Alzheimer’s – new risk for patients trapped on prescriptions

Patients being prescribed benzodiazepines long-term risk dependence and disabling side-effects, but the help they need to withdraw from the drugs and and recover is not available to them - Now, the findings of a new study show they could also be at increased risk of developing Alzheimer's.

Dementia Risk
The  study, published in the in the BMJ,  ‘Benzodiazepine use and risk of Alzheimer’s disease’, found no increase in the  risk of Alzheimer’s with benzodiazepine use of < 3 months, but found an increased risk of up to 51% with > 3 months use and 84% with use >6 months. The risk was also found to be greater with the use of long acting benzodiazepines such as diazepam.
Additionally, a study in 2011 found that the risk of developing dementia decreased as the duration of benzodiazepine discontinuation increased, so the need for people to be able to stop taking them is clear.
Lasting Problems
Concern that prolonged benzodiazepine use could cause dependence and cognitive impairment  was raised with the Medical Research Council (MRC) in 1981. Measures to tackle the problem were agreed between the relevant parties, but the initiative was abandoned and all documents closed in the National Archives see independent on Sunday: Drugs linked to brain damage 30 years ago

The Medicines and Healthcare Regulatory Agency (MHRA) now recognise that benzodiazepines can cause lasting memory impairment.

No Help for Patients Prescribed Benzodiazepines
An estimated  0.5 – 1.5 million patients  in the UK are being prescribed benzodiazepines long-term.  Services to enable patients to withdraw from benzodiazepines and recover are not provided nationally so they are are obliged to continue taking the drugs – often for decades.

A survey of 149 Primary Care Trusts in 2012 found that only 6 of these provided specialist services for patients dependent on prescribed benzodiazepines. The only help  has been left to a few local agencies, charities and voluntary organisations.

Problems caused by benzodiazepines  prescribed beyond the guidelines of 2-4 weeks are rarely documented or reported.  It has therefore been possible to avoid providing services for patients in this position as, unlike those misusing benzodiazepines,  they are statistically invisible.

Public Health
The authors of latest study state their findings are of major importance to public health and it has been brought to the attention of Public Health Minister Jane Ellison, by the All Party Parliamentary Group on Involuntary Tranquilliser Addiction (APPGITA).

It is shameful that so many people are denied the chance of recovery from long-term benzodiazepine use and the associated risks, when the reason is that the drugs have been prescribed to them.

 

 

 

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Coroners call to curb benzodiazepines

In 2013, benzodiazepines contributed to 58%* of drug deaths in the State of Victoria and 71% in Scotland. Diazepam
 is the benzodiazepine found in most of the deaths. A recommendation to increase control of all benzodiazepines, 
including diazepam from Victoria's State Coroner has been refused. Now, the NSW Deputy State Coroner 
has called for it again.

In June, the Deputy State Coroner of New South Wales recommended [1]that all benzodiazepines, particularly diazepam, should be rescheduled as they  contributed to the highest number of overdose deaths in the State of Victoria in 2013.  This is the second call from an Australian coroner to reschedule all benzodiazepines – the first was rejected by the Australian Government’s Therapeutic Goods Administration (TGA) in 2012.

Last year, The State Coroner for Victoria, Judge Ian Gray, took the unusual step of submitting evidence to the Australian Department of Health Therapeutic Goods Administration (TGA) in support of rescheduling all benzodiazepines, after the original  recommendation from Coroner Audrey Jamieson was refused.

“Victoria’s coroners do not ordinarily engage in public submissions processes, as our findings into individual deaths are the primary vehicle through which we highlight public health issues and make recommendations aimed at preventing further deaths. However given the potential for the rescheduling proposal to reduce significantly drug related harms and deaths in the State of Victoria, I have determined it is appropriate for me to respond to your invitation.” Judge Ian Gray, submission to TGA,16.01.13

After wider consultation in 2013 the TGA rejected the recommendation, but the benzodiazepine alprazolam (Xanax) was rescheduled. Alprazolam (a short-acting BZ) was the sixth most frequent individual contributing drug  in drug deaths in Victoria in 2012, whereas diazepam (a long- acting BZ) was the first most frequent.

“…I fail to see why all benzodiazepines were not rescheduled. This inquest has clearly demonstrated that Alprazolam is not the only benzodiazepines of concern. The Victorian Drug Overdose Deaths Register demonstrates that Diazepam, rather than Alprazolam, is of greatest concern in Victoria.” NSW Deputy Coroner Carmel Forbes, June 2014[1]

The TGA decision not to reschedule all benzodiazepines was mainly on the grounds of the negative impact on business. In their 2012 response, the TGA also cited:

  • the cost to Australian taxpayers
  • the  regulatory impact upon the pharmaceutical industry
  • that benzodiazepines continue to be supplied as prescription-only medicines in countries such as the United Kingdom and the USA.

The Royal Australian College of Physicians (RACP) submitted evidence against rescheduling all benzodiazepines, citing the administrative cost and extra work for medical staff and suggested there was little evidence that rescheduling was effective. The Australian Medical Association (AMA) also supported this view:

“The AMA has successfully headed off moves to make all benzodiazepines controlled drugs, which would have added significantly to the administrative burden on GPs and hospital staff.” AMA,12.07.13

IN THE UK

In 1999, the UK  Advisory Council on Misuse of Drugs (ACMD) also recommended rescheduling all benzodiazepines (diazepam was present in 45.3% of Scots drug deaths in 1998).  This was  refused, when in 2004, after inviting submissions regarding rescheduling,  the ACMD overruled their own advice on the grounds that all benzodiazepines were not the same and there was little evidence that rescheduling was effective. This, despite evidence given to them at the time by expert Professor Laurence Gruer:

Temazepam & Diazepam 1996 - 2013

Temazepam was rescheduled in 1996

The rescheduling itself did appear to lead to the drop in the number of overdose deaths that were attributable usually to a combination of heroin and temazepam; but was replaced by an increase in deaths where diazepam was the main benzodiazepine in combination with heroin. There was certainly an impact of the rescheduling of temazepam.” Professor Laurence Gruer, ACMD Minutes 01.04.04

Diazepam was present in 56% of Scottish drug deaths in 2002 (figures available at the time) and is the only commonly misused benzodiazepine in the UK still in schedule 4 – most of the others are schedule 3.

DIAZEPAM

The British National Formulary (BNF) and the ACMD (in their report Reducing Drug Related Deaths) warn of an increased risk of fatal respiratory depression when any  benzodiazepine is taken in combination with other depressant drugs.

Diazepam is the  benzodiazepine  most often found in drug deaths in the State of Victoria and  the UK.  It is a long-acting benzodiazepine with a half-life up to 100 hours (including active metabolites).

In the UK, diazepam is used for long-term maintenance prescribing  and withdrawal treatment because of its long half-life, but this makes it more dangerous if it is used with other depressants  as it can remain active for long periods.  A user may not be aware that diazepam taken hours before  can  have an additive effect when other depressants are taken later.

There  is also a 30-fold variation in diazepam metabolism between individuals [1] so its effects can be unpredictable, particularly if  the person does not take it regularly.  The unpredictable nature of diazepam when combined with another depressant is demonstrated in this case report of unexpected and prolonged respiratory depression after benzodiazepines  were combined  with alcohol.

CONCLUSION

For over 10 years, benzodiazepines have been a major contributor to drug-related deaths in the UK and  Australia. The United Nations Office on Drugs and Crime (UNODC) state in their World Drug Report (2012), that benzodiazepines are highly represented in drug deaths worldwide, second only to opium.  Several attempts to reschedule diazepam have failed, suggesting that it is protected from tighter controls.

In the UK, there are an estimated 0.5 to 1.5million patients maintained on long-term benzodiazepine prescriptions, (mostly  diazepam). This population are invisible, because problems related to prescribed benzodiazepines are so rarely recorded,  they are not seen in  relevant statistics. Would one effect of  rescheduling diazepam  make these patients  visible?

*  Drugs contributing to drug-related deaths in the State of Victoria from January to June 2013 January to June 2013 only.

  1. State Coroner’s Court of new South Wales, Inquest into the deaths of Christopher Salib, Nathan Attard and Shamsad Akhtar , 27 June 2014, State Coroners Court, Glebe, Deputy State Coroner C. Forbes: Findings
    Alternative link to PDF
  2. Factors Influencing the Metabolism of Diazepam, Leif Bertilsson, Thomas A. Baillie, and Jesus Reviriego, Department of Clinincal Pharmacology at the Karolinska Institute, Huddinge Hospital, S-141 86, Huddinge, Sweden. Pharmac. Ther Vol. 45. pp. 85-91. 1990.
  3. United Nations Office on Drugs and Crime (UNODC), World Drug Report 2012, ( p.82).