5.Dec.2021-Expires: 7 days - Do not archive

Charge (BZP)

Charge (BZP)
5.Dec.2021-Expires: 7 days - Do not archive

DESCRIPTION

SUBSTANCE NAME

Benzylpiperazine (BZP)
 

SUBSTANCE CLASS

Psychoactive Central Stimulant

Piperazine-Based Hallucinogenic Stimulant
 

USES

While piperazine-based hallucinogenics or stimulants are not currently used therapeutically, they are misused. It is believed to have a similar action as the hallucinogenic-amphetamines, explaining the reason for its abuse. It is less potent than methamphetamine or MDMA, but is being sold in continuously increasing doses, making the effects more consistent with these more potent drugs.[1]
 

ACTIVE INGREDIENT

Charge Capsule
105 mg Benzylpiperazine (BZP)
 
Recommended dose is 1 to 2 capsules, then another 1 to 2 after 2 hours. Maximum dose 3 capsules. Available in packets of 6 or 18.
 
Warning: Tablets claim to contain "500 mg". However, this refers to total mg of all ingredients, not active ingredients, and is effectively a meaningless statement.
 

INTERVENTION CRITERIA

Intervention Level

The correct identification of the substance is important. If the symptoms are inconsistent with those described in the literature, or the history is considered unreliable, other substances may need to be considered.
 

Acute

Child

Appropriate medical assessment and observation is recommended for:
- Any exposure to a piperazine based hallucinogenic stimulant
 

Adult

Appropriate medical assessment and observation is recommended:
- If > 400 mg of a piperazine-based hallucinogenic stimulant is ingested
- Symptomatic patients (other than mild)
- Exposures with intent to self-harm
 

Observation Period

Observation at Home

If the patient does not require medical observation they can be observed at home for 4 hours in the care of a reliable observer.
 
Medical attention should be sought if ANY symptoms occur, including:
Euphoria
Confusion/agitation
Anxiety
Increased heart rate
Palpitations
Chest pain
Gastrointestinal upset
Fever
Tremor
 

Medical Observation

If medical observation is required, the patient must be observed for 4 hours following exposure for onset or worsening of symptoms.
 
Those with mild signs and symptoms (e.g. euphoria, increased alertness, altered mental status, tachycardia) should be closely observed.
 
If the patient is clinically well except for slight tachycardia at the end of the observation period (there is no agitation or serotonergic signs, and temperature is normal), and provided that appropriate assessment and investigations have been carried out, they may be:
Discharged into the care of a reliable observer, or
Referred for psychological assessment (if the overdose or exposure was intentional)
 

Investigations

Monitoring

Heart rate
Blood pressure
Body temperature
12 lead ECG
Blood glucose
Serum sodium

Concentrations

Serum concentrations are not readily available and do not aid management.
 

Admission Criteria

Admission to a closely monitored environment is recommended for:
Severe hypertension
Hyperthermia > 41 degrees C or > 39 degrees C that is not rapidly resolving with initial intervention
Cardiac ischemia as demonstrated by ECG evidence of ischemia or infarction or a rise in troponin concentration
Significant non-resolving cardiac dysrhythmias, including supraventricular tachycardias
Cerebral hemorrhage
Intractable seizures
Agitated delirium
Multisystem organ failure
 

TREATMENT

TREATMENT SUMMARY

Piperazine based hallucinogenic stimulants are considered to possess an hallucinogenic-amphetamine-like effect.
 
in the majority of cases gastrointestinal decontamination is unlikely to be beneficial. There is no antidote for intoxication and no methods for enhancing elimination can be recommended.
 
The majority of presentations will recover with a period of observation, calming environment and, if required, appropriate titrated doses of a benzodiazepine. Patients may become dehydrated and require significant volume replacement, however, it is imperative to recognize those suffering hyponatremia as administration of fluids may prove fatal. Serum sodium must be measured, and CT brain scan undertaken to exclude cerebral edema in those with CNS signs.
 
The severely toxic may suffer seizure or cardiovascular abnormality. Persistent seizures require treatment with a benzodiazepine or if refractory, a barbiturate. Chest pain may indicate an acute coronary syndrome (arteriospasm) which will likely settle if the patient is calmed with a benzodiazepine, nitrate, or in severe cases a vasodilator such as phentolamine. Hyperthermia should be immediately and actively managed, and the patient carefully monitored for further complications including rhabdomyolysis, DIC, and renal failure. Serotonin syndrome should be considered, especially in those using other serotonergic compounds either therapeutically or recreationally.[2]
 
Stimulant abuse may be via intravenous injection of ground tablets. Pulmonary granuloma formation in chronic abusers predisposes to reduced pulmonary function,[3] vascular obliteration, pulmonary hypertension, and cor pulmonale.[4][5]
 
Emergency Stabilization
Ensure adequate cardiorespiratory function
Cardiac arrest
Seizure
Emergency monitoring
Decontamination
Ingestion
Not recommended
Antidote(s)
None recommended
Enhanced Elimination
Not recommended
Supportive Care
Monitoring
Neurologic
Psychiatric and/or behavioral changes
Seizure
Intracranial hemorrhage
Serotonin toxicity
Cardiovascular
Hypertension
Cardiac dysrhythmia
Acute coronary syndrome
Arterial spasm
Metabolic
Hyperthermia
Metabolic acidosis
Musculoskeletal
Rhabdomyolysis
Renal
Acute kidney injury
Fluid and electrolytes
Hyponatremia
Dehydration
Hyperkalemia
Hepatic
Hepatotoxicity
Other
Movement disorder
Ocular
Corrosive eye injury
Dermatologic
Skin burn
 

EMERGENCY STABILIZATION

Ensure Adequate Cardiopulmonary Function

Airway

Ensure the airway is protected if compromised (intubation may be necessary).
 

Cardiovascular

Immediately establish secure intravenous access.
 
A range of acute cardiovascular emergencies may occur due to vasospasm or vascular rupture. Such events include hemorrhagic or ischemic stroke, cardiac dysrhythmia/arrest, and dissection of large vessels including the aorta.
 
A range of acute cardiovascular emergencies may occur due to vasospasm or vascular rupture. Such events include hemorrhagic or ischemic stroke, cardiac dysrhythmia/arrest, dissection of large vessels including the aorta.
 

Cardiac Arrest

Prolonged cardiac resuscitation following standard protocols may be appropriate in selected cases as recovery with a good neurological outcome is reported in some severely poisoned patients receiving CPR for hours.[6] Artificial circulatory support interventions including veno-arterial or veno-venous extracorporeal membrane oxygenation (VA- or VV-ECMO), where available, can be considered for selected cases of severe refractory shock or severe respiratory failure due to acute respiratory distress syndrome.[6][7] There is growing experience treating poisoned patients at many ECMO-capable centers.[8][9]
 

Seizure

Administer a benzodiazepine as first-line treatment to patients with seizure activity.[10]
 
Blood glucose concentration should be promptly determined. If the result indicates hypoglycemia, or is unobtainable, supplemental dextrose should be administered IV.
 

Emergency Monitoring

Heart rate
Blood pressure
12 lead ECG
Body temperature
Respiratory rate
State of hydration
Serum electrolytes - especially sodium
Blood glucose
Neurological status
 

DECONTAMINATION

Ingestion

Decontamination Not Recommended

Efficacy of gastrointestinal decontamination is questionable as these compounds are rapidly absorbed and the patient is likely a late presenter and less than co-operative. As the risks likely outweigh benefit, activated charcoal is not recommended.
 

ANTIDOTE(S)

There Are No Antidotes For This Substance

There is no specific antidote for the treatment of this poisoning. Treatment is based on symptomatic and supportive care.
 

ENHANCED ELIMINATION

Enhanced Elimination Not Recommended

Hemodialysis, hemoperfusion, or other techniques to increase the rate of removal of this compound are not recommended.
 

SUPPORTIVE CARE

Monitoring

ECG
Blood pressure
Heart rate
Body temperature
Blood glucose
Fluids and electrolytes
Blood gas analysis
Respiration
Chest auscultation
Oxygen saturations
Neurological status
Serum urea
Serum creatinine
Liver function tests
Creatine kinase
 

Psychiatric and/or Behavioral Changes

Severe agitation and psychosis may be prominent following sympathomimetic overdose. Agitation and increased muscular activity increases the risk of excited delirium syndrome and/or hyperthermia and rhabdomyolysis. Excited delirium syndrome caries a significant risk of death and must be managed aggressively.
 
Monitor for signs of:
Agitation
Aggression
Delirium
Depression
Hallucinations
Mania
Paranoia
 
A calming, non-stimulating environment and benzodiazepines are recommended as first-line management.[11][12] Initially, in an adult, diazepam 5 to 10 mg or lorazepam 1 to 2 mg should be administered; doses can be repeated until the patient is sedated.[11] Midazolam 1 to 4 mg can be administered intramuscularly in patients without intravenous access.[11][12] In a minority of patients, escalating doses of benzodiazepines may lead to paradoxical excitation. Droperidol can be administered in an initial dose of 10 mg IV/IM in those with persisting agitation resistant to treatment with benzodiazepines.
 
Ketamine or general anesthetic sedation with intubation should be considered in patients with severe agitation and associated life-threatening physiological derangements (particularly hyperthermia > 40 degrees C), or in those patients with ongoing agitation non-responsive to administration of benzodiazepines or droperidol.
 

Neurologic

Seizures

Seizures secondary to sympathomimetic toxicity occur uncommonly and should be managed with a benzodiazepine, or if still refractory a barbiturate.[11][12] If persistent or prolonged, seizures may result in respiratory or metabolic acidosis, rhabdomyolysis, acute kidney injury, or hyperthermia.[11]
 
Observe the patient closely for onset of seizure activity.
 

Intracranial Hemorrhage

Stroke is well recognized following sympathomimetic overdose and is likely due to acute hypertension, arterial spasm, and/or vascular rupture.[13][14][15][16][17] Patients suffering severe headache, hemiparesis, hemiplegia, or a persistent alteration in conscious state should undergo urgent neuroimaging.[11][12]
 
Closely monitor mental status

Manage intracranial hemorrhage following standard treatment protocols.
 

Serotonin Toxicity (Syndrome)

Serotonin excess may occur following sympathomimetic exposure, and is more likely in individuals taking other serotonergic drugs either therapeutically or recreationally.[18] If severe, complications may include hyperthermia, hypotension, metabolic acidosis, rhabdomyolysis, cardiovascular collapse, acute kidney injury, disseminated intravascular coagulation, and death.[19]
 
Development of serotonin toxicity may be detected by applying the Hunter Serotonin Toxicity Criteria – Decision Rules:[20]
 
In the presence of a serotonergic agent:
  1. IF (spontaneous clonus = yes) THEN serotonin toxicity = YES
  2. ELSE IF (inducible clonus = yes) AND [(agitation = yes) OR (diaphoresis = yes)] THEN serotonin toxicity = YES
  3. ELSE IF (ocular clonus = yes) AND [(agitation = yes) or (diaphoresis = yes)] THEN serotonin toxicity = YES
  4. ELSE IF (tremor = yes) AND (hyperreflexia = yes) THEN serotonin toxicity = YES
  5. ELSE IF (hypertonia = yes) AND (temperature > 38ºC) AND [(ocular clonus = yes) or (inducible clonus = yes)] then serotonin toxicity = YES
  6. ELSE serotonin toxicity = NO
 
NOTE: Multiple non-specific clinical findings may be present in a patient with possible serotonin toxicity and so a wide differential diagnosis must be investigated. Conditions including infection, metabolic derangement, or withdrawal states need to be considered. Neuroleptic syndrome should be considered if the patient has been commenced on neuroleptic agents or had an increase in neuroleptic dose.
 

Cardiovascular

Cardiovascular collapse or shock is associated with very poor outcome.[21] Cardiomyopathy and necrotizing vasculitis are recognized with sympathomimetic misuse,[22][23] and a range of end organs may be damaged by vasospasm or vascular rupture and hemorrhage.
 

Hypertension

Hypertension is very common and is largely secondary to alpha-1 adrenoreceptor stimulation causing vasoconstriction.[24][25]
 
Monitor:
Heart rate/rhythm
Blood pressure
ECG
 
As sympathomimetic-induced hypertensive emergencies are usually of short duration aggressive management may result in hypotension. The following regimen is recommended:[11][26]
Benzodiazepine, and calming environment should be provided initially
Vasoactive agents should generally be reserved for situations of hypertensive or vascular emergencies, where there is clear evidence of end-organ injury. Short-acting vasodilators like glyceryl trinitrate or nicardipine may be considered
Labetalol, in carefully titrated doses, has been suggested by some for treatment of selected sympathomimetic overdoses.[27][28][29] Detractors of this approach are concerned about potential increases in blood pressure due to unopposed alpha-adrenergic receptor agonism; though advocates suggest this is less likely with labetalol due to its alpha-andrenergic receptor blocking properties.
 

Cardiac Dysrhythmia

Dysrhythmias may occur as a consequence of direct catecholamine effects, myocardial ischemia, hypoxia, or possibly electrolyte abnormality.
 
Monitor:
Heart rate/rhythm
Blood pressure
12 lead ECG
 
Narrow complex tachydysrhythmias include sinus tachycardia (most common), atrial fibrillation, and supraventricular tachycardia and are primarily a consequence of sympathomimetic over-stimulation. Initial management is provision of a non-stimulating environment, correction of any electrolyte abnormalities, and titrated doses of a benzodiazepine. Further intervention is only required if hemodynamic compromise occurs.
 
If pharmacological management of a narrow complex tachydysrhythmia is required, titrated doses of labetolol or verapamil may be considered. Administration of beta blockers that do not possess alpha-receptor blocking activity have been associated with increased morbidity, and should be avoided.[11] Hemodynamically unstable narrow complex tachydysrhythmias should be managed with DC cardioversion.
 
For patients suffering hemodynamically stable ventricular tachycardia, both intravenous sodium bicarbonate and lidocaine (lignocaine) are recommended.[30][31] Hemodynamically unstable broad complex tachyarrhythmias should be managed with DC cardioversion.
 

Acute Coronary Syndrome

Myocardial ischemia may occur following sympathomimetic overdose due to coronary artery vasoconstriction, thrombus formation, and platelet aggregation.[32][33] Myocardial ischemia can progress to infarction. Use of beta-adrenergic receptor blockers is contra-indicated as they may lead to unopposed alpha receptor stimulation with worsening hypertension, and increased myocardial oxygen demand.[34][30]
 
Monitor:

Heart rate

Blood pressure

ECG

Recommended management of this condition includes:
Benzodiazepine, and a calming environment
Nitroglycerin in either sublingual, oral, topical or IV form may be used and titrated to effect, with sublingual route preferred for initial therapy[35][36]
Phentolamine may be used as a second-line agent in those refractory to nitrate and benzodiazepine therapy[37][31]
If there is still not adequate improvement, coronary angiography should be considered to assess for thrombosis or coronary artery spasm with, with subsequent intra-coronary (rather than peripheral) administration of thrombolytics or coronary vasodilators[30]
 

Arterial Spasm

Arterial spasm is reported with accidental intra-arterial injection of vasoconstrictors used therapeutically,[38][39][40] and also with recreational use of amphetamines and some other drugs, usually[41] (but not always)[42] via this route. There is clear risk of ischemia and subsequent tissue necrosis.
 
Monitor for arterial spasm.

Manage arterial spasm following standard treatment protocols.

Metabolic

Hyperthermia

Severe hyperthermia may develop as a result of hypothalamic dysfunction, metabolic and muscle hyperactivity, or prolonged seizures.[21][43] Hyperthermia can indicate a poor prognosis and aggressive management is required.[44][21][45][12] In patients with a core body temperature > 39 degrees who do not rapidly respond to active cooling measures and initial benzodiazepine sedation, general anesthetic sedation and intubation should be considered.
 
Closely monitor core body temperature.
 

Metabolic Acidosis

Metabolic acidosis may arise secondary to seizures and/or inadequate tissue perfusion;[11] patients suffering metabolic acidosis have poor outcome.[21]Metabolic acidosis should be aggressively managed through treatment of contributing physiological derangements including agitation, hypotension, and hyperthermia. Administration of sodium bicarbonate is not considered a routine part of management of metabolic acidosis, but may be considered in severe cases resistant to initial interventions.
 
Monitor:
Blood gases
Plasma lactate
 
Manage metabolic acidosis following standard treatment protocols.
 

Musculoskeletal

Rhabdomyolysis

Those suffering severe agitation, excessive muscular activity, or hyperthermia are at risk of developing rhabdomyolysis.[46][47][12]
 
Monitor:
Serum creatine kinase (CK)
Renal function
Urine output
Urinalysis
Myoglobin
pH
 

Renal

Acute Kidney Injury

Sympathomimetic-induced acute kidney injury is considered to occur due to circulatory collapse, rhabdomyolysis, vasculitis, hyperthermia, or a combination of these factors rather than direct toxicity.[21][11][48] Close monitoring and robust supportive care is required. Hemodialysis may be required.
 
Patients should be monitored for the onset of acute kidney injury:
Urine output
Serum creatinine
Blood urea nitrogen (urea)
Proteinuria
 
Manage acute kidney injury following standard treatment protocols.
 

Fluid and Electrolytes

Hyponatremia

Hyponatremia may result from profuse sweating and excessive rehydration and/or SIADH (syndrome of inappropriate secretion of antidiuretic hormone).[49] Further fluid ingestion may have severe consequences. While the majority should settle with fluid restriction and observation, cerebral edema, seizures, life-threatening encephalopathy, and tentorial herniation may occur.
 
Monitor serum sodium

Management is controversial. Rapid correction of hyponatremia with hypertonic fluid is not considered necessary: Fluid restriction to < 1 L/day, and close observation may be all that is required in the majority of cases. Central venous pressure may need to be determined to measure extra-cellular fluid depletion.[50] If there are CNS signs such as confusion, loss of consciousness or seizures, perform a CT brain scan to identify cerebral edema. If there is evidence of cerebral edema then IV mannitol[51] or loop diuretics may be necessary.[52]
 

Dehydration

Profuse sweating, increased activity, tachypnea, and hyperthermia may lead to significant body fluid depletion. Before managing patients for dehydration, it is important to exclude the possibility of hyponatremia as fluid administration in such cases could potentially be fatal.

Monitor for signs of hypovolemia:
Blood pressure
Measure serum electrolytes including sodium and potassium
 
Serum sodium must be measured prior to rehydration to exclude the possibility of hyponatremia. Aggressive intra-venous rehydration with Swan-Ganz monitoring may be required.[21]
 

Hyperkalemia

Development of hyperkalemia suggests a poor prognosis.[21] Management with hemodialysis may rarely be required in severe cases of acute kidney injury.
 
Monitor:
Serum potassium
Blood gas analysis
Renal function and urine output
ECG for changes suggestive of hyperkalemia including
Peaked T waves (tenting)
Flattened P waves
Prolonged PR interval (first-degree heart block)
Widened QRS complex
Deepened S waves and merging S and T waves
Idioventricular rhythm
Sine-wave formation
VF and cardiac arrest
 

Hepatic

Hepatotoxicity

Hepatotoxicity is well recognized with certain hallucinogenic amphetamines. Commonly it is a mild (viral-like) hepatitis with jaundice, hepatomegaly, increased bleeding tendency and liver enzymes, and an acute hepatitis evident on biopsy. Spontaneous recovery usually occurs over a period of weeks or months, though attacks may be repeated in chronic users.[53][54] This picture may however progress to fulminant hepatic failure – fatal unless liver transplant can be arranged. An intermediate stage is reported where recovery may spontaneously occur, after a prolonged course, but permanent liver fibrosis may develop.[55]
 
Hepatic monitoring should include:
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
International normalized ratio (INR)
Serum bilirubin
Blood or plasma glucose
Serum lactate
 
Manage acute hepatotoxicity following standard treatment protocols.
 

Other

Movement Disorder

Choreoathetoid movements are uncommon, but are associated with both acute and chronic abuse of sympathomimetic compounds.[56] They can be managed with a benzodiazepine, or if still refractory, cautious use of an antipsychotic agent such as haloperidol.[57] It must be remembered that haloperidol lowers seizure threshold, interferes with thermoregulation and may precipitate dystonia or cardiac dysrhythmia.
 

Infection

Drug abuse may be via intravenous injection of ground tablets. Bacterial endocarditis is a recognized complication,[4] and there is potential for viral hepatitis/HIV infection.
 

Ocular

Ensure thorough and adequate decontamination using water or saline. Irrigation should be continued until a pH of 7 to 8 is achieved and maintained for 2 hours.[58]
 
Examine for:
Conjunctivitis
Lacrimation
Photophobia
Pupil abnormality
Visual acuity
Corneal defect with fluorescein staining
 

Dermatologic

Skin Burn

Examine patient for skin burns:
Tenderness
Erythema
Blistering
 
Manage chemical skin burns following standard treatment protocols for thermal skin burns.
 

DISCHARGE CRITERIA

Patients may be discharged from hospital care when clearly asymptomatic and fully recovered from any complications. Appropriate psychiatric intervention may be necessary depending on the circumstances of the exposure.
 

FOLLOW UP

Patients should be referred for psychiatric assessment as appropriate.
 
If exposure arose from intentional self-use or dependency, patients should be referred if possible to an appropriate substance abuse program.
 

PROGNOSIS

Following acute recovery from overdose there are rarely on-going physical effects following mild or moderate intoxications, unless withdrawal occurs; this generally peaks at 2 to 3 days, lasting some 6 days. Continuing neuropsychiatric effects such as psychosis may arise, generally resolving after days to weeks.[59]
 
Those recovering from chronic abuse and/or severe intoxications may suffer long-term effects including cardiomyopathy, ischemic organ damage; neurological sequelae resulting from hemorrhage; and renal insufficiency/failure as a consequence of rhabdomyolysis.[46] Pulmonary granulomata with accompanying reduced pulmonary function, and pulmonary hypertension are particular concerns of intravenous abuse.[5][4]
 
Death is uncommon, but can result following severe complications of abuse.
 

SIGNS AND SYMPTOMS

The correct identification of the substance is important. If the symptoms are inconsistent with those described in the literature, or the history is considered unreliable, other substances may need to be considered.
 
Piperazines have a stimulant effect resulting from increased monoamine (dopamine, serotonin, norepinephrine (noradrenaline)) availability.[60]
 
Piperazine toxicity commonly causes tachycardia, hypertension, palpitations, gastrointestinal upset (nausea, abdominal pain, vomiting), dehydration, headache, anxiety, fever, and agitation.[61][62][63][2] Mydriasis, blurred vision, sweating, tremor, and confusion are relatively common. Trismus and paresthesia may uncommonly occur,[61] while hallucinations, hyperventilation, shortness of breath, and flushed skin are rare.[2]
 
In more severe cases, seizures, collapse, myoclonic jerking, and extrapyramidal features (choreoathetoid movements, dystonic reactions) may occur.[61] Serotonin syndrome has also been reported.[64] Hypertension can be severe.[61] If prolonged or severe, fever and excessive motor activity may lead to hyperthermia, metabolic acidosis, disseminated intravascular coagulation, and acute kidney injury.[65] Psychosis has been reported.[66] Given piperazine's mechanism of action, theoretical concerns are cardiac dysrhythmia, acute hepatitis/liver failure, and death.[67]
 
Hypersensitivity reactions, such as bronchospasm, Stevens-Johnson syndrome, acute hepatitis, thrombocytopenia, hemolytic anemia and angioedema have occurred in individuals taking piperazine therapeutically.
 

Routes of Exposure

Benzylpiperazine (BZP) liquid and dust is known to be corrosive. This may cause burns to the gastrointestinal tract if swallowed or to the eye or skin if these areas are contaminated. Piperazine based hallucinogenic stimulants are also smoked by some individuals and there is also the potential for effects similar to inhalation of a corrosive (or acid) gas to manifest.
 
Tablets are often dissolved and directly injected. Due to the bulk of these tablets being composed of non-water soluble agents such as talc there is a high rate of complications following granuloma formation and vascular obliteration.[5][4] While the lung is a particular target with resultant pulmonary hypertension/cor pulmonale, other organs can be affected. Infection following such abuse is also a concern.[3]
 

Onset/Duration of Symptoms

Onset of affect is usually delayed about 2 hours post-ingestion.[1][68] Effects generally persist for about 12 to 24 hours, but may occur for up to 72 hours following use.[61] There may be a role for monoamine depletion/withdrawal in prolonged toxicity.

Severity of Poisoning

Mild Piperazine ToxicityModerate Piperazine ToxicitySevere Piperazine Toxicity
Increased alertness
Mydriasis
Bruxism (grinding of teeth)
Altered mental status
Tachycardia
Hypertension
Agitation
Paranoia
Hallucinations
Diaphoresis
Vomiting
Abdominal pain
Palpitations
Chest pain
Hyperthermia
Hyponatremia
Metabolic acidosis
Rhabdomyolysis
DIC (disseminated intravascular coagulation)
Acute renal failure
 

ACUTE EFFECTS (ORGAN SYSTEM)

Neurologic

Hallucinations[73][74][76]
Paranoia[69][73][76]
Dysphoria[75][78]
Bruxism (teeth grinding)[72]
Paresthesia[73][79]
Psychosis[66]
Decreased level of consciousness[62]
Choreoathetoid movements[61]
Myoclonic jerking[62]
 

Cardiovascular

Respiratory

Dyspnea[70]
Shortness of breath[73]
Hyperventilation[61][63]
Respiratory failure[79]
 
Sympathomimetic compounds have been associated with the development of severe non-cardiogenic pulmonary edema.[81]
 

Gastrointestinal

Metabolic

Hyperthermia[65][70]
Respiratory or metabolic acidosis[61][65]
Hypoglycemia[65]
 

Fluid and Electrolytes

Hyponatremia[61][65]
 

Renal

Acute urinary retention[61][63][69][73]
Flank pain[82]
Acute renal impairment or failure[65][82][83]
 

Hepatic

Hepatotoxicity[65]
 

Dermatologic

Diaphoresis[61][73]
Flushing[68]
Pruritus[70]
 

Ocular

Mydriasis (dilated pupils)[65][70][71][72]
Blurred vision[73][79]
 

Hematologic

Serious exposures may cause:
Disseminated intravascular coagulation[65]
 

Musculoskeletal

Bruxism (tooth grinding)[72]
Trismus (tonic spasms of jaw muscles)[61]
Muscular/joint aches[73]
Rhabdomyolysis[65]
 

Other

Serotonin Toxicity (Syndrome)

Serotonin syndrome has been reported following exposure to piperazine compounds.[64][65] There is significantly increased risk if there is coningestion of other serotonergic drugs, either therapeutically or recreationally (e.g. SSRI’s, MAOI’s).[84] Onset is usually within 2 hours of the first dose/overdose of the precipitating agent, and generally resolves within 6 to 24 hours of removal of the offending compound(s). Severe cases may persist for more than 48 hours[85] (potentially longer than 96 hours if there are complications, or a drug with prolonged duration of action is involved).[86] If severe, complications may include hypotension, metabolic acidosis, rhabdomyolysis, cardiovascular collapse, renal failure, disseminated intravascular coagulation, and death.
 
Serotonin toxicity is usually associated with multiple drug ingestion or large overdoses.[87] Onset is usually within 2 hours of ingestion of the precipitating agent, and generally resolves within 6 to 24 hours of removal of the offending compound(s). Severe cases may persist for more than 48 hours[85] (potentially longer than 96 hours if there are complications, or a drug with prolonged duration of action is involved).[86] Combinations recognized to cause severe serotonin toxicity include MAOI’s (including reversible inhibitors), SSRIs, SNRIs, or serotonin releasing agents such as MDMA.[84]
 
Serotonin toxicity is characterized by a spectrum of neuroexcitation with a triad of clinical effects:[84]
Neuromuscular hyperactivity (hyperreflexia, clonus, myoclonus, tremor, and rigidity);
Autonomic hyperactivity (hyperthermia, tachycardia, and diaphoresis), and;
Altered mental status (agitation, anxiety, hypomania, and confusion)
 
A set of decision rules has been developed to aid the identification of serotonin toxicity.[20]
    1. IF (spontaneous clonus = yes) THEN serotonin toxicity = YES
    2. ELSE IF (inducible clonus = yes) AND [(agitation = yes) OR (diaphoresis = yes)] THEN serotonin toxicity = YES
    3. ELSE IF (ocular clonus = yes) AND [(agitation = yes) or (diaphoresis = yes)] THEN serotonin toxicity = YES
    4. ELSE IF (tremor = yes) AND (hyperreflexia = yes) THEN serotonin toxicity = YES
    5. ELSE IF (hypertonia = yes) AND (temperature > 38ºC) AND [(ocular clonus = yes) or (inducible clonus = yes)] then serotonin toxicity = YES
    6. ELSE serotonin toxicity = NO
 
NOTE: Multiple non-specific clinical findings may be present in a patient with possible serotonin toxicity and so a wide differential diagnosis must be investigated. Conditions including infection, metabolic derangement, or withdrawal states need to be considered. Neuroleptic syndrome should be considered if the patient has been commenced on neuroleptic agents or had an increase in neuroleptic dose.
 

Lead Poisoning

Lead may be incorporated in the illicit manufacturing process of amphetamine and amphetamine-like compounds, resulting in sporadic outbreaks of lead contamination and subsequent poisoning of abusers.[88][89][90] Signs and symptoms include:
 
Abdominal pain
Nausea
Vomiting
Low back and leg pain
Weakness
Anorexia
Weight loss
 

ACUTE EFFECTS (ROUTE OF EXPOSURE)

Ingestion

Ingestion of liquid free-base BZP is corrosive and may cause burns to the mouth, throat, esophagus and stomach. Ingestion of tablets or capsules is not likely to cause any local effects.

Skin

BZP liquid may cause burns if left on the skin for a prolonged period of time.

Eye

BZP liquid or dust may cause corrosive injury to the eye. The exact nature of injury has not yet been determined.

Injection of Dissolved Tablets

Tablets are often dissolved and directly injected. As the bulk of these tablets are composed of non-water soluble agents such as talc there is a high rate of complications following granuloma formation and vascular obliteration.[5][4] While the lung is a particular target with resultant pulmonary hypertension risking cor pulmonale (dysfunction of the right ventricle); other organs can also be affected. Vasculitis and infection following such abuse is also a concern;[3] and inadvertent arterial injection or tissue extravasation may cause granuloma formation, vasospasm, ischemia, and necrosis.[91][92]
 
Infection[4]
Pyrexia[4]
Foreign body reaction[93]
Bacterial endocarditis[4]
Pulmonary granuloma
Foreign body granuloma[5][4]
Pulmonary hypertension[5]
Cor pulmonale[5]
Congestive heart failure[5][4]
 

Inhalation

BZP is sometimes dried in air or salted out with hydrochloric acid to form a solid which is then smoked in a manner similar to crack cocaine. This may cause effects similar to inhalation of a corrosive (or acid) gas, as the liquid and dust forms of BZP are known to be corrosive. These effects may include respiratory irritation, chest pain, cough and bronchospasm. This may progress to pneumonia or pulmonary edema.

CHRONIC EFFECTS

Hypersensitivity reactions, such as bronchospasm, Stevens-Johnson syndrome, acute hepatitis, thrombocytopenia, hemolytic anemia and angioedema have occurred in individuals taking piperazine therapeutically.[94]
 
Given their mechanism of action, theoretical concerns following chronic us/abuse of piperazines would be similar to hallucinogenic amphetamines.
 

Cardiovascular

Chronic oral amphetamine abuse has been associated with:[95][96]
Cardiomyopathy (non-ischemic)
Vascular spasm
Aortic dissection
Congestive heart failure[5][93]
Pulmonary hypertension[5]
 
Chronic intravenous abuse with:[22]
Widespread necrotising angiitis
Aneurysm
Sacculations
Segmental stenosis
Vascular rupture
Thrombosis
Hypertension
Pulmonary edema
Renal failure
 

Neurologic

If large amounts of amphetamine or amphetamine-like compounds are consumed over a long period of time, amphetamine psychosis can develop, which is similar to paranoid schizophrenia. The psychosis is manifested by hallucinations, delusions and paranoia. Symptoms usually disappear within a few weeks after drug use stops.
 
A range of sequelae have been noted following chronic human abuse including:
Choreoathetoid movements[97]
Hallucinations[98]
Visual
Tactile
Olfactory
Auditory (less common)
 
A lasting paranoid psychotic reaction may develop,[99] and behavior can become destructive and violent. While the majority of patients recover within 10 days, effects persist for more than 6 months in 10% of cases.[100][101][102] Single re-exposures may produce acute exacerbations even after long periods of abstinence.
 

Gastrointestinal

Ischemic colitis can occur following long-term use of amphetamines.[103]
 

Other

Diffuse hair loss has been associated with long-term amphetamine use.[104][105]
 
Amphetamine and amphetamine-like compounds have rarely produced aplastic anemia and a fatal pancytopenia after prolonged use.[106]
 
Infections such as hepatitis B and C and HIV are possible complications of intravenous use of amphetamine and amphetamine-like compounds.[106]
 

Tolerance

Tolerance can develop to the anorectic and various autonomic effects including body temperature, blood pressure, heart rate and respirations.[107]
 

Withdrawal Syndrome

Acute withdrawal may precipitate severe depression and suicidal thoughts. Symptoms usually peak after 2 to 3 days and are seldom directly life-threatening.
 
Physical symptoms associated with withdrawal are:[11][108][109]
Abdominal cramps
Anxiety
Craving
Moderate to severe depression
Diaphoresis
Dyspnea
Exhaustion
Gastroenteritis
Headache
Increased appetite
Irritability
Insomnia
Lethargy
Mental confusion
Psychotic reaction
Restlessness
 

Washout Syndrome

A washout syndrome has been reported following cocaine use[110][111][112] and it is thought a similar syndrome with may occur with amphetamines or other stimulants. Most commonly observed after extended binges, the mechanism is thought to be depletion of adrenergic neurotransmitters due to prolonged and persistent CNS stimulation.[110][111][112]
 
Effects associated with washout are:[110][111]
Hypersomnolence
Decreased level of consciousness
Psychomotor retardation
Hypotension
Bradycardia
Hyporeflexia
Dysconjugate gaze
 

TOXICITY

HUMAN

Clinical observation is more relevant than an estimate of the actual dose.

Acute

An ingestion of 50 to 100 mg of BZP in an adult is unlikely to cause serious toxicity. It is likely to produce mild effects, such as wakefulness and alertness and very mild increases in heart rate and blood pressure.[1]
 
It is predicated that doses over a total of 250 mg of a piperazine-based designer drug would be likely to cause moderate toxicity, such as anxiety, agitation, hypertension, tachycardia, palpitations, gastrointestinal upset and headache. This may be uncommonly accompanied by seizure, tremor, hallucinations, fever, chest pain, jaw clenching, fever and hallucinations.
 
An increase in dose to 500 mg may cause these toxic effects to be prolonged. Symptoms appear to last approximately 24 to 48 hours, but anecdotally, have been reported to last up to 3 days.
 

Chronic

There is no conclusive evidence of the effects of chronic use of piperazine-based designer drugs in humans.
 
In one study, former amphetamine addicts were given separate single doses of 100 mg BZP and 7.5 mg dexamphetamine. Subjects rated both drugs as equally pleasurable, and both doctor and patient subjective ratings of stimulant effects were similar for both drugs.[68]
 
There are no studies to show the effects of multiple doses, or long term effects of this drug.
 

BIOLOGICAL LEVELS - TOXIC

Blood concentrations may be used to confirm exposure but are not a reliable guide to patient management.
 

REPRODUCTION

PREGNANCY

The effects of exposure to this substance during pregnancy are unknown.
 
It is recommended that this substance should not be used during pregnancy.

Piperazine itself does cross the placenta and may affect the infant. Taking piperazine during pregnancy is generally not considered acceptable, particularly in the first trimester, unless immediately essential.
 
Piperazine is reported as teratogenic in rabbits. There have been two isolated cases of human fetal malformation, but a causal link was not established.[113]
 
Maternal misuse of injectable substances carries a high risk of exposure to infections such as HIV or hepatitis through exchange of needles and lack of sterile equipment/procedures. During pregnancy, many of these infections, if developed, can be passed directly on to the fetus.
 
Given the mechanism of action, chronic use/abuse of piperazines may pose the same risks of dependence and withdrawal in the fetus and neonate.
 

Withdrawal Syndrome

Child

Amphetamine withdrawal pattern in infants:[114]
- Abnormal sleep patterns
- Tremors
- Hypertonia
- High-pitched cry
- Poor feeding
- Vomiting
- Sneezing
- Frantic sucking
- Tachycardia
 
Australian Classification:
X
 
FDA Classification (before July 2015):
X
 

LACTATION

It is recommended that this substance should not be used while breast feeding.

Piperazine itself is excreted into breastmilk and may affect the infant. Piperazine is cautiously administered to nursing mothers, provided that there is no breastfeeding for 8 hours post ingestion, and any milk is expressed and discarded during this time.[115]
 

TOXIC MECHANISM

Piperazines act to increase monoamine availability.[2] Different piperazines have varying effects on the different monoamines, but in overdose this selectivity is generally lost.
 
Benzylpiperazine (BZP) has direct serotonin[116]and dopamine agonist activity,[60]and also inhibits uptake of serotonin, dopamine, and norepinephrine (noradrenaline).[116][117][118] Trifluoromethylphenylpiperazine (TFMPP) has direct serotonin agonist activity[119][60] but lacks the dopaminergic and noradrenergic action of BZP.[120][121] When administered together, BZP and TFMPP mimic the release of both dopamine and serotonin following methylenedioxymethamphetamine (MDMA),[60][122]to a greater degree than when BZP or TFMPP are given alone.[118] Other piperazines are less well studied. Methoxyphenylpiperazine (MeOPP) is a serotonin (5HT-1) agonist,[117] methylenedioxybenzylpiperazine (MDBP) inhibits serotonin uptake[118]and m-chlorophenylpiperazine (mCPP) acts similarly to MDMA,[123]probably via its action on monoamines.[124]Methylbenzylpiperazine (MBZP), and p-fluorophenylpiperazine (pFPP) remain unstudied.
 

THERAPEUTIC DRUG INFORMATION

PHARMACOLOGICAL ACTION

Piperazines act to increase monoamine availability.[2] Different piperazines have varying effects on the different monoamines, but in overdose this selectivity is generally lost.
 
Benzylpiperazine (BZP) has direct serotonin[116]and dopamine agonist activity,[60]and also inhibits uptake of serotonin, dopamine, and norepinephrine (noradrenaline).[116][117][118] Trifluoromethylphenylpiperazine (TFMPP) has direct serotonin agonist activity[119][60] but lacks the dopaminergic and noradrenergic action of BZP.[120][121] When administered together, BZP and TFMPP mimic the release of both dopamine and serotonin following methylenedioxymethamphetamine (MDMA),[60][122]to a greater degree than when BZP or TFMPP are given alone.[118] Other piperazines are less well studied. Methoxyphenylpiperazine (MeOPP) is a serotonin (5HT-1) agonist,[117] methylenedioxybenzylpiperazine (MDBP) inhibits serotonin uptake[118]and m-chlorophenylpiperazine (mCPP) acts similarly to MDMA,[123]probably via its action on monoamines.[124]Methylbenzylpiperazine (MBZP), and p-fluorophenylpiperazine (pFPP) remain unstudied.
 
Amphetamines and amphetamine-like compounds have greater stimulating activity than catecholamines. These compounds work to increase post-synaptic catecholamines and stimulate dopaminergic cortical centres to produce a central stimulant response.[11]
 
Mechanism of Action:
 
Indirect sympathomimetic action through:
The inhibition of presynaptic vesicular storage and catecholamine reuptake
The reduction of catecholamine metabolism, via monoamine oxidase inhibition
A stimulating effect on several brain regions including the:
Cerebral cortex
Medullary vasomotor centre
Reticular activating system
Direct action on both alpha- and beta-adrenoreceptors.
 

KINETICS

ABSORPTION

Oral Absorption
Yes, rapidly absorbed[125]
Onset of Action
Onset usually delayed about 2 hours post-ingestion.[1][68]
Duration of Action
Effects may persist for about 12 to 24 hours or longer.[61]
Time to Peak Plasma Levels
60 to 75 minutes[125][126]
 

DISTRIBUTION

Distribution
  1. Distributed throughout the body
 

METABOLISM

Metabolism
  1. Extensively metabolized[2]
Metabolites
  1. 3-hydroxy-BZP
  2. 4-hydroxy-BZP
  3. 4-hydroxy-3-methoxy-BZP
  4. Piperazine
  5. Benzylamine
  6. N-benzylethylenediamine[127]
Major Metabolic Pathways
Parent:
  1. Hydroxylation
  2. Methylation
  3. Dealkylation[127]
 

ELIMINATION

Excretion
Urine
  1. 12.5 to 13.3% of BZP and its metabolites recovered in urine after 24 hours[125][126]
Half-life
Overdose
  1. 4.3[126] to 5.5[125] hours
Time to Completion
  1. Approximately 44 hours[125]
 

IDENTIFICATION

The correct identification of the substance is important. If the symptoms are inconsistent with those described in the literature, or the history is considered unreliable, other substances may need to be considered.
 

PRODUCT INFORMATION

This substance may be available in a stated dosage, however, this should be treated with some caution particularly if obtained illicitly, due to variables such as uncontrolled manufacturing process, inappropriate packaging, and product bulking.
 
Some names for piperazine-based designer drugs are actually street names that refer to the imprint on the tablet, rather than a brand name. These pills are sometimes sold to a consumer as MDMA (Ecstasy) but may contain anywhere between zero to 500 mg of benzylpiperazine (BZP) plus trifluoromethylphenylpiperazine (TFMPP).

Generally, tablets and capsules contain Benzylpiperazine (BZP). These capsules can range from 70 to 1000 mg BZP. Some products contain BZP in combination with Trifluoromethylphenylpiperazine (TFMPP), generally in a ratio of 2:1 (e.g. 200 mg BZP plus 100 mg TFMPP).
 
Some products may contain flipiperazine (PFPP), m-chlorophenylpiperazine (MCPP), p-methoxyphenylpiperazine (MEOPP) or methylenedioxybenzylpiperazine (MDBP).
 
Some products come with separate "recovery" capsules containing 5-hydroxytryptophan (5-HTP), which is a serotonin precursor and causes serotonergic symptoms. These capsules generally contain between 50 and 500 mg of 5-HTP.
 
Some capsules claim to contain an "anti-seizing" agent, which is actually therapeutically inactive.
 

FORM

Caplet
 

OTHER NAME(S)

Common Names

1-benzylpiperazine
A2
Benzylpiperazine
 

Chemical Name

BZP:
1-Benzyl-1,4-diazacyclohexane dihydrochloride
 

“Street” Names

  1. A2
  2. Amp
  3. Black pepper extract
  4. Blizzard
  5. Chanel
  6. Cosmic bliss
  7. Crystal
  8. ESP
  9. Exodus - the journey
  10. Good stuff
  11. Groove
  12. Herbal E
  13. Herbal speed
  14. Ice Diamonds
  15. Jet
  16. Kandi
  17. Legal E
  18. Move
  19. Mr Grin
  20. Pulse
  21. Purple hooters
  22. Purple tart
  23. Rapture gold
  24. Shotgun
  25. Sweet tarts
  26. The good stuff
  27. Triple crown
  28. Up
  29. Wannabe
  30. X
  31. Zoom
  1. Altitude
  2. Aquarius
  3. Blast
  4. Bolts
  5. Charge
  6. Cosmic jet
  7. Divine
  8. Euphoria
  9. Extra sensory pill
  10. Green fly
  11. Grunter
  12. Herbal ecstasy
  13. Herbal X
  14. Jax
  15. Jet pills
  16. Kandis
  17. Legal X
  18. MPH
  19. Nemesis
  20. Purple dome
  21. Purple passion
  22. Question mark
  23. Red Hearts
  24. Smiley
  25. Synthetic black pepper extract
  26. The grunter
  27. Triple stacked crown
  28. Viper
  29. White butterfly
  30. X Extreme
  1. Altitude Ultra Premium
  2. Big Grin
  3. Bliss
  4. C4
  5. Charge herbal
  6. Crown
  7. Double T
  8. Exodus
  9. Frenzy
  10. Grin
  11. Guerrilla mini
  12. Herbal high
  13. Hummer
  14. Jaxx
  15. Jump
  16. Kiniside
  17. Mashed
  18. MPH 750
  19. Nemi
  20. Purple frenzy
  21. Purple pills
  22. Rapture
  23. Scarfies
  24. Smurfs
  25. The big grin
  26. Torque
  27. Twisted
  28. Voyager
  29. Whizzers
  30. Xtreme
 

CODES

CAS NUMBER

1-Benzylpiperazine:
2759-28-6
 

MOLECULAR FORMULA

Benzylpiperazine:
C11H16N2
 

PHYSICOCHEMICAL PROPERTIES

Pale yellow viscous liquid, sensitive to light, air and moisture. No odor
Molecular Weight
176.26 176.26
Melting Point
0 degrees C0 degrees C
Flash Point
> 112 degrees C> 112 degrees C
 

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