm...pubmed/27147406
Trazodone and milnacipran are the active antidepressant drugs that are being used in the treatment of psychiatric disorders. In this study, the in vitro genotoxic effects of trazodone and milnacipran have been determined in human peripheral blood lymphocytes by using chromosomal aberrations (CAs), sister chromatid exchanges (SCEs), micronuclei (MN), and comet assays. 3.13; 6.25; 12.50; 25.00; 50.00; and 75.00 μg/mL concentrations of trazodone and 2.50; 5.00; 10.00; 20.00; 30.00; and 40.00 μg/mL concentrations of milnacipran were used. Trazodone and milnacipran significantly increased the frequency of CAs and SCEs compared with the control. Both of the active ingredients raised the MN frequency in a dose-dependent manner. Mitotic index was significantly decreased, but replication and nuclear division indices were not affected at all treatments. Trazodone was statistically increased the mean comet tail intensity, tail length, and tail moment at three concentrations (6.25; 12.50; and 25.00 μg/mL) compared with control. Two highest concentrations (50 and 75 μg/mL) of trazodone were toxic in the comet assay. Milnacipran increased the comet tail intensity, tail length, and tail moment at all concentrations. It is concluded that trazodone and milnacipran have clastogenic, mutagenic, and cytotoxic effects on human lymphocytes in vitro.

https://www.ncbi.nlm...pubmed/26187900
The second-generation selective 5-HT2 receptor antagonists and reuptake inhibitors (SARIs) class antidepressants are known to have fewer cardiovascular side effects than the older ones. However, several case reports showed that trazodone, one of the second-generation SARIs, induces QT prolongation, cardiac arrhythmia, and ventricular tachycardia. Although these clinical cases suggested trazodone-induced cardiotoxicity, the toxicological actions of trazodone on cardiac action potentials (APs) beyond the human ether-a-go-go related gene (hERG) remain unclear. To elucidate the cellular mechanism for the adverse cardiac effects of trazodone, we investigated its effects on cardiac APs and ion channels using whole-cell patch clamp techniques in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and transiently transfected human embryonic kidney cells (HEK293) with cardiac ion channel complementary DNA. Trazodone dose-dependently decreased the maximum upstroke velocity (Vmax) and prolonged the AP duration, inducing early after depolarizations at 3 and 10 μM that triggered ventricular arrhythmias in hiPSC-CMs. Trazodone also inhibited all of the major ion channels (IKr, IKs, INa, and ICa), with an especially high inhibitory potency on hERG. These data indicate that the prolonged AP duration and decreased Vmax due to trazodone are mainly the result of hERG and sodium ion inhibition, and its inhibitory effects on cardiac ion channels can be exhibited in hiPSC-CMs.

https://www.ncbi.nlm...les/PMC3987616/
A 26-year-old female outpatient presenting with a depressive state suffered from auditory hallucinations at night. Her auditory hallucinations did not respond to blonanserin or paliperidone, but partially responded to risperidone. In view of the possibility that her auditory hallucinations began after starting trazodone, trazodone was discontinued, leading to a complete resolution of her auditory hallucinations.

https://www.ncbi.nlm...pubmed/23661283
Acute treatment of mirtazapine impaired road-tracking performance and increased sleepiness, but sedative effects disappeared under repeated administrations. Trazodone did not affect driving performance or cognitive function under acute or repeated administrations.

https://www.ncbi.nlm...pubmed/23450804
The number of individual impairment clues detected is increased with trazodone. Trazodone 100 mg may cause cognitive driving impairment.

https://www.ncbi.nlm...les/PMC3693429/
Trazodone is effective in controlling a wide range of symptoms of depression, while avoiding the negative effects on sleep seen with SSRI antidepressants. The recently approved prolonged-release formulation should provide further optimization of this antidepressant and may be useful for enabling an appropriate therapeutic dose to be administered with improved patient compliance.

https://www.ncbi.nlm...les/PMC3165092/
Trazodone produced small but significant impairments of short-term memory, verbal learning, equilibrium, and arm muscle endurance across time points. Relative to placebo across test days, trazodone was associated with fewer nighttime awakenings, minutes of Stage 1 sleep, and self-reports of difficulty sleeping. On Day 7 only, slow wave sleep was greater and objective measures of daytime sleepiness lower with trazodone than with placebo. Although trazodone is efficacious for sleep maintenance difficulties, its associated cognitive and motor impairments may provide a modest caveat to healthcare providers.

https://www.ncbi.nlm...pubmed/22239013
Its performance was analyzed in individuals dependent on alcohol, benzodiazepines and opiates, as well as mixed addictions. Also raised the problem of influence of trazodone on the experience of pain, which maybe helpful in relieving withdrawal symptoms. The data show a positive effect of trazodone in individuals addicted to the SPA, although the mechanism by which trazodone works in the body is very complex and not yet fully understood. Its advantage is the relatively small panel of side effects. Although many of the analyzed studies were not placebo-controlled, the results are so promising that you can recommend on the basis of trazodone therapy in individuals addicted to the SPA.

https://www.ncbi.nlm...pubmed/22574377
Yimusake combined with trazodone hydrochloride is highly efficacious for primary PE (premature ejaculation).

https://www.ncbi.nlm...pubmed/21740694
We found that patients taking trazodone can produce urine with sufficient m-CPP to result in false-positive Amphetamines II results.

https://www.ncbi.nlm...pubmed/22732813
The purpose of the study was to highlight the cytoarchitectural changes in the frontal cortex and hippocampus by comparing two antidepressant substances: amitriptyline with a strong anticholinergic effect and trazodone, without anticholinergic effect. The superior neuroprotective qualities of trazodone for the frontal cortex, hippocampus and dentate gyrus are revealed. The particular neurobiological vulnerability of depression in women requires a differentiated therapeutic approach, avoiding the use of antidepressants with anticholinergic action.

https://www.ncbi.nlm...pubmed/21575194
Trazodone significantly improved fibromyalgia severity and associated symptomatology. Its combination with pregabalin potentiated this improvement and the tolerability of the drugs in association was good.

https://www.ncbi.nlm...pubmed/22115401
Various other attributes of trazodone, including interaction with adrenergic receptors, formation of an active metabolite with potent serotonergic activity, low abuse potential and putative utility in various disorders, warrant further exploration. The adverse effects of trazodone generally mirror its serotonergic activity and include sedation, headache, sweating, weight changes and gastrointestinal effects such as nausea and vomiting. Clinicians and patients should be cognizant of the risk for potential, but rare, cardiovascular adverse effects of trazodone.

https://www.ncbi.nlm...pubmed/21220793
It is generally approved for the treatment of major depression, its efficacy is well-documented in elderly patients, and it has been widely used for replacement of benzodiazepines or benzodiazepine-type sleeping drugs due to its anxiolytic efficacy and sleep normalizing effect in depression. Trazodone was further found to be clinically useful in generalized anxiety disorder, agitation of patients with dementia and organic disorders, chronic pain disorders, alcohol and benzodiazepine dependence. Tolerability of trazodone is comparable to the novel antidepressants. It is weight neutral and does not decrease sexual function

https://www.ncbi.nlm...les/PMC2945951/
Trazodone markedly improved sleep quality, with large effect sizes in total PSQI score as well on sleep quality, sleep duration and sleep efficiency. Significant improvement, although with moderate effect sizes, were also observed in total FIQ scores, anxiety and depression scores (both HADS and BDI), and pain interference with daily activities. Unexpectedly, the most frequent and severe side effect associated with trazodone in our sample was tachycardia, which was reported by 14 (21.2%) patients

https://www.ncbi.nlm...pubmed/20712254
Sexual dysfunctions may be main cause of social disability. The knowledge of the rates of occurrence of sexual dysfunctions in the general population and the primary risk factors for these conditions is very important to assist in assessing the risk and planning treatment. Sexual dysfunctions are highly prevalent in our society worldwide, and that the occurrence of sexual dysfunctions increases directly with age for both men and women. Specific medical conditions and health behaviors represent major risk factors for sexual disorders. Trazodone is sedative antidepressant drug, which is effective, safe, fast acting, with a few side effects, with proved efficiency in the treatment of sexual dysfunction.

https://www.ncbi.nlm...pubmed/15816789
Evidence for the efficacy of trazodone in treating insomnia is very limited; most studies are small, conducted in populations of depressed patients, raise issues of design, and often lack objective efficacy measures. Side effects associated with trazodone are not inconsequential, with a high incidence of discontinuation due to side effects, such as sedation, dizziness, and psychomotor impairment, which raise particular concern regarding its use in the elderly. There is also some evidence of tolerance related to use of trazodone.

https://www.ncbi.nlm...pubmed/15291651
It is concluded that there are very few data to suggest that trazodone improves sleep in patients without mood disorder, though it does increase total sleep in patients with major depressive disorder. There are virtually no dose-response data for trazodone vis-à-vis sleep and, similarly, no available data on tolerance to its possible hypnotic effects. Areas of concern with its use include reports of significant dropout rates and induction of arrhythmias, primarily in patients with histories of cardiac disease, as well as the development of priapism (a potentially painful medical condition in which the erect penis does not return to its flaccid state, despite the absence of both physical and psychological stimulation, within four hours).
.
https://www.ncbi.nlm...pubmed/11518472
Trazodone appears effective for the treatment of insomnia and nightmares associated with chronic PTSD. However, controlled trials are needed before any definite conclusions can be drawn. The higher than expected occurrence of priapism warrants clinicians asking directly about this side effect.

https://www.ncbi.nlm.../pubmed/9315494
In a group of patients, that was not selected on the basis of the etiology of the erectile dysfunction, nor selected on the duration of the complaint, the efficacy of trazodone 150 mg/d, could not be shown.

https://www.ncbi.nlm.../pubmed/8057411
The effects of trazodone on penile erection may be due to a peripheral alpha adrenoceptor antagonism and central unknown mechanism. We conclude that trazodone may prove an effective treatment for impotent patients.

https://www.ncbi.nlm.../pubmed/3284752
Although unwanted effects were generally mild, the incidence of dizziness was greater in those patients receiving trazodone. Caution is advised, however, when prescribing either drug to patients with transient cerebral ischaemic attacks or those with coronary artery disease receiving medication.

http://www.lb7.uscou...IED/10-1191.pdf
Trazodone may cause side effects. Tell your doctor if any of these symptoms are severe or
do not go away:
headache or heaviness in head
nausea
vomiting
bad taste in mouth
stomach pain
diarrhea
constipation
changes in appetite or weight
weakness or tiredness
nervousness
decreased ability to concentrate or remember things
confusion
nightmares
muscle pain
dry mouth
sweating
blurred vision
tired, red, or itchy
Some side effects can be serious. If you experience any of the following symptoms or those
listed in the IMPORTANT WARNING section, call your doctor immediately:
chest pain
fast, pounding, or irregular heartbeat
shortness of breath
fever, sore throat, chills, or other signs of infection
hives
skin rash
itching
difficulty breathing or swallowing
swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs
hoarseness
decreased coordination
uncontrollable shaking of a part of the body
numbness, burning, or tingling in the arms, legs, hands, or feet
dizziness or lightheadedness
fainting
painful erection that lasts longer than normal
Trazodone may cause painful, long lasting erections in males. In some cases emergency
and/or surgical treatment has been required and, in some of these cases, permanent

https://www.drugs.co...de-effects.html
In Summary

Commonly reported side effects of trazodone include: blurred vision, dizziness, drowsiness, nausea, vomiting, headache, and xerostomia. Other side effects include: syncope, edema, diarrhea, ataxia, insomnia, sedation, confusion, tachycardia, and hypotension.

More common:
⦁ Blurred vision
⦁ confusion
⦁ dizziness
⦁ dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
⦁ lightheadedness
⦁ sweating
⦁ unusual tiredness or weakness
Less common:
⦁ Burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
⦁ confusion about identity, place, and time
⦁ decreased concentration
⦁ fainting
⦁ general feeling of discomfort or illness
⦁ headache
⦁ lack of coordination
⦁ muscle tremors
⦁ nervousness
⦁ pounding in the ears
⦁ shortness of breath
⦁ slow or fast heartbeat
⦁ swelling
Rare:
⦁ Skin rash
⦁ unusual excitement
Severity: Minor

Some trazodone side effects may not need any medical attention. As your body gets used to the medicine these side effects may disappear. Your health care professional may be able to help you prevent or reduce these side effects, but do check with them if any of the following side effects continue, or if you are concerned about them:

More common:
⦁ Dry mouth (usually mild)
⦁ muscle or bone pain
⦁ trouble sleeping
⦁ trouble with remembering
⦁ unpleasant taste
Less common:
⦁ Constipation
⦁ continuing ringing or buzzing or other unexplained noise in the ears
⦁ diarrhea
⦁ hearing loss
⦁ muscle aches or pains
⦁ weight loss

For Healthcare Professionals
Applies to trazodone: compounding powder, oral tablet, oral tablet extended release

General
The most commonly reported side effects were dry mouth, nausea, vomiting, drowsiness, dizziness/light-headedness, headache, and nervousness.[Ref]

Cardiovascular
Common (1% to 10%): Hypertension, hypotension, syncope, tachycardia, palpitations
Frequency not reported: Sinus bradycardia, chest pain, ventricular couplets
Postmarketing reports: Cardiospasm, cerebrovascular accident, congestive heart failure, vasodilation, conduction block, orthostatic hypotension, atrial fibrillation, myocardial infarction, cardiac arrest, arrhythmia, ventricular ectopic activity, prolonged QT interval, torsade de pointes, ventricular tachycardia[Ref]

Psychiatric
Common (1% to 10%): Anger/hostility, excitement, insomnia, nightmares/vivid dreams
Frequency not reported: Hallucinations/delusions, mania/hypomania, impaired speech, suicidal ideation, disorientation, aggressive reaction, withdrawal syndrome
Postmarketing reports: Abnormal dreams, agitation, anxiety, paranoid reaction, psychosis[Ref]

Nervous system
Very common (10% or more): Drowsiness (up to 40.8%), dizziness/light-headedness (up to 28%), headache (up to 19.8%), nervousness (up to 14.8%)
Common (1% to 10%): Confusion, decreased concentration, disorientation, impaired memory, incoordination, paresthesia, tremors
Frequency not reported: Akathisia, muscle twitches, numbness, serotonin syndrome, convulsion, neuroleptic malignant syndrome, vertigo, restlessness, decreased alertness, cognitive/motor impairment
Postmarketing reports: Aphasia, ataxia, extrapyramidal symptoms, grand mal seizures, stupor, tardive dyskinesia, myoclonus,[Ref]

Genitourinary
Common (1% to 10%): Decreased libido, delayed urine flow, early menses
Frequency not reported: Hematuria, impotence, increased libido, increased urinary frequency, missed periods, retrograde ejaculation
Postmarketing reports: Breast enlargement or engorgement, clitorism, lactation, priapism, urinary incontinence, urinary retention[Ref]

Hematologic
Frequency not reported: Anemia, hemolytic anemia, granulocytosis, thrombocytopenia, eosinophilia, leucopenia
Postmarketing reports: Leukocytosis, methemoglobinemia[Ref]

Metabolic
Common (1% to 10%): Decreased appetite, weigh gain/loss
Frequency not reported: Increased appetite, anorexia, hyponatremia[Ref]

Ocular
Very common (10% or more): Blurred vision (up to 14.7%)
Common (1% to 10%): Red/tired/itching eyes
Frequency not reported: Angle-closure glaucoma
Postmarketing reports: Diplopia[Ref]

Dermatologic
Common (1% to 10%): Sweating/clamminess
Frequency not reported: Hyperhidrosis
Postmarketing reports: Alopecia, leuconychia, pruritus, psoriasis, rash, urticaria[Ref]

Endocrine
Postmarketing reports: Hirsutism, inappropriate ADH syndrome[Ref]

Gastrointestinal
Very common (10% or more): Dry mouth (up to 33.8%), nausea/vomiting (up to 12.7%)
Common (1% to 10%): Constipation, abdominal/gastric disorder, bad taste, diarrhea
Frequency not reported: Flatulence, increased salivation, dyspepsia, stomach pain, gastroenteritis, paralytic ileus
Postmarketing reports: Increased amylase[Ref]

Hepatic
Postmarketing reports: Cholestasis, hyperbilirubinemia, jaundice, liver enzyme alterations[Ref]

Hypersensitivity
Frequency not reported: Allergic reactions[Ref]

Musculoskeletal
Common (1% to 10%): Musculoskeletal aches/pains
Frequency not reported: Limb pain, back pain, myalgia, arthralgia[Ref]

Other
Very common (10% or more): Fatigue (up to 11.3%)
Common (1% to 10%): Edema, malaise, tinnitus
Frequency not reported: Chills, fever
Postmarketing reports: Unexplained death, weakness[Ref]

Respiratory
Common (1% to 10%): Shortness of breath, nasal/sinus congestion
Frequency not reported: Dyspnea
Postmarketing reports: Apnea

References
1. "Product Information. Desyrel (trazodone)." Bristol-Myers Squibb, Princeton, NJ.
2. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
It is possible that some side effects of trazodone may not have been reported. These can be reported to the FDA. Always consult a healthcare professional for medical advice.

http://link.springer...45?view=classic
http://www.ncbi.nlm..../pubmed/3624211
http://www.ncbi.nlm..../pubmed/8056996
Three cases developed withdrawal symptoms of trazodone despite gradual discontinuation of therapeutic doses of the drug. This report suggests that effects of trazodone and its metabolite m-chlorophenylpiperazine on the serotonergic system, which may result in noradrenergic rebound after discontinuation, and short half-lives of these compounds are involved in the development of these symptoms. From a clinical point of view, we suggest that trazodone should be tapered off at a very slow rate.




 


#18 fishinghat

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Posted 08 August 2016 - 10:49 AM

Not bad. except for the heart issues. 


#19 gail

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Posted 09 August 2016 - 03:12 PM

FN, can you explain in real plain language what SARI means?

Serotonin antagonist reuptake inhibitor? What?

Any other ad from that class? Thank you!

#20 fishinghat

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Posted 09 August 2016 - 07:28 PM

Serotonin antagonist and reuptake inhibitors (SARIs) are a class of drugs used mainly as antidepressants, but also as anxiolytics and hypnotics. They act by antagonizing serotonin receptors such as 5-HT2A and inhibiting the reuptake of serotonin, norepinephrine, and/or dopamine. Additionally, most also antagonize α1-adrenergic receptors.

Translation - Serotonin antagonist and reuptake inhibitors (SARIs) are a class of drugs used mainly as antidepressants, but also to treat anxiety and induce sleep. They act by stimulating serotonin receptors and inhibiting the reuse of serotonin, norepinephrine, and/or dopamine.

List of SARIs
Etoperidone (Axiomin, Etonin) (Europe only)
Lorpiprazole (Normarex) (Experimental)
Lubazodone (YM-992, YM-35995) Was experimental but failed drug tests due to side effects, withdrawn)
Mepiprazole (Psigodal) (Available by prescription)
Nefazodone (Serzone, Nefadar) (Discontinued in 2003 due to excessive liver damage and death)
Trazodone (Desyrel)


#21 gail

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Posted 16 December 2016 - 02:53 PM

Part 1
Benzo Notes
Usage datahttps://www.ncbi.nlm...pubmed/25517224
In 2008, approximately 5.2% of US adults aged 18 to 80 years used benzodiazepines. The percentage who used benzodiazepines increased with age from 2.6% (18-35 years) to 5.4% (36-50 years) to 7.4% (51-64 years) to 8.7% (65-80 years). Benzodiazepine use was nearly twice as prevalent in women as men. The proportion of benzodiazepine use that was long term (> 120 days) increased with age from 14.7% (18-35 years) to 31.4% (65-80 years), while the proportion that received a benzodiazepine prescription from a psychiatrist decreased with age from 15.0% (18-35 years) to 5.7% (65-80 years). In all age groups, roughly one-quarter of individuals receiving benzodiazepine involved long-acting benzodiazepine use.https://www.ncbi.nlm...pubmed/25613443
Estimates of the number of benzodiazepine-dependent persons in Germany range from 128 000 to 1.6 million.
Use benzodiazepines for only 4 weeks or less to minimize risk of addiction.https://www.ncbi.nlm...les/PMC4318457/
Dependency problems with benzodiazepines have been a familiar phenomenon for
about 40 years for this reason, pharmaceutical companies and the German Federal Institute for Drugs and Medical Devices (BfArM) have restricted the standard period of use to 2–4 weeks since the 1980s. According to the current law on prescriptions of medical drugs, hypnotics and tranquillizers can be prescribed for period can be extended if sound reasons exist.http://www.smw.ch/co...smw-2011-13277/
Within weeks of chronic use, tolerance to the pharmacological effects can develop and withdrawal becomes apparent once the drug is no longer available, which are both conditions indicative of benzodiazepine dependence.
Withdrawal symptoms are observed following discontinuation or abrupt reduction of BDZs dosage, even after a relatively short treatment period (three to four weeks). Such physiological symptoms are the main signs of physical dependence. The most frequent are insomnia, gastric problems, tremors, agitation, fearfulness and muscle spasms. Less frequently observed are irritability, sweating, depersonalisation, hypersensitivity to stimuli, depression, suicidal behaviour, psychosis, seizures and delirium tremens. Over-rapid withdrawal from BDZs also increases the severity of the symptoms. Slow and gradual reduction of dosage customised to the individual accompanied by psychological support are the most effective way of managing withdrawal. Complete withdrawal can require four weeks to several years.
National Health Committee. Guidelines for assessing and treating anxiety disorders. Wellington (New Zealand): National Health Committee; 1998.
Recommend restricting their use to no more than 3–4 weekshttps://www.ncbi.nlm...pubmed/17535048
Recommend restricting their use to no more than 3–4 weekshttps://www.ncbi.nlm...t1-ndt-11-1885/
Review of research listing proper use of benzos.
In general, compounds with higher potency and a shorter half-life are associated with a greater likelihood of developing withdrawal syndromes and dependence.
A significant risk of dependence is recognized in some patients receiving treatment for longer than one month, and health professionals should be aware of this when considering the relative treatment benefits and risks.https://www.ncbi.nlm...pubmed/16639148
Benzodiazepine dependence could be prevented by adherence to recommendations for short-term prescribing (2-4 weeks only when possible).
Clinical Guideline 22 (amended). Anxiety: management of anxiety (panic disorder, with or without agoraphobia, and generalised anxiety disorder) in adults in primary, secondary and community care" (PDF). National Institute for Health and Clinical Excellence. 2007. pp. 23–25. Retrieved 2009-08-08.
According to National Institute for Health and Clinical Excellence (NICE), benzodiazepines can be used in the immediate management of GAD, if necessary. However, they should not usually be given for longer than 2–4 weeks. The only medications NICE recommends for the longer term management of GAD are antidepressants.
McIntosh A, Cohen A, Turnbull N, et al. (2004). "Clinical guidelines and evidence review for panic disorder and generalised anxiety disorder" (PDF). National Collaborating Centre for Primary Care. Retrieved 2009-06-16.
Barbui C, Cipriani A (2009). "Proposal for the inclusion in the WHO Model List of Essential Medicines of a selective serotonin-reuptake inhibitor for Generalised Anxiety Disorder" (PDF). WHO Collaborating Centre for Research and Training in Mental Health. Retrieved 2009-06-23.
Based on the findings of placebo-controlled studies, they do not recommend use of benzodiazepines beyond two to four weeks, as tolerance and physical dependence develop rapidly, with withdrawal symptoms including rebound anxiety occurring after six weeks or more of use.https://www.ncbi.nlm...pubmed/25613443
Benzodiazepines are generally highly effective when first given, but they should generally be given only for strict indications and for a limited time. If these drugs still need to be given beyond the short term, timely referral to a specialist is indicated, and possibly also contact with the addiction aid system.http://www.rcpsych.a...diazepines.aspx
Royal College of Psychiatrists
How long should I take a benzodiazepine for?
Up to 4 weeks - no longer. This should really be just to give other (often psychological) treatments a chance to work.Limited effectiveness/Long-term use and Addiction
http://www.ncbi.nlm....pubmed/16933543
The Canadian Psychiatric Association (CPA) recommends benzodiazepines alprazolam, bromazepam, lorazepam, and diazepam only as a second-line choice, if the treatment with two different antidepressants was unsuccessful. Although they are second-line agents, benzodiazepines can be used for a limited time to relieve severe anxiety and agitation. CPA guidelines note that after 4–6 weeks the effect of benzodiazepines may decrease to the level of placebo, and that benzodiazepines are less effective than antidepressants in alleviating ruminative worry, the core symptom of GAD. However, in some cases, a prolonged treatment with benzodiazepines as the add-on to an antidepressant may be justified.https://www.ncbi.nlm...pubmed/16639148
Tolerance to anti-anxiety effects develops more slowly with little evidence of continued effectiveness beyond four to six months of continued use.
Curran, H. V.; Collins, R.; Fletcher, S.; Kee, S. C. Y.; Woods, B.; Iliffe, S. (2003-10-01). "Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life". Psychological Medicine 33 (7): 1223–1237. doi:10.1017/s0033291703008213. ISSN 0033-2917. PMID 14580077.
"Holbrook AM. %282004%29. Treating insomnia. - PubMed - NCBI". www.ncbi.nlm.nih.gov. PMID 25282004. Retrieved 2015-12-10.
Poyares, Dalva; Guilleminault, Christian; Ohayon, Maurice M.; Tufik, Sergio (2004-06-01). "Chronic benzodiazepine usage and withdrawal in insomnia patients". Journal of Psychiatric Research 38 (3): 327–334. doi:10.1016/j.jpsychires.2003.10.003. ISSN 0022-3956. PMID 15003439.
Friedman MJ (1998). "Pharmacotherapy for posttraumatic stress disorder: a status report". Clinical Neurosciences Supplement 52: S115–S121.
Heather N, Bowie A, Ashton H, McAvoy B, Spencer I, Brodie J, Giddings D (2004). "Randomised controlled trial of two brief interventions against long-term benzodiazepine use: outcome of intervention". Addiction Research and Theory 12 (2): 141–154. doi:10.1080/1606635310001634528.
Bandelow, Borwin; Zohar, Joseph; Hollander, Eric; Kasper, Siegfried; Möller, Hans-Jürgen; Zohar, Joseph; Hollander, Eric; Kasper, Siegfried (2008-01-01). "World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders HYPERLINK "http://www.ncbi.nlm....ubmed/18949648"HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/18949648" The World Journal of Biological Psychiatry 9 (4): 248–312. doi:10.1080/15622970802465807. ISSN 1562-2975. PMID 18949648.
Ashton, Heather (2005-05-01). "The diagnosis and management of benzodiazepine dependence". Current Opinion in Psychiatry 18 (3): 249–255. doi:10.1097/01.yco.0000165594.60434.84. ISSN 0951-7367. PMID 16639148.
Morin, Charles M.; Bélanger, Lynda; Bastien, Célyne; Vallières, Annie (2005-01-01). "Long-term outcome after discontinuation of benzodiazepines for insomnia: a survival analysis of relapse". Behaviour Research and Therapy 43 (1): 1–14. doi:10.1016/j.brat.2003.12.002. ISSN 0005-7967. PMID 15531349.
Michelini S, Cassano GB, Frare F, et al. (2016). "Long-term use of benzodiazepines: tolerance, dependence and clinical problems in anxiety and mood disorders.". Pharmacopsychiatry 29: 127–134http://www.ncbi.nlm....pubmed/24434093
Several studies (listed above) have confirmed that long-term benzodiazepines are not significantly different from placebo for sleep or anxiety. This may explain why patients commonly increase doses over time and many eventually take more than one type of benzodiazepine after the first loses effectiveness.https://www.ncbi.nlm...pubmed/15078112
Discontinuation of benzodiazepines or abrupt reduction of the dose, even after a relatively short course of treatment (three to four weeks), may result in two groups of symptoms—rebound and withdrawal. Rebound symptoms are the return of the symptoms for which the patient was treated but worse than before. Withdrawal symptoms are the new symptoms that occur when the benzodiazepine is stopped. They are the main sign of physical dependence.https://www.ncbi.nlm...pubmed/26164054
While benzodizapines may have short-term benefits for anxiety, sleep and agitation in some patients, long-term (i.e., greater than 2–4 weeks) use can result in a worsening of the very symptoms the medications are meant to treat.https://www.ncbi.nlm...pubmed/26545257
The relative proportion of long-term BZD users in adult BZD users ranged from 6% to 76% (mean 24%) The estimates were higher in studies only on the elderly (47%). Long-term use involved typically steady treatment with low BZD doses. However, in elderly patients long-term BZD use and exceeding recommended doses was relatively common. Several characteristics associated with long-term use were found.https://www.ncbi.nlm.../pubmed/2222129
Patients who were able to remain free of benzodiazepines for at least 5 weeks obtained lower levels of anxiety than before benzodiazepine discontinuation.


Back up, interesting material!



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