Introduction - Uppsala Monitoring Centre

symptoms.’ (Willcox, 1934).
SED 1952: prolonged use may give rise to habituation and addiction. When
the drug is stopped abstinence symptoms may occur, even epileptiform
attacks have been seen (there was no differentiation between the various
barbiturates).
SED 1957: the state induced by the chronic use of barbituric acid derivatives
may resemble chronic alcoholism and withdrawal resembles delirium tremens.
By 1976 there was a campaign to stop the use of barbiturates as hypnotics
(Leader, 1976). Phenobarbital is possibly carcinogenic in humans (IARC vol
79, 2001).
Withdrawn: in Sweden, where it was associated with fatal poisoning and abuse in
1985 and in Argentina in 1996. It was also withdrawn in South Africa and
Switzerland. Restricted to epilepsy and anaesthesia in Germany in 1994, USA in
1997 and in France and Mauritius in 2001 (except for epilepsy).
Availability: in the UK it is restricted to epileptic patients (BNF, 1999).
Worldwide.
Drug Lifespan: 73 years
Delay in recognition: 62 years before the campaign to stop its use.
Delay in regulatory action: 9 years
Time span of restrictions: 16 years
Comment: dependence of the ‘barbiturate type’ has been described as being
different from morphine, cocaine and amphetamine types with its own
characteristics (Current Practice, 1964).
1921 Dipyrone noramidopyrine/noraminosulfone/metamizole sodium (Novalgin, Baralgin,
Analgin, Conmel) It was also known as ‘Mexican Aspirin’.
Use: analgesic
ADR: dipyrone is the sodium sulfonate derivative of aminopyrine and has the
same pharmacological properties, so there is no reason to suspect that they
are not equally likely to produce agranulocytosis (Huguley, 1964). The first
case of agranulocytosis associated with dipyrone was reported in 1935
(Blake, 1935).
SED 1952: rarely causes blood changes. Erythema multiforme, purpura,
haemorrhagic exanthemata and other rashes.
SED 1960: ‘agranulocytosis is so generally known….’
Reported as causing agranulocytosis with an incidence of 0.86% in 1952
(Discombe, 1952) and of 0.79% in 1964 (Huguley, 1964), but these papers
had major flaws. The International Agranulocytosis and Aplastic Anaemia
Study (IAAAS) gave a figure of 1.1 case per million. In Sweden three warnings
(February, September and December 1967) were sent by the ADR
committee, but it was only after the third warning that there was any drop in