Benzodiazepine Poisoning and Withdrawal

Benzodiazepine poisoning

Poison control centers phone 1-800-222-1222

short-acting (half-life of less than 12 hours), intermediate-acting (half-life between 12 and 24 hours), and long-acting (half-life greater than 24 hours). Short-acting benzodiazepines generally have few active metabolites, do not accumulate with repeated doses, and demonstrate clearance that is largely unaffected by age and liver disease. Examples include triazolam and oxazepam. Although midazolam possesses a short half-life, it has active metabolites that can accumulate with repeated dosing.Intermediate-acting benzodiazepines include lorazepam and temazepam. Longacting benzodiazepines generally have pharmacologically active metabolites, accumulate in tissues after multiple doses, and demonstrate impaired clearance in older patients and those with liver disease. Examples include diazepam and chlordiazepoxide BZDs are rapidly absorbed in the GI tract , highly protein bound, metabolism of BZDs is primarily hepatic .Interactions with other drugs that are metabolized by CYP enzymes may prolong the half-lives of certain BZDs include macrolide antibiotics, diltiazem, HIV protease inhibitors, and grapefruit juice . Oxazepam, temazepam, and lorazepam are directly conjugated to an inactive, water-soluble glucuronide metabolite that is excreted by the kidney and are less likely to accumulate in patients with CYP inhibition. Chlordiazepoxide, diazepam, and flurazepam are metabolized to active metabolites, which then are conjugated and excreted Oral benzodiazepines (BZD) taken in overdose without a coingestant rarely cause significant toxicity .Isolated BZD overdose consists of CNS depression with normal vital signs. Many patients are arousable and able to provide an adequate history , slurred speech, ataxia, and altered (most commonly depressed) mental status. Respiratory compromise is uncommon with isolated oral ingestions, but may be seen when patients ingest additional sedative hypnotic agents (such as ethanol) .Severe toxicity can present stuporous or comatose. Propylene glycol (1,2 propanediol) is the diluent used in parenteral formulations of diazepam and lorazepam and the cause of a unique complication related to the prolonged parenteral administration of these BZDs. The potential effects of PG toxicity include skin and soft tissue necrosis (from extravasation), hemolysis, cardiac dysrhythmias, hypotension, lactic acidosis, anion gap metab acidosis, the osmolar gap correlates with PG concetrations,seizure, coma, and multisystem organ failure. Any number of sedative-hypnotic medications share clinical features with BZDs in overdose, including ethanol, barbiturates, gamma hydroxybutyrate (GHB), and chloral hydrate. The sedative hypnotic toxidrome is characterized by a depressed mental status, an unremarkable physical examination, and normal vital signs, hence the common description "coma with normal vitals." Get serum concentrations of ethanol and phenobarbital .Gamma hydroxybutyrate intoxication often manifests abrupt alterations in mental status without intervention and severe respiratory depression can occur. ( An isolated overdose with oral BZDs rarely causes profound respiratory depression requiring invasive airway management or cardiopulmonary instability. In such cases, the presence of coingestants should be investigated.

In general, BZD metabolites can be detected as early as three hours after ingestion and may remain detectable for up to two weeks in the urine .Serum BZD concentrations are poorly with clinical findings, and do not aid management. General diagnostic testing ●Fingerstick glucose, ●Acetaminophen and salicylate levels, ●Electrocardiogram (ECG), to rule out conduction system poisoning ●Pregnancy test serum ethanol concentration -biochemistry, cbc pannel In cases of isolated BZD overdose, particular attention paid to signs of respiratory dysfunction, trauma, and poisoning from coingestants and regular monitoring are likely to be all that is necessary. BZD overdose involving a coingestant, such as an opioid or alcohol, increases the risk for dangerous complications .If a concomitant opioid overdose may be present administer naloxone. Gastrointestinal decontamination with activated charcoal (AC) is usually of NO benefit in cases of isolated BZD ingestion and increases the risk of aspiration. Flumazenil is a nonspecific competitive antagonist of the BZD receptor. It can be used to reverse BZD-induced sedation following general anesthesia, procedural sedation, or overdose Administration of flumazenil can precipitate withdrawal seizures in patients who have developed a tolerance to BZDs through chronic use or abuse. Such risks may be further increased if the patient has taken coingestants with proconvulsant properties. Of note, flumazenil does NOT consistently reverse respiratory depression caused by BZD overdose . Because oral BZD overdose has a low rate of morbidity and mortality is rare, the risks of flumazenil treatment often outweigh its benefits. The purported benefit of flumazenil is to avoid the need for procedures, such as endotracheal intubation, CT imaging, and lumbar puncture, should the patient's mental status return to normal when the BZD's sedative effects are reversed. We suggest consultation with a poison control center. Flumazenil appears to be safe and effective when used to reverse the sedating effects of a BZD given for procedural sedation in patients who do not use BZDs chronically . In adults, the recommended initial dose is 0.2 mg given intravenously (IV) over 30 seconds. Repeated doses of 0.2 mg, to a maximum dose of 1 mg, In the event of resedation, the dosing regimen described here can be repeated, but no more than 3 mg of flumazenil should be given within any one hour In children, the initial dose is 0.01 mg/kg given IV over 15 seconds (maximum dose 0.2 mg). The initial dose may be followed at one or more minute intervals with up to four repeat doses of 0.005 to 0.01 mg/kg (maximum 0.2 mg) per dose. The maximum dose should NOT exceed 1 mg total or 0.05 mg/kg; The peak effect of a single flumazenil dose occurs approximately 6 to 10 minutes after IV administration. For patients at greater risk of seizure or agitation with BZD reversal, a longer wait of several minutes between subsequent doses may be warranted. The duration of flumazenil is short (0.7 to 1.3 hours) and the duration of effect of a long-acting BZD or a large BZD dose can exceed that of flumazenil. Resedation may be treated in adults by using 0.2 mg doses (maximum total dose 1 mg) until the desired effect is achieved. For patients with exposures to BZDs with prolonged durations of

action or those with hepatic insufficiency with prolonged exposure to BZDs, a continuous flumazenil infusion (0.25 to 1 mg per hour) may be needed isolated BZD ingestion can be safely discharged or transferred for psychiatric evaluation following an observation period of four to six hours, if any concerning symptoms, such as CNS depression, have resolved and they ambulate safely WITHDRAWAL Any abrupt or overly rapid reduction in benzodiazepine (BZD) dose among chronic users .The syndrome can be life-threatening. Can include tremors, anxiety, perceptual disturbances, dysphoria, psychosis, and seizures The onset of withdrawal varies according to the half-life of the BZD involved. Symptoms may be delayed up to three weeks in BZDs with long half-lives, but may appear as early as 24 to 48 hours after cessation of BZDs with short half-lives. The severity and duration of withdrawal depends on period of BZD use, how rapidly use was tapered (if at all), the pharmacokinetics of the particular drug, as well as possible genetic factors .Most symptoms last from one to two weeks . Withdrawal can usually be avoided or minimized through the use of BZDs with a long half-life, such as diazepam or chlordiazepoxide, and a gradual tapering of the patient's BZD dose over several months, BZD withdrawal is treated with a BZD that has a prolonged clinical effect, such as diazepam, given intravenously if serious symptoms and then changed to oral .In mild BZD withdrawal, a long-acting oral BZD may be given; it is also reasonable to give such a patient the BZD that they had been using chronically.. Pending further study, treatments other than BZDs cannot be recommended for the management of BZD withdrawal. Acute opioid intoxication in adults Hypothermia should be treated.. Mental status can range from euphoria to coma, or be nearly normal. Seizures typically occur in the setting of tapentadol, tramadol, or meperidine overdose, or as a result of hypoxia from any opioid.Look for signs of trauma , presence of aspiration or acute respiratory distress syndrome. If attempting to hide drugs, rectal and vaginal examination should be done Buprenorphine induces withdrawal in opioid-dependent patients ●Dextromethorphan – Serotonin toxicity; at high doses exhibits some µ effects of opioids (miosis, respiratory and CNS depression) ●Loperamide – QRS and QT prolongation; Wide-complex tachycardia ●Meperidine – Seizure, serotonin toxicity (in combination with other agents) ●Methadone – Very long-acting; QT prolongation, Torsade de Pointes Oxycodone possible QT interval prolongation ●Tramadol and tapentadol – Seizure DD Ethanol, clonidine, and sedative-hypnotics (eg, benzodiazepines). While clonidine produces miosis and obtundation, bradycardia, and hypotension are more prominent. The sine qua non of opioid toxicity is a clinical response to an antagonist. Any medical condition that produces coma may be mistaken for (or occur in conjunction with) opioid poisoning. Laboratory evaluation — serum glucose, acetaminophen , salycylate levels, CK for rhabdomyolysis, CMP .Urine toxicologic screens should NOT be routinely obtained. A positive test indicates recent use but does not confirm active toxicity, and may even represent a false positive. Conversely, many opioids, especially the synthetic drugs, will

produce false-negative .ECG if coexposure (eg, cocaine or a cyclic antidepressantor opiates that cause card effects If QRS or QT prolongation is identified on the initial ECG, continuous cardiac monitoring including serial ECGs should be continued until intervals normalize or return to baseline. If the initial ECG is normal, it is reasonable to repeat the test in four to six hours if there is suspicion of a large exposure. MANAGEMENT Attention should be paid to the depth and rate of ventilation. Pulse-oximetry is useful for monitoring oxygenation but not for ventilation so capnography can be used to monitor patient ventilation. naloxone,Apneic patients should receive higher initial doses of naloxone (0.2 to 1 mg). Patients in cardiorespiratory arrest use a minimum of 2 mg of naloxone . When spontaneous ventilations are present, an initial dose of 0.04 to 0.05 mg intravenously titrated upward every few minutes until the respiratory rate is 12 or greater .The goal of naloxone administration is NOT a normal level of consciousness, but adequate ventilation. In the absence of signs of opioid withdrawal, there is no maximum safe dose of naloxone. However, if a clinical effect does not occur after 5 to 10 mg, the diagnosis should be reconsidered. Naloxone may be given nasally, subcutaneously, or intramuscularly but there is slower absorption and delayed elimination, Naloxone is absorbed in the respiratory tract can be administered into an endotracheal tube or nebulized.. If the clinician "overshoots" the appropriate dose of naloxone in an opioid-dependent individual, withdrawal will ensue. Symptoms of withdrawal should be managed expectantly only, NOT with additional opioids. After ventilation is restored with naloxone, repeat doses may be required, depending on the quantity and duration of action of the opioid. As an alternative to repeat dosing, a naloxone infusion can be prepared by determining the total initial dose required to reinstate breathing, and delivering two thirds of that dose every hour. If the patient develops withdrawal signs or symptoms during the infusion, stop the infusion. If toxicity returns, restart the infusion at half the initial rate. If the patient develops respiratory depression during the infusion, re-administer half the initial bolus every few minutes until symptoms improve, then increase the infusion by half the initial rate. Activated charcoal and gastric emptying are almost never indicated in opioid toxicity. The large volume of distribution of the opioids precludes removal of a significant quantity of drug by hemodialysis. Body packing is described as the act of swallowing packets or containers of drug for the purposes of smuggling. Heroin and cocaine are more frequently implicated . "Body stuffing" refers to the swallowing of a smaller quantity of drug because of fear of arrest. Compared with body packers, body stuffers typically carry a far smaller quantity of drug, but the drug is more poorly packaged. Severe toxicity from leaking packages or large ingestions poses a major threat . Large amounts of heroin or other opioids may be released from a leaking package, requiring extremely high doses of naloxone.

ARDS is a potential adverse effect of morphine, heroin, methadone, and other opioids and often occurs as a patient is recovering from opioid-induced respiratory depression.. In these cases , naloxone causes rapid precipitation of withdrawal in the setting of elevated PCO2 which brings a surge in catecholamine concentrations, thereby increasing afterload, which causes interstitial edema .Because of this, very small doses of naloxone (0.04 to 0.05 mg to start) should be used on those patients with marked hypoventilation and they should be ventilated with a bag-valve mask prior to administration of naloxone. TREATMENT OF TOXICITY OF SPECIFIC OPIOIDS In extreme overdose, loperamide causes QRS prolongation, QT prolongations, idioventricular rhythm, and ventricular tachycardia .If QRS prolongation is encountered, we recommend administering a bolus of 1 to 2 mEq/kg of sodium bicarbonate intravenously in the absence of contraindications. If the complex narrows, a bicarbonate infusion is reasonable. We mix 132 mEq of NaHCO3 in one liter of D5W, and infuse at 250 mL/hour. Since loperamide also causes QT prolongation, monitor potassium and magnesium if bicarbonate is given, Methadone can cause QT interval prolongation and Torsade de Pointes. If the QTc is greater than 500 msec, cardiac monitor for a 24-hour period. Hypocalcemia, hypokalemia, and hypomagnesemia should be corrected when present Fentanyl and fentanyl analogs — Fentanyl and fentanyl analogs alfentanil, remifentanil, and sufentanil, as well as drugs that are not approved for use in humans, such as carfentanil, furanylfentanyl, Despite anecdotal reports of a higher naloxone requirements for treatment, standard doses of naloxone should be sufficient Buprenorphine and naloxone Buprenorphine is a partial agonist at the opioid receptor. When taken alone, buprenorphine can cause respiratory depression, but likely to a limited degree .It binds to the opioid receptor with high affinity.High doses of naloxone may be needed to reverse respiratory depression. Interestingly, because of complex physiology, respiratory depression can recur with very high doses of naloxone so respiratory depression from buprenorphine may be difficult to reverse with naloxone. We suggest that clinicians start with standard naloxone doses (0.04 to 0.05 mg IV) when treating patients with buprenorphine-associated respiratory depression, but be prepared to titrate to higher doses (single doses of up to 2 mg, for a total of 10 mg) . After initial reversal is achieved, a naloxone infusion is often preferable to serial boluses Opioid adulterants, including krokodil — One example is "krokodil" (from the Russian word for crocodile), a homemade formulation of the potent, short-acting opioid desomorphine. Derived from codeine, which is available without prescription in Russia, krokodil is reported to contain solvents, such as gasoline and lighter fluid. Other potential contaminants include iodine, hydrochloric acid, and red phosphorous. Subcutaneous injection has resulted in local tissue damage, including ulcers, skin necrosis, and infection. The name of the drug is derived from the scaly skin lesions observed in some users. Such lesions are likely the result of infection and/or direct tissue injury from adulterants, Alkaloids, such as quinine and strychnine, are additional

examples of harmful adulterants .Heroin has also been tainted with the anticholinergic scopolamine With the exception of overdoses involving the long-acting opioids such as methadone, most adult patients can be discharged or transferred for psychiatric evaluation once respiration and mental status are normal and naloxone has not been administered for two to three hours Bystander-administered naloxone by the intramuscular and intranasal routes can be used successfully to resuscitate opioid overdose patients