Lancet on piperazine Adverse Events

Lancet on piperazine AEs

Two papers: one on a piperazine ED visit and the other a commentary

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http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T1B-4NKCD9Y-18&_user=861681&_coverDate=05%2F04%2F2007&_rdoc=1&_fmt=full&_orig=browse&_cdi=4886&_sort=d&_docanchor=&view=c&_ct=1&_acct=C000046147&_version=1&_urlVersion=0&_userid=861681&md5=ce218b61dfc43491ead6fb867504e5cb

The Lancet Volume 369, Issue 9571,
28 April 2007-4 May 2007, Page 1490

Case Report

Collapse, reported seizure—and an unexpected pill

David M Wood, Paul I Dargan, Jennifer Button, David W Holt, Hanna Ovaska, John Ramsey and Alison L Jones

In May, 2006, on a Bank Holiday weekend, an 18-year-old woman presented to an inner-city London emergency department. She had been at a nightclub with friends and purchased tablets, which she understood to be Ecstasy or amphetamines, from a dealer. After ingesting five tablets, she collapsed in the nightclub and appeared to have a seizure lasting 10 min. On arrival in the emergency department, she was agitated and had dilated pupils (8 mm), sinus tachycardia (156 bpm), and a blood pressure of 150/51 mm Hg. Her score on the Glasgow coma scale was 15 and she was apyrexial (35·9°C). She had no significant past medical history and was on no regular medication.

She was one of seven patients to attend the department that night with a similar presentation. We therefore considered it possible that she had taken a contaminated drug, or a substance not previously sold in the area; and we took a serum sample for analysis, in addition to treating the patient symptomatically with intravenous benzodiazepines (4 mg lorazepam followed by 15 mg diazepam). After 12 h, she was asymptomatic and discharged with advice to avoid recreational drugs. The serum sample was analysed by gas chromatography with mass-spectrometric detection (GCMS); 1-benzylpiperazine was detected at a concentration of 2·5 mg/L. Toxicological screening of the same serum sample did not detect the presence of other piperazines, other drugs, or ethanol. A tablet purchased by the patient (figure) was also analysed, and found to contain 1-benzylpiperazine.

1-benzylpiperazine is one of the piperazine family of drugs, initially developed as veterinary anthelmintic agents in the 1950s. Its chemical structure is similar to that of amphetamine.1 Piperazines are marketed in the UK, where they are legally available in shops and over the internet, as having similar effects to controlled recreational drugs; pills containing piperazines are known as “pep pills”.2 No reliable data are available on the consumption of piperazines in the UK, although one manufacturer claims that “over 20 million pills have been consumed in New Zealand with no deaths, or significant lasting injuries”.2 However, in initial clinical trials of 1-benzylpiperazine, adverse effects similar to those of amphetamines were noted.3 A prospective study in New Zealand identified adverse effects including nausea, vomiting, tachycardia, hypertension, anxiety, and agitation among 80 patients presenting to emergency departments after 1-benzylpiperazine ingestion.4 Seizures were reported in 15 (19%), at up to 8 h after ingestion. Three patients had potentially life-threatening recurrent seizures; ingestion of 1-benzylpiperazine by these patients was confirmed by toxicological screening of their urine. Other potentially serious adverse effects included QTc prolongation (QTc duration 430–490 ms in 32 patients) and hyponatraemia (serum sodium concentration 118 mmol/L and serum osmolality 242 mmol/kg) in one patient. Clinicians should be aware of the potential presenting features of piperazine toxicity, particularly because commercially available urine toxicological screening kits for drugs of abuse may not detect piperazines. All patients with strongly suspected or reported ingestion of 1-benzylpiperazine should have an initial baseline ECG, to seek features of cardiotoxicity. They should be observed for up to 8 h after ingestion, because the onset of seizures can be delayed. Initial treatment should be based on the clinical presentation. Further management can require the advice of a clinical toxicologist.

References

1 M Wikstrom, P Holmgren and J Ahlner, A2 (N-benzylpiperazine) a new drug of abuse in Sweden, J Anal Toxicol 28 (2004), pp. 67–70. View Record in Scopus Cited By in Scopus

2 Spiritualhigh.co.uk – Staying Safe on PEP Pillshttp://www.spiritualhigh.co.uk/information/drug-harm-minimisation-and-legal-highs/staying-safe-on-pep-pills/3-7-7-19 (accessed April 2, 2007)..

3 C Bye, AD Munro-Faure, AW Peck and PA Young, A comparison of the effects of 1-benzylpiperazine and dexamphetamine on human performance tests, Eur J Clin Pharmacol 6 (1973), pp. 163–169. Full Text via CrossRef View Record in Scopus Cited By in Scopus


4 P Gee, S Richardson, W Woltersdorf and G Moore, Toxic effects of BZP-based herbal party pills in humans: a prospective study in Christchurch, New Zealand, N Z Med J 118 (2005), p. U1784.

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Comment

Piperazine designer drugs of abuse
Roland F Staack


In today's Lancet, David Wood and colleagues report on the first case of poisoning with 1-benzylpiperazine (BZP) in the UK.1 This case report is a valuable contribution to the development of a better understanding of the toxicity of this new drug of abuse. To date, only a few cases of poisonings and deaths with BZP have been reported.2, 3 and 4 However, in these reports, no detailed clinical data were given, the cases were polydrug intoxications, or only limited analytical toxicological analysis was available. The case reported by Wood and colleagues describes for the first time the clinical symptoms of an acute mono-intoxication with BZP, which was confirmed by toxicological analysis.

BZP is the most prevalent compound of a new class of designer drugs of abuse called piperazines (figure). Besides BZP and 1-(3,4-methylenedioxybenzyl)piperazine (MDBP), there are the phenylpiperazine derivatives: 1-(3-trifluoromethylphenyl)piperazine (TFMPP), 1-(3-chlorophenyl)piperazine (mCPP), and 1-(4-methoxyphenyl)piperazine (MeOPP).5

The amfetaminergic effects of BZP have been known since the 1970s. A mixture of BZP and TFMPP mimics the molecular mechanism of 3,4-methylenedioxymethamfetamine (MDMA, ecstasy).3, 5, 6, 7 and 8 The phenylpiperazines are well-characterised serotonergic compounds, which is also the reason for the use of 1-(3-chlorophenyl)piperazine (mCPP) as a probe drug in psychiatric research.5, 6 and 7 Commonly, piperazines are sold as party pills in the form of tablets, capsules, or powders on the black drug-market and in so-called headshops or over the internet. They are also found in tablets sold as ecstasy or amfetamine. Generally, piperazine blends are consumed. Besides the most prevalent mixture of BZP with TFMPP, there are also blends of up to four different piperazines (named X4). Furthermore, mixtures of piperazines with other drugs of abuse, such as ecstasy or cocaine, have been reported.6 and 7 Since the end of the 1990s, piperazines are often proffered as a legal and safe alternative to amfetamine-derived drugs. The discussion on their legal status is ongoing in many countries. However, some countries (eg, the USA, Australia, Japan, and some European countries) already control BZP under drug control or equivalent legislation.6, 7 and 9 Thus the claimed advantage of legality is not given anymore in these countries. In March, 2007, in the UK, the Medicines and Healthcare products Regulatory Agency declared the selling of BZP products illegal.10 Predictably, the legal measures started a kind of cat-and-mouse play. Instead of BZP, other, not yet scheduled, piperazines, mainly mCPP, increasingly appeared on the market.

The widespread use of piperazines with only a low record of attributable toxicity is stated by activists as proof of safety for legalisation of these drugs. However, from a toxicological point of view, such a stance cannot be affirmed. In view of the similar pharmacological modes of action of piperazines and amfetamines, similar toxicity has to be assumed. This assumption is supported by the reported cases of piperazine poisonings1, 2, 3 and 4 and by the occurrence of serotonin syndromes in a clinical study.11

Special attention should be paid here to polydrug use. Synergistic effects of piperazine blends have been described.8 Furthermore, particularly the phenylpiperazines are extensively metabolised, mainly by the polymorphically expressed cytochrome P450 2D6 (CYP2D6) which might result in an increased risk of toxic side-effects for CYP2D6 poor-metabolisers.5 In addition, these compounds are liable for drug–drug interactions with inhibitors or other substrates of this enzyme (eg, MDMA, cocaine), which might similarly increase the risk of toxicity, especially because piperazines seem to have a narrow safety margin.6, 8 and 11

The low record of reported poisonings with piperazines has also to be put into perspective. Many clinicians are not aware of newer classes of drugs of abuse. Piperazines and amfetamines are similarly marketed, consumed by the same population, and show similar pharmacological symptoms. Therefore a piperazine poisoning can easily be wrongly diagnosed as an amfetamine poisoning. Furthermore, piperazines are not detected by routinely used immunochemical screening procedures for drugs of abuse, but require an appropriate toxicological analysis (eg, by gas-chromatography mass-spectrometry).12 and 13

Hence Wood and colleagues' case report is an excellent example to raise clinicians' awareness of newer drugs of abuse and substantiates the importance of a sound toxicological analysis for a correct clinical diagnosis. As a result, more cases of abuse of new designer drugs will be detected, which in turn will yield data essential for a toxicological risk assessment. Besides piperazines, there are also further new classes of designer drugs of abuse, such as phenethylamines (2C-series), α-pyrrolidinophenones, and new phencyclidine derivatives.5 and 9



References

1 DM Wood, PI Dargan and J Button et al., Pills, collapse, and a negative drug screen, Lancet 369 (2007), p. 1490. SummaryPlus Full Text + Links PDF (73 K)

2 C Balmelli, H Kupferschmidt, K Rentsch and M Schneemann, Fatal brain edema after ingestion of ecstasy and benzylpiperazine, Dtsch Med Wochenschr 126 (2001), pp. 809–811. Full Text via CrossRef View Record in Scopus Cited By in Scopus

3 P Gee, S Richardson, W Woltersdorf and G Moore, Toxic effects of BZP-based herbal party pills in humans: a prospective study in Christchurch, New Zealand, N Z Med J 118 (2005), p. U1784.

4 M Wikström, P Holmgren and J Ahlner, A2 (N-benzylpiperazine) a new drug of abuse in Sweden, J Anal Toxicol 28 (2004), pp. 67–70. View Record in Scopus Cited By in Scopus

5 RF Staack and HH Maurer, Metabolism of designer drugs of abuse, Curr Drug Metab 6 (2005), pp. 259–274. Full Text via CrossRef View Record in Scopus Cited By in Scopus

6 European Monitroing Centre for Drugs and Drug Addiction, Europol-EMCDDA Joint Report on a new psychoactive substance: 1-benzylpiperazine (BZP)http://www.emcdda.europa.eu/?nnodeID=1346 (March 23, 2007) (accessed April 17, 2007)..

7 European Monitroing Centre for Drugs and Drug Addiction, Europol-EMCDDA Joint Report on a new psychoactive substance: 1-(3-chlorophenyl)piperazine (mCPP)http://www.emcdda.europa.eu/?nnodeID=1346 (March 23, 2007) (accessed April 17, 2007)..

8 MH Baumann, RD Clark, AG Budzynski, JS Partilla, BE Blough and RB Rothman, N-substituted piperazines abused by humans mimic the molecular mechanism of 3,4-methylenedioxymethamphetamine (MDMA, or ‘Ecstasy’), Neuropsychopharmacology 30 (2005), pp. 550–560. Full Text via CrossRef View Record in Scopus Cited By in Scopus

9 Anonymous, Schedules of controlled substances; placement of 2,5-dimethoxy-4-(n)-propylthiophenethylamine and N-benzylpiperazine into Schedule I of the Controlled Substances Act. Final rule, Fed Regist 69 (2004), pp. 12794–12797.

10 MHRA, Press release: benzylpiperazine (PEP) pills are dangerous and illegalhttp://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&useSecondary=true&ssDocName=CON2030603&ssTargetNodeId=389 (March 20, 2007) (accessed April 17, 2007)..

11 T Klaassen, KL Ho Pian, HG Westenberg, JA den Boer and HM van Praag, Serotonin syndrome after challenge with the 5-HT agonist meta-chlorophenylpiperazine, Psychiatry Res 79 (1998), pp. 207–212. Abstract Full Text + Links PDF (73 K) View Record in Scopus Cited By in Scopus

12 HH Maurer, Position of chromatographic techniques in screening for detection of drugs or poisons in clinical and forensic toxicology and/or doping control, Clin Chem Lab Med 42 (2004), pp. 1310–1324. Full Text via CrossRef View Record in Scopus Cited By in Scopus

13 FT Peters, S Schaefer, RF Staack, T Kraemer and HH Maurer, Screening for and validated quantification of amphetamines and of amphetamine- and piperazine-derived designer drugs in human blood plasma by gas chromatography/mass spectrometry, J Mass Spectrom 38 (2003), pp. 659–676. Full Text via CrossRef View Record in Scopus Cited By in Scopus