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Clonidine, xylazine, and related imidazoline poisoning

Clonidine, xylazine, and related imidazoline poisoning
Literature review current through: Jan 2024.
This topic last updated: Jun 16, 2023.

INTRODUCTION — The clinical features, evaluation, and management of clonidine and related imidazoline intoxication will be reviewed here. The clinical approach to the poisoned patient is discussed separately. (See "General approach to drug poisoning in adults" and "Approach to the child with occult toxic exposure".)

EPIDEMIOLOGY — Clonidine, an alpha-2 adrenergic agonist, is a biochemical derivative of imidazoline that was initially introduced as a topical nasal decongestant over 40 years ago [1]. Subsequently, clonidine has been primarily utilized for its potent antihypertensive effect but is also administered for a wide variety of indications. Clonidine poisoning may occur from exploratory ingestion by young children (most common mechanism), transdermal exposure from a clonidine patch, malicious drug administration, intentional ingestion, or therapeutic error. Clonidine exposure is frequently symptomatic in children, and pediatric clonidine poisoning is frequently complicated by coma and respiratory depression; fortunately, deaths due to pediatric exploratory ingestion of clonidine are rare [2-6].

In the United States, more than 10,000 calls regarding clonidine exposure are made annually to regional poison control centers, and serious clinical findings often requiring hospitalization are common [7,8]. As an example, among about 28,000 unintentional clonidine exposures in United States children reported to poison control centers over 11 years, approximately 20 percent had moderate or major clinical effects [2]. In Australia, calls to its largest poison center pertaining to clonidine among children under age 6 years rose steadily each year between 2006 and 2016 and correlated with increased dispensing of clonidine by pediatricians [6].

Exposures and poisoning caused by imidazoline chemically related to clonidine are less frequent. Guanfacine, and the anti-spasticity agent tizanidine, are also oral central alpha-2 adrenergic agonist medications that are being more commonly prescribed. Guanfacine received US Food and Drug Administration approval for the treatment of Attention Deficit Hyperactivity Disorder for children aged 6 years and older in 2009, and a dramatic increase in pediatric cases of guanfacine ingestion were noted by US poison centers between 2009 and 2012 [9]. Approximately 1500 exploratory guanfacine ingestions by children less than age 6 years are noted by US poison centers annually [2]. Other related imidazolines are found in topical eye and nose decongestants. Adverse events from topical use, and poisoning from oral ingestion, are sporadically reported and can be serious.

Xylazine has been found as an adulterant in heroin for decades [10]. It is now commonly found in heroin and illicit fentanyl, often with the street name "Tranq" due to xylazine's reputation as a veterinary tranquilizer [11,12]. In the city of Philadelphia, xylazine was detected in less than 2 percent of fatal opioid overdose cases in 2010 but in 31 percent of such cases in 2019 [13]. Detection of xylazine in illicit opioid samples is spreading across the US [12,14].

PHARMACOLOGY AND CELLULAR TOXICOLOGY

Imidazoline agents — Imidazolines and their common uses include:

Clonidine and other imidazoline medications — Common medical uses for clonidine and other medically approved imidazolines include:

Clonidine – Clonidine is indicated for the treatment of hypertension in adults, but is also used for adjunctive anesthetic sedation and analgesia, spinal anesthesia, opioid detoxification, alcohol withdrawal, smoking cessation, and amelioration of postmenopausal hot flashes [15-20]. In children, it is used in the treatment of attention deficit disorder with hyperactivity, refractory conduct disorder, and Tourette syndrome [21-23]. It is often prescribed (off-label) for treating sleep disturbances in children [24].

Guanfacine and guanabenzGuanfacine and guanabenz are central alpha-2 adrenergic agonist medications that are chemically related to clonidine. Guanfacine is frequently prescribed to treat children with behavioral disorders and less commonly to treat hypertension. It is available in regular-release and extended-release formulations [25]. Guanabenz is less commonly prescribed for hypertension.

Topical decongestants and glaucoma medications (eg, tetrahydrozoline, oxymetazoline, and brimonidine) – Imidazoline derivatives, such as tetrahydrozoline, naphazoline, oxymetazoline, and xylometazoline, are found in topical eye and nose decongestant drops. Brimonidine and apraclonidine eye drops are prescribed for treatment of glaucoma. Ingestion or systemic absorption of small amounts of these agents can produce toxicity syndromes strikingly similar to those produced by clonidine [26-29]. (See 'Physical examination' below.)

TizanidineTizanidine is a muscle relaxant used for the treatment of spasticity that has caused poisoning similar to clonidine [27,30]. (See 'Physical examination' below.)

LofexidineLofexidine is used as an alternative to clonidine for opioid detoxification. Toxicity in humans has not been described. (See "Opioid withdrawal: Medically supervised withdrawal during treatment for opioid use disorder", section on 'Alpha-2 adrenergic agonists'.)

DexmedetomidineDexmedetomidine is an alpha-2 agonist frequently used for sedation. (See "Pediatric procedural sedation: Pharmacologic agents", section on 'Dexmedetomidine' and "Sedative-analgesia in ventilated adults: Management strategies, agent selection, monitoring, and withdrawal", section on 'Dexmedetomidine'.)

Toxic dose — No minimum toxic dose of clonidine has been established. A review of low-dose clonidine poisonings among children details eight children who developed some combination of central nervous system (CNS), cardiovascular, or respiratory depression after alleged exposure to just one or two tablets [31]. An autistic child who was taking compounded clonidine developed sedation, bradycardia, and hypotension because of an eightfold compounding error by the pharmacy [32].

By contrast, survival has been documented after ingested doses that were 1000-fold of regular daily dosing in both children and adults [33,34].

Topical imidazoles (eg, tetrahydrozoline, oxymetazoline, and brimonidine), though structurally similar to clonidine, are more polar than clonidine and less likely to cross the blood-brain barrier. Still, they have been implicated in pediatric poisoning after ingestion of small amounts of drug or after therapeutic use [26,29,35].

Mechanism of action — The pharmacological mechanisms through which clonidine lowers blood pressure and causes sedation are complex and derive from action at the central and peripheral alpha-2 adrenergic receptors and imidazoline receptors [36-39]:

Clonidine and related imidazolines stimulate central alpha-2 adrenergic receptors and imidazoline receptors that are located primarily in the rostral ventrolateral medulla. This effect leads to decreased sympathetic outflow from the CNS and reduced plasma norepinephrine levels [37,39]. Imidazoline-1 receptors are involved in the hypotensive effects of clonidine [39].

Endothelium-derived nitric oxide (NO) also plays a role in the antihypertensive effects of clonidine [36].

Further sedative effects may occur from the stimulation of alpha-2 adrenergic receptors in the locus coeruleus, by augmented release of gamma-aminobutyric acid (GABA), and by interaction with opioid and serotonergic receptor systems [36].

Stimulation of peripheral alpha-2 adrenergic receptors located in peripheral vascular smooth muscle causes vasoconstriction. This action explains the utility of imidazoline compounds as topically applied vasoconstrictors and the early and transient hypertension that is occasionally seen following clonidine overdose [38].

Xylazine — Xylazine is an alpha-2 agonist used in veterinary medicine for sedation and analgesia. Although it has no approved indications in humans, xylazine has become a drug of abuse and is also found as a common adulterant in heroin and illicit fentanyl, including powder and pill forms [10,13,14,40-48]. The US Food and Drug Administration has issued an alert to health care professionals and a letter to stakeholders to raise awareness of the ubiquitous presence of xylazine in illicit drugs [43].

In humans, xylazine overdose, alone and in combination with opioid intoxication, can cause major toxicity similar to clonidine and consisting of coma, apnea, bradycardia, and hypotension as well as severe, necrotic skin ulcerations (picture 1) and abscesses after repeated parenteral use [10,40,41,44,49].

KINETICS — The absorption, distribution, and elimination of clonidine vary depending upon the formulation of clonidine and route of exposure:

Clonidine tablets – The pharmacokinetics for oral ingestion of clonidine tablets are as follows [50-52]:

Bioavailability is 75 to 100 percent.

Peak plasma clonidine concentrations occur at approximately 2 hours, and absorption is complete by 2.5 hours in hypertensive, fasting adults [50].

Maximal blood pressure reduction occurs between three and eight hours after a routine daily dose [51].

Clonidine in the bloodstream is 20 to 40 percent protein bound and has an apparent volume of distribution of 3.2 to 5.6 L/kg.

Elimination half-life in therapeutic use ranges from 6 to 24 hours with more than half excreted unchanged in the urine [52].

Clonidine patchClonidine patch formulations are available in doses of 2.5, 5, and 7.5 mg contained in a timed matrix delivery system [53].

Clonidine is delivered at a constant rate over seven days.

The elimination half-life while the patch is adherent varies from 26 to 55 hours.

Up to 75 percent of the total dose may remain in a clonidine patch after seven days of use.

Tetrahydrozoline — A child with central nervous system (CNS) depression, bradycardia, hypotension and hypothermia after tetrahydrozoline ingestion was found to have a plasma concentration of 24 ng/mL measured three hours after ingestion; in that case series, the drug had an apparent elimination half-life of 4.4 hours [54].

CLINICAL FEATURES

History — The history should include:

Specific agent – In young children, the parent/primary caregiver frequently provides the history of ingestion. If the ingestant is unknown, a history of glaucoma or hypertension in an adult patient or household member suggests a clonidine exposure, as does a tablet or patch medication prescribed for behavioral disturbance in a pediatric patient or sibling. (See "Approach to the child with occult toxic exposure".)

In older children, adolescents, or adults, any witnesses and emergency medical services (EMS) personnel who may have recovered pill bottles at the scene should be contacted. The patient's pharmacy may provide valuable information regarding prescribed medications, the date of the most recent refill, and the total number of pills dispensed.

Xylazine is a common adulterant of heroin, illicit fentanyl, and other illegal drugs. The patient may not be aware that they are exposed to xylazine.

Type of exposure – For clonidine and related imidazolines, oral ingestion is most common, but transdermal exposure (eg, clonidine transdermal patch) is also described [55].

Any patient being treated for illicit fentanyl or heroin poisoning via snorting or injection may also be exposed to xylazine as well.

For ingestions, amount ingested, time of ingestion, and any co-ingestions provide important information. A detailed knowledge of the patient's co-ingestants and chronic medications is essential because clonidine exacerbates the hypotension of co-ingested antihypertensive medications (eg, beta blockers, calcium channel blockers) and the lethargy or coma following ingestion of ethanol, barbiturates, and other sedative hypnotics (eg, benzodiazepines, zolpidem, chloral hydrate). The clinical approach to the poisoned patient is discussed separately. (See "General approach to drug poisoning in adults" and "Approach to the child with occult toxic exposure".)

Cause of exposure – In young children, serious toxicity can occur with an exploratory ingestion of one to two clonidine pills.

Major and life-threatening toxicity is more common when clonidine is ingested with an intention for self-harm or xylazine exposure inadvertently occurs in combination with heroin or fentanyl overdose.

Medical history – It is also important to review the medical history for conditions that may predispose patients to the toxic effects of clonidine, such as airway compromise or preexisting cardiac conduction abnormalities.

Physical examination

Clonidine and imidazoline medications — Clinical findings and timing of toxicity vary by agent and preparation:

Clonidine – The classic clonidine toxic syndrome, or "toxidrome” after ingestion consists of [56-58]:

Depressed mental status

Miosis

Depressed respirations

Bradycardia and hypotension

Signs of toxicity are usually appear soon after clonidine tablet ingestion; new findings of poisoning rarely emerge more than four to eight hours after exposure [55,57,58].

Clonidine patch exposure through ingestion or self-application to the skin may result in signs of toxicity that develop several hours after exposure [59,60]. A full body search for adherent transdermal patches including the skin, palate, anus, and genitalia should occur during physical examination.

Up to 60 percent of clonidine exposures that are reported to regional poison control centers result in signs or symptoms [3]:

Depressed mental status – Depressed mental status, ranging from lethargy to coma, is the most common finding after clonidine poisoning occurring in up to 90 percent of poisoned patients [2,3,55,57,58,61]. Miosis, hyporeflexia, and hypotonia often accompany CNS depression and make the differentiation of clonidine poisoning from opioid toxicity difficult (table 1). Compared with individuals with opioid poisoning, patients with clonidine poisoning are more likely to respond transiently to painful stimuli.

Respiratory depression – Respiratory depression may accompany clonidine poisoning and may include apnea. The frequency of respiratory depression in patients with clonidine poisoning ranges from 20 to over 50 percent of hospitalized pediatric patients and up to 5 percent of all exposures based on reports to regional poison control centers [2,3,55,57,58,61]. It is less common in older children, adolescents, and adults. Children with apnea will often resume breathing with tactile stimulation. However, endotracheal intubation is occasionally necessary [2,9].

Bradycardia and hypotension – Bradycardia and hypotension are frequent signs of clonidine and related imidazoline toxicity among children and are seen in up to 50 percent of hospitalized patients [2,55]. Among adolescents and adults with clonidine poisoning, up to 75 percent of patients may develop bradycardia and 25 percent hypotension [62].

Depending upon the ingested dose, bradycardia may persist for hours to days. Sinus bradycardia is the usual rhythm, although atrioventricular (AV) block and sinus arrest have also been described [63,64]. Second-degree AV block or complete AV dissociation are uncommon and should prompt consideration of toxicity from other cardioactive agents, such as digoxin, beta blockers, or calcium channel blockers (waveform 1 and waveform 2). Tizanidine is notable because it may prolong the QT interval on electrocardiogram (ECG) [65].

Other findings – Hypertension occurs transiently in many patients with clonidine overdose, particularly after a large ingestion [36,57]. In addition, hypertension has been reported in patients with clonidine poisoning who receive naloxone. Hypertension progressing to hypotension has also been reported after guanfacine overdose [66]. Hypertensive emergency requiring treatment is very rare [67].

Pallor, hypothermia, and dry mouth may also occur after clonidine poisoning [57,68].

Related imidazolines – Other imidazoline agents cause similar toxicity as clonidine after exposure:

Guanfacine and guanabenz – Clinical features of regular-release guanfacine or guanabenz ingestion include lethargy, bradycardia, and hypotension [2,9]. Respiratory depression has been described but appears to be less frequent with these agents than clonidine [2].The duration of effect is typically <24 hours [9]. Prolonged orthostatic hypotension has been described in a 12-year-old boy after poisoning with extended-release guanfacine [69].

Imidazoline-containing eye and nose drops – In young children, ingestion or ocular exposure to liquid imidazoline preparations, such as ocular and nasal decongestants (tetrahydrozoline, naphazoline, oxymetazoline, and xylometazoline) or eye drops prescribed for glaucoma (brimonidine and apraclonidine) can cause serious poisoning within 30 minutes [26,28,29]. (See 'Clonidine and other imidazoline medications' above.)

Tizanidine – Poisoning with tizanidine has caused lethargy, coma, bradycardia, hypertension, and hypotension [27,30].

Xylazine — Xylazine overdose has caused major toxicity consisting of coma, apnea, bradycardia, and hypotension after inhalation or intravenous (IV) administration with heroin or illicit fentanyl [10,13,14,40-44,49]. However, compared with opioid overdose alone, overdose of xylazine and an opioid was associated with a lower risk of cardiac arrest or coma in one multicenter cohort study [46].

Severe, necrotic skin ulcerations (picture 1) and skin abscesses have also occurred after repeated parenteral use [12,70-73]. These patients require drug use disorder support to stop injecting and using xylazine and specialized wound care as described separately. (See 'Xylazine withdrawal' below and "Overview of treatment of chronic wounds".)

Ancillary studies — For patients with altered mental status and suspected clonidine poisoning, we recommend the following tests:

Bedside glucose determination to exclude hypoglycemia as the cause of reduced consciousness.

Venous or arterial blood gas combined with pulse oximetry to assess adequacy of ventilation in patients with serious and persistent respiratory depression.

Serum acetaminophen level in patients who ingest clonidine with intent for self-harm.

Serum ethanol level to identify patients at a higher risk for coma and respiratory depression due to co-ingestion of clonidine and ethanol.

ECG to evaluate for drug-induced cardiac electrical dysfunction.

Chest radiography if the history or exam suggests the possibility of pulmonary aspiration.

Other studies that may be helpful in selected patients include:

Serum electrolyte determination, in the setting of co-ingestants, to assess for electrolyte disturbance or metabolic acidosis and to calculate the anion gap.

Serum blood urea nitrogen and creatinine to identify patients with renal insufficiency who may have delayed elimination of clonidine after overdose.

Rapid urine pregnancy test in post-menarcheal women.

Quantitative and qualitative testing for clonidine is available from dedicated toxicology reference laboratories with methodology, such as gas chromatography or mass spectroscopy. However, the results usually cannot be obtained in time to be useful for patient management. Thus, specific measurement of clonidine in the urine or other fluids is typically performed for forensic or other non-clinical purposes and is not routine.

Similarly, rapid hospital-based tests for xylazine are usually not available, but it may be detected by specific analytical testing. In addition, test strips can detect xylazine in liquid or powder illicit drug samples with high sensitivity and specificity [47,74]. The strips are available for use by overdose outreach workers, forensic laboratories, and prehospital personnel.

For asymptomatic patients, the need for laboratory evaluation of clonidine poisoning varies depending on the circumstances of exposure. For example, a witnessed exploratory ingestion in a toddler or a known therapeutic error in a hospitalized patient may merit little laboratory investigation, whereas an unwitnessed ingestion with intent of self-harm may warrant more extensive testing, especially if clonidine is not the definite cause of symptoms. Other ancillary studies may be indicated in selected patients in whom trauma, infection, or other etiologies besides poisoning are suspected. (See "Evaluation of stupor and coma in children" and "Stupor and coma in adults" and "Approach to the child with occult toxic exposure" and "General approach to drug poisoning in adults".)

DIAGNOSIS — The diagnosis of clonidine, xylazine, or related imidazoline poisoning relies upon clinical findings obtained from a careful history that indicates a confirmed or suspected exposure to an imidazoline and a physical examination that has a combination of (table 2) (see 'Clinical features' above):

Lethargy, coma, and small pupils (miosis)

Respiratory depression

Bradycardia and hypotension

Transient hypertension followed by hypotension

For patients with suspected chronic xylazine use, severe necrotic skin lesions (picture 1) and/or skin abscesses

For patients with suspected or confirmed overdoses of heroin or illicit fentanyl, lack of responsiveness to naloxone therapy may suggest co-administration of xylazine [44].

DIFFERENTIAL DIAGNOSIS — There are many causes of coma that deserve consideration when evaluating the patient with suspected clonidine poisoning (table 3). In the poisoned patient, it is especially important to consider hypoglycemia and potential traumatic brain injury. (See "Evaluation of stupor and coma in children" and "Stupor and coma in adults".)

As in all poisonings, the clinician should determine the potential for co-ingested toxic agents. Clonidine exacerbates the lethargy or coma following ingestion of opioids, ethanol, benzodiazepines, zolpidem, barbiturates, and other sedative hypnotics. (See "Approach to the child with occult toxic exposure".)

Among toxic agents that may cause coma, the centrally acting, though chemically distinct, anti-hypertensive medication methyldopa also decrease sympathetic outflow and mimic clonidine's toxic effects. In patients with a history of heroin or fentanyl use, xylazine may be an adulterant and contribute to the toxicity of these illicit drugs. (See "Acute opioid intoxication in adults", section on 'Opioid adulterants, including krokodil'.)

The combination of central nervous system depression and pupillary miosis closely resembles the toxic syndrome seen with opioid intoxication, which may be further confused by the variable response of clonidine poisoning to naloxone  (table 1). Many other sedative-hypnotic and psychoactive agents may also produce somnolence and bradycardia. Xylazine poisoning is suggested in patients with suspected opioid poisoning who have a suboptimal response to naloxone administration [11]. (See "Acute opioid intoxication in adults" and "Opioid intoxication in children and adolescents".)

MANAGEMENT

Symptomatic patients — A rapid overview summarizes the initial management of clonidine and imidazoline poisoning (table 2). The management for patients with symptomatic clonidine and related imidazoline poisoning primarily consists of attentive supportive care with decontamination, as indicated. (See 'Decontamination' below.)

For patients with xylazine poisoning, additional considerations may include acute management of concurrent opioid poisoning. (See "Acute opioid intoxication in adults", section on 'Management'.)

Consultation with a clinical toxicologist is available to provide guidance in managing individual patients. To obtain emergency consultation with a medical toxicologist, in the United States, call 1-800-222-1222, or the nearest international regional poison center. Contact information for poison control centers around the world is available at the WHO website and separately. (See "Society guideline links: Regional poison control centers".)

Coma with respiratory depression — Coma with respiratory depression often responds transiently to tactile stimulation of the patient. Naloxone has been utilized to treat seriously poisoned patients with inconsistent results. For patients with suspected clonidine, xylazine, or related imidazoline poisoning and with marked central nervous system (CNS) depression and respiratory depression, we suggest a trial of intravenous (IV) naloxone, However, clinicians should proceed with endotracheal intubation and mechanical ventilation if there is no immediate response to naloxone and there is any doubt about the patient's ability to breathe adequately on their own or protect their airway.

Naloxone — The dose of naloxone depends upon the patient's suspected tolerance to opioids (table 2):

Opioid-naïve patients – For opioid-naïve patients, the dose is 0.1 mg/kg, maximum single dose: 2 mg; which may be repeated every one to two minutes up to a total dose of 10 mg. Clinicians particularly knowledgeable of naloxone pharmacology and of clonidine poisoning physiology might consider higher maximum single doses, especially in children [5].

Opioid-tolerant patients – For opioid-tolerant patients, the dose depends upon respiratory status.

-Apneic patients: Initial dose 0.2 to 1 mg, repeat if no response (maximum total dose 10 mg).

-Patients with spontaneously respirations and pulse oximetry <90 percent: Initial dose 0.04 mg IV and repeat until respiratory rate is in the normal range (maximum total dose 10 mg).

Naloxone dosing in patients with suspected opioid tolerance is discussed in greater detail separately. (See "Acute opioid intoxication in adults", section on 'Basic measures and antidotal therapy'.)

Many patients who respond to the initial dose of naloxone do not require additional doses [57]. However, if altered mental status and respiratory depression recur, we suggest the administration of additional intermittent doses as needed, rather than a continuous infusion.

Regardless of dose used, patients not responding to naloxone treatment should receive timely provision of supportive care of airway and breathing. Patients who improve after naloxone administration still warrant hospital admission and intensive monitoring for recurrence of symptoms. Although generally safe, naloxone therapy for clonidine overdose has rarely been associated with the onset of acute hypertension [5,75].

Evidence regarding the benefit of naloxone for reversal of clonidine toxicity is limited, and some experts do not routinely recommend naloxone for clonidine and imidazoline poisoning, especially in adolescents and adults [76]. In case reports and case series, IV naloxone administration at a dose of 0.05 to 0.1 mg/kg (maximum single dose 10 mg) has reversed signs of clonidine, guanfacine, tetrahydrozoline, and tizanidine poisoning in some pediatric patients [5,56-58,77-80]. In one of the largest studies (51 children), naloxone reversed depressed mental status in approximately 80 percent of patients; a single dose of 10 mg did not appear to increase the rate of response compared to 6 mg or less [5].

By contrast, in a cohort of 108 adolescent and adult patients with clonidine poisoning, naloxone (dose range 0.1 to 14 mg) was not found to result in improvement of Glasgow Coma Scale (GCS) unless concomitant opioid poisoning was suspected [62]. Experience with naloxone administration for related imidazolines in adults is limited [58]. An adult with tizanidine poisoning had improved mental status after high-dose (10mg IV) naloxone with minimal improvement in bradycardia [30].

Medications to avoid — The nonselective alpha adrenergic antagonist, tolazoline, and the specific alpha-2 adrenergic antagonist, yohimbine, were proposed in the past as potential antidotes for clonidine poisoning [81,82], but the risk associated with these agents exceeds any expected benefit [57,81,83,84]. Thus, we strongly discourage the use of these agents for treatment of clonidine or xylazine poisoning.

The selective alpha-1 adrenergic antagonist phentolamine would be expected to promote hypotension and should also be avoided.

Bradycardia and hypotension — The approach to bradycardia and hypotension includes:

Bradycardia – Bradycardia is typically mild and associated with signs of good tissue perfusion and, in these patients, requires no specific treatment. Patients with bradycardia and hypotension require rapid supportive care to restore adequate heart rate and blood pressure.

For treatment of bradycardia, we suggest IV atropine, although other chronotropic treatments are reasonable options. For patients who improve after atropine administration, the response may be short-lived, and redosing of atropine may be needed until toxicity resolves [62]. Based upon case reports and case series in children and adults, when bradycardia compromises circulation, it is often responsive to atropine [57,62].

Patients who do not respond to atropine and continue to have circulatory impairment should receive treatment for bradycardia per Advanced Cardiac Life Support (adults, (algorithm 1)) or Pediatric Advanced Life Support (children, (algorithm 2)).

Hypotension – Hypotension usually resolves with improvement in mental status (comatose patients) or reversal of severe bradycardia [55]. Hypotension that persists despite treatment of bradycardia may initially be treated with Trendelenburg positioning and rapid administration of IV isotonic crystalloid fluids (normal saline or Ringer's lactate solution). Continuous infusion of epinephrine, or similar agents such as norepinephrine or dopamine, may be useful in the rare patient with persistent shock that is refractory despite treatment of bradycardia and fluid resuscitation.

Hypertension — Hypertension may be noted early after clonidine overdose and reflects peripheral alpha-2 adrenergic-mediated vasoconstriction. Hypertension is typically of short duration and is often followed by hypotension. Thus, in most patients, hypertension treatment is unnecessary and may be harmful.

In the unlikely event that hypertension becomes symptomatic and must be treated, a short-acting, easily titratable agent such as nitroprusside is advised. Beta adrenergic antagonist agents should be avoided because they may lead to unopposed alpha-adrenergic action with worsening of hypertension. (See "Evaluation and treatment of hypertensive emergencies in adults" and "Approach to hypertensive emergencies and urgencies in children".)

Hypothermia — Hypothermia is typically mild and responds to external warming such as forced air rewarming, warm blankets, or radiant heat lamps. (See "Accidental hypothermia in adults" and "Hypothermia in children: Management".)

Asymptomatic patients — The approach to the initially asymptomatic patient with a potentially toxic clonidine or related imidazoline medication exposure depends upon the preparation and type of exposure (algorithm 3):

Ingestion of regular-release tablets or liquid preparations – Management of patients who are asymptomatic after a potentially toxic ingestion of clonidine, regular-release guanfacine, or liquid preparations (such as tetrahydrozoline, oxymetazoline, naphazoline, or brimonidine) is provided in the algorithm (algorithm 3). Administration of activated charcoal is suggested, followed by observation for at least six hours. Patients who are asymptomatic at six hours are unlikely to develop serious toxicity and may be medically cleared for mental health evaluation (intended self-harm) or discharged home, although ability for close observation and timely return if symptoms developed must be assured.

Ingestion of a transdermal clonidine patch – Asymptomatic patients who ingest a transdermal clonidine patch are at risk for delayed and ongoing toxicity until the patch has passed out of the gastrointestinal tract [59]. They require decontamination as described separately and admission for observation. (See 'Clonidine patch' below.)

Transdermal patch on skin – For asymptomatic patients with a transdermal exposure, patch removal is the most important intervention. These patients should undergo careful and full examination of the patient’s skin removal of all adherent patches, and careful history to exclude ingestion of a transdermal patch. Once accomplished, these patients may be discharged home, or, if the exposure was intended for self-harm, medically cleared for mental health evaluation.

DECONTAMINATION

Cutaneous decontamination — All patients with signs of potential clonidine or imidazoline poisoning warrant careful examination and removal of any adherent transdermal patch from the skin, palate, genitalia, or anus.

Gastrointestinal decontamination — Clonidine and related imidazolines bind well to activated charcoal (AC), the primary means of decontamination after drug overdose. Whole bowel irrigation (WBI) is suggested in patients who ingest a transdermal clonidine patch. Gastric emptying by gastric lavage or by syrup of ipecac-induced emesis in patients who ingest clonidine or related imidazolines should be avoided because of minimal benefit and risk of aspiration for patients who undergo gastric emptying after poisoning. (See "Gastrointestinal decontamination of the poisoned patient".)

Tablet or liquid preparation — For patients who present within one hour of a known or suspected ingestion of a potentially toxic dose of clonidine tablets or regular-release guanfacine or within 30 minutes of ingestion of an imidazoline liquid preparation, we suggest AC (1 g/kg, maximum dose 50 g) by mouth or nasogastric tube. Great care must be taken to ensure that the airway is not compromised prior to administration and that pulmonary aspiration risk be minimized. Patients with respiratory depression or coma should first have their airway secured as needed based on clinical evaluation prior to AC administration.

For patients who present for care more than one hour after ingestion of clonidine, regular release guanfacine, or liquid imidazoline preparations, the likelihood of preventing medication absorption is low outweighed by the risk of pulmonary aspiration.

The recommendation for AC administration following clonidine overdose derives from indirect evidence of benefit in volunteers, animal studies, and evidence of benefit following ingestions of other medications [85,86]. Because of adverse effects such as vomiting and dehydration, the combination of a cathartic (eg, sorbitol) and AC should be used sparingly if at all, and only a single dose of a cathartic should be given to any patient. This approach is especially pertinent after clonidine ingestion because sedation and coma are common. The greatest benefit occurs if AC is given within one hour. The efficacy of AC as a function of time from ingestion is discussed in detail separately. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Evidence of efficacy and adverse effects'.)

Clonidine patch — During the initial assessment, patients with patch ingestion or exposure should be undressed, and any adherent transdermal patches removed. For patients who have ingested a clonidine transdermal patch, we suggest the nasogastric administration of WBI (500 mL to 1 L of polyethylene glycol per hour) after oral or nasogastric administration of AC (1 g/kg, maximum dose 50 g). In this setting, AC may also prevent delayed absorption of clonidine when administered more than one hour after ingestion. Safe administration of WBI requires the following [87]:

Airway adequacy must be assessed and if it is inadequate, it should be secured prior to the procedure.

The patient should have bowel sounds present and no evidence of gastrointestinal obstruction.

Nasogastric tube placement must be confirmed by radiograph or bedside ultrasonography prior to initiation of WBI.

The patient should be maintained in an upright position (minimum 45-degree elevation of the head) throughout the procedure.

Gastrointestinal decontamination is discussed in detail separately. (See "Gastrointestinal decontamination of the poisoned patient".)

EXTRACORPOREAL REMOVAL — Clonidine is not amenable to extracorporeal removal including multiple dose activated charcoal, hemodialysis, or hemoperfusion.

DISPOSITION — Further management depends on the presence of symptoms and circumstances for the ingestion (algorithm 3):

Symptomatic patients — All patients displaying clonidine or related imidazoline toxicity warrant hospital admission and intensive medical care regardless of their response to naloxone. These patients often fully recover within 24 to 48 hours. Bradycardia and hypotension associated with extended-release guanfacine poisoning may be prolonged [88].

Asymptomatic patients — Disposition of asymptomatic patients depends upon the clonidine formulation ingested:

Oral imidazoline tablets or liquid preparations – Patients who remain asymptomatic at six hours after exploratory or inadvertent ingestion of clonidine or related imidazoline tablets (as well as imidazoline liquids) may be discharged home as long as close observation and ability to rapidly return for medical care, if needed, is assured. Extended release guanfacine formulations may warrant longer observation periods.

Clonidine patch – Asymptomatic patients who ingest a clonidine transdermal patch should undergo gastrointestinal decontamination and be admitted for close monitored because signs of poisoning may be delayed for up to 24 hours [59]. (See 'Clonidine patch' above.)

Intentional overdose – Patients who ingest clonidine or related imidazolines with intent of self-harm warrant mental health consultation, measurement of serum acetaminophen levels, and careful evaluation for other co-ingestants. (See 'Ancillary studies' above.)

These individuals warrant mental health evaluation before discharge from medical care. Psychiatric evaluation should be deferred in symptomatic patients until after they have recovered. (See "Approach to the child with occult toxic exposure" and "General approach to drug poisoning in adults".)

ADDITIONAL PEDIATRIC CONSIDERATIONS — Clonidine is frequently prescribed for behavior problems in children. Clonidine exposure often involves young children who ingest their own medication or that of another child in the household [55,57,61]. Ingestion of as little as one clonidine tablet or one swallow of imidazoline containing eye drops has been associated with life-threatening toxicity in children, but fortunately pediatric deaths are rare and typically associated with large-dose exposures [2].

In addition to routine anticipatory guidance regarding poisoning prevention, clinicians should counsel caretakers about measures to prevent clonidine or imidazoline poisonings as follows:

Used transdermal clonidine patch preparations contain a significant amount of clonidine. These patches should be carefully discarded so that young children cannot find them in the trash. Caretakers should be alerted to the serious toxicity these patches pose if ingested or reapplied to the skin.

Topical imidazoline preparations such as eye or nose drops containing tetrahydrozoline, oxymetazoline, and brimonidine, are tasteless and highly potent after ingestion. They often do not have child-resistant closures and need to be kept out of reach of children. (See "Prevention of poisoning in children", section on 'Anticipatory guidance'.)

XYLAZINE WITHDRAWAL — Xylazine has entered the illicit drug supply, and xylazine poisoning has become an important public health issue [89]. (See 'Xylazine' above.)

As xylazine use has increased, xylazine withdrawal has been described [90,91]. In a 2022 study using an internet survey of 61 individuals who admitted to xylazine use alone or with opioids, about one-half of the respondents reported experiencing xylazine withdrawal [90].

Clinical manifestations – Reported findings of xylazine withdrawal include [90,91]:

Irritability

Craving

Anxiety

Dysphoria

Tachycardia

Hypertension

Body aches

In addition to these symptoms, almost 60 percent of survey respondents described worsening withdrawal from opioids or other substances with some also reporting lowered perceived effectiveness of methadone or buprenorphine to control opioid withdrawal [90].

Diagnosis – There are no established criteria for the diagnosis of xylazine withdrawal [12]. The clinical findings described by users overlap with opioid withdrawal likely due to co-use with opioids.

Management – Evidence is lacking regarding the management of xylazine withdrawal. Consultation with an addiction specialist or medical toxicologist is advised.

Potential replacement oral agents include clonidine, tizanidine, and lofexidine [89]. In a case report of one patient with opioid use disorder and chronic xylazine use, successful treatment of withdrawal symptoms included a combination of continuous dexmedetomidine infusion, phenobarbital for autonomic symptoms, and tizanidine, which was later changed to oral clonidine to better control residual symptoms (rigors) [91].

Patients who report chronic xylazine use require careful evaluation to identify other agents that may be contributing to clinical findings of withdrawal including opioids, alcohol, and/or benzodiazepines and initiate appropriate treatment as described separately [12]:

(See "Opioid withdrawal in the emergency setting" and "Opioid withdrawal: Medically supervised withdrawal during treatment for opioid use disorder".)

(See "Management of moderate and severe alcohol withdrawal syndromes".)

(See "Benzodiazepine withdrawal".)

ADDITIONAL RESOURCES

Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)

Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: General measures for acute poisoning treatment".)

SUMMARY AND RECOMMENDATIONS

Rapid overview – A rapid overview table provides the common clinical features and essential initial management of clonidine or related imidazoline poisoning (table 2). (See 'Clinical features' above and 'Management' above.)

For patients with xylazine poisoning, additional considerations may include acute management of concurrent opioid poisoning. (See "Acute opioid intoxication in adults", section on 'Management'.)

Related imidazolines that have similar properties and toxicity as clonidine are provided in the graphic (algorithm 3). Ingestion of as little as one clonidine tablet or one swallow of imidazoline-containing eye drops is a serious exposure in young children. Xylazine poisoning, alone and in combination with heroin or illicit fentanyl poisoning, can cause major toxicity and death. (See 'Clonidine and other imidazoline medications' above.)

DiagnosisClonidine, xylazine, and related imidazoline poisoning is a clinical diagnosis based upon a history of suspected or confirmed exposure and clinical features of poisoning (ie, lethargy/coma with miosis, depressed respirations, bradycardia and hypotension, and/or transient hypertension). (See 'Diagnosis' above.)

Poisoning often develops within one hour of ingestion of clonidine or regular release tablet formulations of other imidazolines; new findings rarely appear more than four to eight hours after ingestion. In young children, ingestion or ocular exposure to liquid imidazoline preparations, such as ocular and nasal decongestants or eye drops prescribed for glaucoma can cause serious poisoning within 30 minutes. Clonidine patch ingestion or self-application to the skin may cause delayed toxicity.

Management of symptomatic patients – Most clonidine poisoned patients will have good outcomes with attentive supportive care of airway, breathing, and circulation. (See 'Symptomatic patients' above.):

Coma with respiratory depression – For patients with suspected clonidine, xylazine, or related imidazoline poisoning and coma with respiratory depression, we suggest a trial of intravenous (IV) naloxone (Grade 2C). The dose of naloxone depends upon the patient’s suspected tolerance to opioids (table 2). In patients who do not respond, further naloxone treatment should not delay the timely provision of supportive care for coma, respiratory depression, and/or circulatory impairment. The benefit of naloxone in patients with clonidine or related imidazoline poisoning is uncertain and some experts do not routinely use naloxone in this setting, especially in adult patients. (See 'Coma with respiratory depression' above.)

Bradycardia and hypotension – Patients with bradycardia and hypotension require rapid supportive care to restore adequate heart rate and blood pressure (see 'Bradycardia and hypotension' above):

-Bradycardia – For patients with bradycardia associated with poor perfusion, we suggest IV atropine as the first-line agent (Grade 2C). Epinephrine is a reasonable alternative. For patients who improve after atropine administration, the response may be short-lived and atropine redosing may be needed until toxicity resolves. Patients who do not respond to atropine should receive treatment for bradycardia per Advanced Cardiac Life Support (adults, (algorithm 1)) or Pediatric Advanced Life Support (children, (algorithm 2)).

-Hypotension – Hypotension usually resolves with reversal of bradycardia or, in comatose patients, improvement in mental status. Patients with persistent hypotension require Trendelenburg positioning and rapid administration of intravenous isotonic crystalloid fluids (normal saline or Ringer's lactate solution). In the rare patient with refractory shock despite initial fluid resuscitation, continuous infusion of epinephrine or similar agents such as norepinephrine or dopamine are warranted. (See "Shock in children in resource-abundant settings: Initial management" and "Evaluation of and initial approach to the adult patient with undifferentiated hypotension and shock".)

Hypertension – Because hypertension is usually transient, treatment is unnecessary and may be harmful. (See 'Hypertension' above.)

Management of asymptomatic patients – Management of patients who are asymptomatic after a potentially toxic ingestion of clonidine, xylazine, or related imidazolines is provided in the algorithm (algorithm 3).These patients require decontamination, as summarized below, and observation for at least six hours to see if signs of poisoning develop. (See 'Asymptomatic patients' above.)

Decontamination – All patients with potential clonidine or imidazoline poisoning warrant careful examination and removal of any adherent transdermal patches from the skin, palate, genitalia, or anus. (See 'Cutaneous decontamination' above.)

After initial assessment and stabilization, performance of gastrointestinal decontamination depends upon the time since ingestion and/or specific preparation ingested (see 'Gastrointestinal decontamination' above):

Clonidine tablet or imidazoline preparation ingestion – For patients who present within one hour of a known or suspected ingestion of a potentially toxic dose of clonidine tablets or regular-release guanfacine or within 30 minutes of ingestion of an imidazoline liquid preparation, we suggest activated charcoal (AC, 1 g/kg, maximum dose 50 g) by mouth or nasogastric tube (Grade 2C). AC should be withheld in patients who are sedated and unable to protect their airway unless endotracheal intubation is performed first. However, endotracheal intubation should not be performed solely for the purpose of giving AC. (See 'Tablet or liquid preparation' above.)

Clonidine transdermal patch ingestion – For patients who have ingested a clonidine transdermal patch, we suggest oral or nasogastric administration of AC followed by whole bowel irrigation (WBI) (500 mL to 1 L of polyethylene glycol per hour) (Grade 2C). In these patients, AC may also prevent delayed absorption of clonidine when administered more than one hour after ingestion. Prior to starting WBI, endotracheal intubation may be necessary in symptomatic patients to reduce the risk of aspiration. In addition, gastrointestinal integrity must be assured. (See 'Clonidine patch' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Kevin C Osterhoudt, MD, MS, who contributed to earlier versions of this topic review.

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Topic 6509 Version 41.0

References

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