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Sue Bibby, UK
Is There Really "No Proven Link"?
John Hutton MP on behalf of the Department of Health in a parliamentary debate on benzodiazepines, states that "there is no proven link between benzodiazepine use and damage to developing foetuses."
Benzodiazepines are foetal neurotoxins ( ) and evidence that they can interfere with foetal development is growing. Major malformations such as cleft palate remain an area of contention ( ) but other adverse effects in the neonate have been known for decades ( ). The possibility that these drugs can cause long term neurological deficits, sometimes not manifested until puberty has been recently confirmed in animal studies ( ).
As 30 – 40% of all pregnant women will be given an antianxiety drug (usually a BDZ) at some time during pregnancy (1) it is vital that all women of childbearing potential are warned of any dangers to their children from BDZ exposure. Presently they are not.
Recent patient information leaflets from the manufacturers warn about the use of BDZs in pregnancy, for example: "benzodiazepines including lorazepam, may cause damage to the foetus," (patient information leaflet from Wyeth re: lorazepam). They also warn of many adverse effects in the neonate.
Adverse effects at birth
The brain undergoes massive developmental activity and fourfold increase in bulk in the last two months of gestation and the first months after birth. This is a vulnerable time.
Research showing that BDZs pass through the placenta causing effects such as "floppy infant syndrome", respiratory depression, hypothermia, feeding difficulties, abnormal heart rate, abnormal EEG (2) and withdrawal syndrome has been in the public domain since the early seventies.
Paediatricians, from Sweden and England voiced their concern in letters to the Lancet in 1977 (3,4).
Many research papers were published over the years warning of the dangers of BDZs to newborn babies but the public was not informed.
BDZs can accumulate in the newborn infant and may remain active, (sometimes for months). Symptoms ranging from: "mild sedation, hypotonia, and reluctance to suck," to "apnoeic spells, cyanosis, and impaired metabolic responses to cold stress" have been reported "for periods from hours to months after birth." (1)
The high risk to the neonate from apnoeic spells and the accumulation of BDZs in infants unable to metabolise them, together with the danger of impaired mental development was stated. [Rowlatt 1978] (5)
Warnings of the above have been available from the manufacturers for over ten years and newborn babies so affected may need treatment in special care baby units, (sometimes for months).
Flumazenil, a BDZ antagonist which reverses the effects of BDZs (licensed for use in surgical procedures and overdose), has been used at birth in emergencies, (not under licence) successfully reversing most of the above adverse effects in neonates. (6,7,8,9)
Extensive animal, and more recently human, research has shown that BDZs affect neurodevelopment in animals and humans, some of which is not manifest until later in development.
Again, flumazenil was found, when administered to pregnant rats concomitantly with diazepam (2.5 mg/kg) to reverse the effects of diazepam in the hypothalamus of the adult offspring. (10)
Animal research is now reflected in human research, for example:
The enzyme Na,K-ATPase holds a key position in the biochemical development of the brain. Its activity is changed in mice after exposure to diazepam [Weber and Schmahl, 1983] and it was also inhibited in vitro in human foetal brain tissue. [Das et al.,1979] (5)
The evidence is increasing that behavioural disorders may be linked to prenatal BDZ exposure.
Diazepam (Valium) is implicated in a wide variety of regulatory dysfunctions in the newborn and may exert long range deleterious influences, as some forms of learning disabilities or attention deficit disorders. (11)
Evidence that prenatal exposure to drugs such as diazepam (Valium) has profound effects in the mammalian brain on a range of adaptive responses of a kind that are often not expressed until adolescence (a stage when many clinical behavioural disorders appear) was published in 1995. (12)
Recent results from prospective Swedish studies revealed for instance:
"Infants born to mothers exposed to the long term regular use of BDZ in therapeutic doses run the risk of an overall deviation in neurodevelopment during their first 18 months of life, seen most prominently as a delay in voluntary grasping. This finding was not thought to be explained by disturbed social interaction between mother and infant alone. A teratogenic effect by BDZ on the developing brain is supported by the presence of craniofacial anomalies found in several children. Many studies show that infants with transient neurologic deviations in the first year of life are a high risk group for attention deficit disorder in early school years. A follow up of our series is urgent and in progress for evaluating the long term hazards of BDZ." (13)
And: "Mothers using BDZ alone continuously throughout pregnancy do not deviate much from others in general in social terms, and that their newborn infants tend to be wasted, have a significantly increased frequency of perinatal complications and a significantly deviating neuro-behaviour." (14)
Dr Patricia McElhatton, in her review 'The Effects of Benzodiazepine use during pregnancy and lactation' (1) states that "in approximately 550 children who were followed up for various times up to four years of age, there is no increase in either the malformation rate or adverse effects on neurobehavioural development and IQ although some of the data indicate that a small number of children were slower to develop normally by four years of age".
If important statements such as this represent empirical research, it is vital that references are supplied, if not why not?
It should be clear from the above evidence that the statement "no proven link" is inaccurate.
At present the public has not been warned of the danger of BDZs to the unborn child and prescribing to women of childbearing age continues.
Additionally, the recent trend to prescribe BDZs (outside of licence) to opiate and alcohol misusers guarantees a corresponding increase in the number of babies exposed to the above dangers. Many substance misusers are of childbearing age and the increasing illicit use of BDZs at very high dosage is a growing problem. (15)
The in utero damage potential of BDZs increases with dosage.
It has been left to "the clinical judgement" of prescribers as to whether they choose to warn the public or not.
Unless empirical data proving that BDZs do not damage the developing foetus and neonate exist, avoidable exposure to the above dangers remains the responsibility of this government.
Today, only women who are prescribed a BDZ that comes in a packet receive a warning. This is left to the discretion of the manufacturer.
We ask that immediate action be taken to inform the public so that all women of childbearing potential are warned and make an informed choice.
"It is a matter of common clinical experience to encounter an individual in a detoxification unit who appears reasonably happy about the prospect of living without opiates but is much more apprehensive about managing without benzodiazepines." (1) Nicholas Seivewright Barcelona 1991
Brazilian Street Children – S„o Paulo
Anecdotal accounts of drug abuse among street youths in Brazil are commonplace. Numerous media stories have reported the widespread use of inhalants (such as glue, gasoline, lighter fluid, bim – a mixture of ethyl alcohol, sugar and benzene), marijuana and cocaine, and Valium among street children in Rio de Janeiro (Brookes, 1991; Larmer, 1992). Also common is the use of coca paste and Rohypnol.
KEY ISSUES RELATING TO BENZODIAZEPINE
USE IN AUSTRALIA
ADCA's position on the use of benzodiazepines as outlined in the publication, Drug Matters (1997), is provided below. There are a number of key issues which ADCA would like to highlight in relation to misuse of benzodiazepines in Australia.
Illicit Use of Benzodiazepines
There is much current evidence that benzodiazepines are being used among intravenous drug users (IDUs) in an unsafe and uncontrolled manner for indications other than medical use. Surveys of IDUs show much higher levels of benzodiazepine use than in the general population. Between 33 – 75% of IDUs use benzodiazepines (Darke: 1994, Strang et al:1994).
Studies in Australia, the United States and the United Kingdom, indicate that a significant proportion of IDUs also use large quantities of benzodiazepines via injection (ACT Alcohol and Drug Service: 1997).
The reasons given by IDUs for taking benzodiazepines for non medical indications include: to increase the effect of heroin; to boost and prolong the intoxicating effect of methadone, particularly with the use of diazepam; to become high by combining benzodiazepines with large quantities of alcohol; because of easy access and availability, curiosity, to strengthen the sensation of wellbeing, to reduce anxiety and withdrawal symptoms and to overcome insomnia (ACT Alcohol and Drug Service: 1997).
Different benzodiazepines also have different abuse potential (Darke, Ross and Hall: 1995). The more rapid the increase in plasma level following ingestion, the greater the intoxicating effect and the more open to abuse the drug becomes. The speed of action of a particular benzodiazepine correlates with the popularity of the drug for abuse (ACT Alcohol and Drug Service: 1997). Flunitrazepam is a popular drug of use among IDUs.
The formulation of the drug being prescribed is also important in relation to the likelihood of the drug being injected (Strang et al: 1994). For example, gel-filled capsules are more likely to be injected than tablets and syrup preparations are least likely to be injected. Gel-filled capsules are associated with the greatest morbidity and mortality following injection (ACT Alcohol and Drug Service: 1997).
Intravenous use of benzodiazepines is associated with arterial and venous thrombosis which can cause serious morbidity including gangrenous limb loss or damage (ACT Alcohol and Drug Service: 1997).
Multiple Benzodiazepine/Polydrug Use
The use of other drugs of dependence in combination with benzodiazepines is common. The use of benzodiazepines is common amongst the injecting drug user population (IDUs) in all cities of Australia (NDARC: 1997). The use of benzodiazepines among heroin users was reported to be 91% of one study sample, with 67% being current users at the time of the study (Ross and Darke: 1997).
A significant proportion (up to 27% in NSW) of overdose fatalities are related to the use of benzodiazepines (Zador et al: 1996). In one study by Loxley et al (1997), benzodiazepines were nominated as the second most significant drug (after heroin) associated with overdose. Benzodiazepines are involved in about one third of overdose cases (Loxley et al: 1997).
The use of benzodiazepines in combination with alcohol, methadone, heroin, amphetamines or other prescribed medications is a significant concern.
Benzodiazepines and Methadone
One study found that 36.5% of methadone clients had used benzodiazepines in the month preceding interview, with 26.6% using them daily. (Darke et al: 1994)
The use of benzodiazepines by methadone-maintenance clients reduces the effectiveness of the treatment. Methadone-maintenance clients using benzodiazepines also have: higher levels of personal distress, anxiety and depression (Darke et al: 1994); increased rates of injecting and more frequent rates of borrowing injecting equipment (Darke et al: 1993); represent a subgroup of methadone-maintenance clients who do not respond as well to treatment as other clients (Darke et al:1993); and have unexpectedly low levels of serum methadone concentration which indicates that benzodiazepines may affect the metabolism of methadone.
HEA Report 1999 (Scotland)
One trend particular to Scotland is the high incidence of benzodiazepine use among its problem users as shown in the Scottish Drug Misuse Database (see the following section for details). Diazepam appears to hold particular sway in parts of central Scotland, chiefly Glasgow and Edinburgh, possibly replacing heroin and other opiates which, in comparison to the rest of the UK, have a lower level of reporting among this group.
Secondary Drug of Choice
If a client is using heroin, they are highly likely to be using it as their main drug. Only 12 per cent for example, of heroin users were using it as a secondary drug. Benzodiazepines however are clients' most common secondary drug of choice, with 86 per cent of those who use it, using it as a secondary drug. From these figures it would appear that benzodiazepines are often used when other drugs, usually heroin, are not available.
Another trend specific to Scotland is the exceptionally high level of use of benzodiazepines. Although the latest figures show a fall since prescribing restrictions were introduced in 1995, figures for Scotland are still three times that of England at 9 per cent for main drug. Looking at all drugs of use, benzodiazepines again score very highly among those presenting for treatment. 40 percent for example admit to using diazepam, and 13 per cent temazepam, despite its prescription being restricted.
This would indicate that benzodiazepines feature regularly in a polydrug userís cabinet of choice, substituting opiates and other depressants in times of poor availability or, as in some cases, as a first drug of choice. Therefore, while it is true that temazepam use has seen a sharp fall among this group of users – from 41 per cent in 1992/3 for any drug to 13 per cent in 1997/8, this drop is overshadowed by the equally sharp rise in other benzodiazepine use, in particular diazepam (up from 18 per cent all drugs in 1992/3 to 40 per cent in 1998/9), and in other depressants such as heroin (up from 43 per cent of all drugs in 1992/3 to 60 per cent in 1997/8).
5.32 "We were told that misuse of benzodiazepine (BDZ) tranquillisers was a major problem in South Wales and we have been told the same in other South Wales prisons. We have been told that prescribing of BDZs beyond the guidelines in the British National Formulary is by no means uncommon outside prison. Certainly BDZs were the commonest drug found by health care staff urine screening new receptions to Swansea. The governor should discuss with the HA the possibility of including a reduction in the availability of benzodiazepines as a target in the area's HIP." – Statement on Inspection of Swansea Prison, June 1999.
See also Sue Bibby's Pages at faxfn.org
Heminevrin (chlormethiazole) – Four capsules four times a day
Epilim (sodium valproate)
At the age of fourteen Simon was prescribed diazepam for teenage problems and he was being bullied. After suffering side effects from the diazepam, more drugs were prescribed to counteract these symptoms. They did not help, only contributing to an unnecessary cocktail. Two of these drugs were Heminevrin and Epilim. Epilim and Valium were prescribed outside the product licence and Heminevrin was prescribed at nearly eight times the recommended maximum daily dose unless a patient is under hospital in-patient supervision.
Data sheets also caution of potential interactions between all three drugs respectively.
Simon was twenty-eight when he died this year. He was prescribed diazepam all of his adult life. Since 1988, data sheets and the BNF state that benzodiazepines should not be prescribed for more than four weeks. Simon spent fourteen years suffering from the side effects of diazepam, exacerbated by the drugs prescribed to 'treat' the side effects of the first drug.
Simon spent fourteen years trying to stop taking diazepam, but there is no effective help available in this country.
Simon died on a "cocktail" of drugs prescribed by his doctor.
Simon Hervey, BBC Radio 4, 'You and Yours', October 27, 1999. Transcript.
Simon Hervey's Story: Little boy lost, Guardian, August 15, 2000
House of Commons
Notice of questions given
on Monday 26 July,1999
(For Tuesday, 19 October, 1999)
Re: Phil Woolas MP
To ask the Minister for the Cabinet Office what plans he has to review the classification of benzodiazepine drugs.
To ask the Minister for the Cabinet Office what action he is taking to prevent the illegal trade of benzodiazepine drugs.
To ask the Secretary of State for Health if he will establish respite care and detoxification units for people who are addicted to benzodiazepine drugs.
To ask the Secretary of State for Health what plans he has to carry out research into the effects of long term use of benzodiazepine drugs.
To ask the Secretary of State for Health what plans he has to implement the advice of the Committee on Review of Medicines on the prescription of benzodiazepine drugs.
To ask the Secretary of State for Health what plans he has to implement the advice of the Committee on Review on Medicines that benzodiazepines should not be prescribed to pregnant women.
To ask the Secretary of State for Health what plans he has to request the Medicines Control Agency to review the use and prescription of benzodiazepine drugs.
To ask the Secretary of State for Health how many newborn babies in each of the last five years have been damaged by the prescribing of benzodiazepine drugs to their mothers.
To ask the secretary of State for Social Security what advice he has issued regarding the handling of disability and incapacity benefit claims by people suffering from addiction to benzodiazepine drugs.
Patient Information Leaflets
"New medicines are now required to have a patient information leaflet (PIL) and all other medicines are required to have these by the end of 1998. As part of the planned introduction of PILs, all current benzodiazepine PILs were reviewed to ensure the information complied with the guidelines and products which had not previously had a PIL had one introduced which carried the appropriate warnings. The PIL is provided to patients to complement the information provided to the patient by the prescribing doctor."
This was written by Dr Ennis Lee, Head of the Pharmacovigilance Evaluation Unit, Medicines Control Agency, 21st April, 1998.
In September 1999 PILs are still not provided with prescriptions for benzodiazepines (BDZs) unless they happen to be sold in a packet. This excludes all BDZs dispensed in bottles, including diazepam (one of the most commonly prescribed BDZs).
The aim of PILs is to inform patients directly so that they can make an informed choice and evaluate the risks they may be taking. They are provided by the manufacturers.
An example of this is the risk posed by BDZs to the unborn child:
Dr Ennis Lee at The Medicines Control Agency in 1998 states:
"It has been known for some time that exposure to BDZs in utero, particularly late in pregnancy, can lead to withdrawal symptoms in the new born infant. The product information for BDZs gives appropriate warnings that BDZs should be avoided during pregnancy, especially the first and last trimesters, unless there are compelling reasons for such treatment. Warnings include information about the possible withdrawal symptoms which may be experienced by the infant. A warning is also given to avoid breast feeding when the mother is taking a BDZ."
Some doctors are not warning their patients about these risks. Regular reports come from around the country from women who have been prescribed BDZs during pregnancy and given no warnings. They have also not been warned about breastfeeding and the advisability of becoming pregnant. If there is no PIL available, how many unborn children are being exposed to BDZs needlessly when it is known to be harmful?
For those fortunate enough to be prescribed a BDZ that comes in a packet, a warning concerning pregnancy is included. A typical example of this is a recent PIL for Lorazepam, a commonly prescribed BDZ:
Patient Information Leaflet
BEFORE YOU TAKE YOUR MEDICINE
YOU SHOULD NOT TAKE LORAZEPAM IF:
– You are breastfeeding, since the drug may pass into breast milk
TELL YOUR DOCTOR OR PHARMACIST IF:
– You are pregnant or trying to become pregnant (see below).
– Benzodiazepines including lorazepam may cause damage to the foetus if taken during early pregnancy. Therefore do not take this medicine if you are pregnant or might become pregnant without consulting your doctor. If you take this medicine during late pregnancy or during labour, your baby, when born, may be less active than other babies, have a low body temperature, be floppy, or have breathing or feeding difficulties for a while. Your baby's response to the cold might be temporarily impaired also. If this medicine is taken regularly in late pregnancy your baby may develop withdrawal symptoms after birth.
In September 1997 The Committee on Safety of Medicines issued this reminder to the medical profession concerning benzodiazepines which reads:
REMINDER: AVOID BENZODIAZEPINES IN PREGNANCY AND LACTATION
"Benzodiazepines cross the placenta and there is a risk of adverse effects in the foetus. If benzodiazepines are administered at high doses, during late pregnancy, or during labour, effects on the neonate such as hypothermia, hypotonia and moderate respiratory depression may occur."
"Infants born to mothers who take benzodiazepines chronically during the latter stages of pregnancy may develop physical dependence and be at risk of developing withdrawal symptoms (irritability or difficulty with feeding) in the post-natal period.
"If a benzodiazepine is prescribed to a woman of childbearing potential, she should be advised to contact her physician regarding discontinuation of the drug if she intends to get pregnant, or suspects that she is pregnant.
"Since benzodiazepines are excreted in breast milk, they should not be given to lactating mothers."
This raises two questions. Firstly, why after receiving warnings two years ago are many doctors still not informing their patients of the risks to their babies? Secondly, who is responsible for those babies who have been exposed before birth to BDZs needlessly because their mothers could not get the information?
Benzodiazepines: A Risk Factor in Sudden Infant Death?
Susan Bibby, Beat The Benzos Conference Speech,
London, November 1, 2000
Benzodiazepines: A Hidden Epidemic, May 2003 by Susan Bibby of Benzact.