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).

 

 

Benzodiazepines Underestimated in Drug Deaths

 

Benzodiazepines are present in a high proportion of Scottish drug related deaths, but judged to have contributed to less than half of the deaths. Further investigation suggests that benzodiazepines may be contributing to more deaths than currently reported.
Drugs found in drug deaths in Scotland 2007 - 2013

Selected drugs found in drug deaths in Scotland 2007 – 201

Figures for drug related deaths from the National records of Scotland (NRS) show that in 2013 benzodiazepines were found in more drug-related deaths than all other reported drugs. Of a total 526 deaths, benzodiazepines were found in 377 (71.6%) and judged to have contributed to 149 (28.3%) of those deaths.

In 2008, it became a requirement that all the drugs found in drug-related deaths be reported, (before 2008, only drugs which were thought to be implicated needed to be reported).

Since 2009, pathologists have also been asked to report which drugs contribute to each death as well as all the drugs found in the bodies. From 2008 to 2013, deaths where benzodiazepines were found outnumbered deaths where they were implicated by > 2:1.

Benzodiazepines found vs. benzodiazepines implicated in Scotland, 2007 - 2013d

Fig 2.  Increase in benzodiazepines reported in drug deaths after 2007 & divergence between those found & those implicated, 2008 – 2013

It is unclear whether the other UK countries differentiate between the drugs found and those implicated in the same way as Scotland.  Figures for drug deaths in England, Wales and Northern Ireland do not present separate data for the two categories. Benzodiazepines reported in drug deaths in England and Wales vary; 7% (2012) from the Office for National Statistics and 26.6%; 37.7% from the National Programme on Substance Abuse Deaths (NPSAD) for England and Wales respectively (2012) and 38.2%(2013) in Northern Ireland from the Northern Ireland Statistics and Research Agency (NISRA).

BENZODIAZEPINES FOUND WITH OTHER DEPRESSANTS

“Benzodiazepines potentiate the effects of other central nervous system depressants taken concomitantly.” British National Formulary

Benzodiazepines can increase the risk of fatal overdose if taken in combination with other depressant drugs. Methadone, heroin/morphine and alcohol are the other depressant drugs reported to the NRS.

The ACMD report: Reducing Drug Related Deaths (2000) stressed the high proportion of drug related deaths in which benzodiazepines taken in combination with other depressants were implicated and in 1999 recommended that all benzodiazepines should be rescheduled to schedule 3.

It has been suggested that benzodiazepines are merely a feature of drug-related deaths, ie. they are present in fatal overdoses, but have not contributed to them. The findings of a case-controlled study commissioned by the National Treatment Agency (NTA) in 2007 shows this is not the case. The study found that benzodiazepines increase the risk of fatal overdose when taken with opioids by 2.5 times and with methadone by nearly 10 times.

There is also a wide variation in individual response to benzodiazepines. For instance, there is a 30-fold variation in plasma concentration between individuals when given the same dose of diazepam.[1] This suggests that there may be no safe dose when benzodiazepines are mixed with other depressants.

FINDINGS FROM INDIVIDUAL DEATHS
nospie2013
Fig 3.Deaths where benzodiazepines found combined with other depressants, with non-depressants or not present (2013).

The details of individual deaths in Scotland, the drugs found and whether they were implicated are available in the GROS Vital Events Tables (table 6.12). When the information on each drug related death in 2013 was examined, it showed benzodiazepines had been taken in combination with other depressants in more deaths than they were implicated in.

Figure 3 shows that of the 526 drug-related deaths in 2013, benzodiazepines were found with other depressants or alone in 346 deaths (70.2%), with non-depressant drugs in 14 (2.3%) deaths and no benzodiazepines were found in 161 (27.5%) deaths.

CONCLUSION

Since 2008 in Scotland, Reporting all the drugs found present in the body reveals that benzodiazepines are present in more deaths than previously reported. It also shows that in a large proportion of deaths where benzodiazepines have been taken in combination with other depressant drugs, pathologists have excluded them as a contributory factor.

In 2013, Benzodiazepines were found in 377 (71%) of Scottish drug related deaths and implicated in 149(28.3%) of of those deaths. The above suggests that in the 228 (43.3%) deaths where benzodiazepines had been taken with other depressants (but not implicated), they could have contributed them. If this is the case, rather than 28.3% of deaths, benzodiazepines could have contributed in up to 65.7% of the deaths.

If the true contribution of benzodiazepines to drug-related deaths is being underestimated, it would be useful to know on what criteria pathologists are basing their findings when benzodiazepines are found in combination with other depressants in a drug-related death.

 

Reference

1.  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.