Continuing Education Activity

Cocaine hydrochloride topical solution contains 4% cocaine. It is not FDA-approved but allowed for only the following indications: topical anesthesia of the mucous membranes of the oral, laryngeal, and nasal cavities. Its vasoconstrictive properties also make it useful for the temporary treatment of epistaxis before cauterization or packing, which is considered off-label use. This activity reviews the mechanism of action, adverse event profile, toxicity, dosing, pharmacodynamics, and monitoring of cocaine pertinent for interprofessional team members when used as indicated in the clinical setting.

Objectives:

• Identify medical indications for the clinical use of cocaine.
• Summarize the pharmacology of cocaine.
• Explain the toxicity of cocaine and its treatment.
• Review the importance of improving care coordination among interprofessional team members to improve patient outcomes for whom cocaine is a therapeutic option.

Indications

Cocaine hydrochloride topical solution contains 4% cocaine and the following inactive ingredients: citric acid, D and C Yellow No. 10, FD and C Green No. 3, sodium benzoate, and water. It is not FDA-approved but allowed for only the following indications: topical anesthesia of the mucous membranes of the oral, laryngeal, and nasal cavities. Its vasoconstrictive properties also make it useful for the temporary treatment of epistaxis before cauterization or packing, which is considered off-label use. Based on a recent systematic review, cocaine is the most commonly used agent by ENT physicians in preparation for diagnostic and therapeutic nasal procedures.[1]

Cocaine is otherwise an illegal drug of abuse listed on DEA Schedule II because of its 1) high potential for misuse; 2) accepted medical use in treatment in the United States or a currently accepted medical use with severe restrictions; 3) abuse may lead to severe psychological or physical dependence. People who misuse cocaine ingest it by snorting it in powder form, injecting it, and smoking it in its "crack" formulation (by processing it with sodium bicarbonate). Cocaine acts as a central nervous system stimulant, creating euphoria with increased energy and motor activity and enhancing feelings of competence and sexuality. The drug's effects generally last between 15 minutes and one hour. Cocaine's effects and duration depend on the dose and administration route.[2]

Mechanism of Action

Cocaine pharmacodynamics involves multiple complex mechanisms, although its half-life is short (approximately 1 hour). Topical cocaine has an anesthetic effect similar to local anesthetics (such as lidocaine) from sodium channel blockade and interference with action potential propagation. This Vaughn-Williams class IC effect also increases the risk of conduction disturbance and tachyarrhythmias. Cocaine binds and blocks monoamine (dopamine, norepinephrine, epinephrine, and serotonin) and reuptake transporters with equal affinity.[3] Monoamines accumulate in the synaptic cleft resulting in enhanced and prolonged sympathetic effects.

The principal action of cocaine on the mucosa is anesthesia and vasoconstriction; however, significant systemic absorption may occur; this may adversely affect the cardiovascular system, after which alpha- and beta 1-adrenoceptor stimulation results in increased heart rate, systemic arterial pressure, and myocardial contractility, which are major determinants of myocardial oxygen demand. Cocaine and its metabolites may cause arterial vasoconstriction hours after use. Epicardial coronary arteries are especially vulnerable to these effects, leading to a decreased myocardial oxygen supply. Cocaine-induced platelet activation and thrombus formation is another unique mechanism of action caused by alpha-adrenergic- and adenosine diphosphate-mediated increase in platelet aggregation.[4] This action may benefit patients by enhancing the hemostasis of mucosal hemorrhage. Plasminogen activator inhibitor is also increased following cocaine use, thereby promoting thrombosis. Adding to its complex toxicity, cocaine targets muscarinic acetylcholine, N-methyl-D-aspartate (NMDA), sigma, and kappa-opioid receptors.[5]

Administration

Cocaine is absorbed from mucous membranes if applied topically or snorted, through the alveoli if smoked, and the gastrointestinal mucosa if swallowed. Cocaine is degraded by plasma esterases, with a half-life of approximately one hour.

Cocaine has only received FDA approval for adult nasal mucosal surgery anesthesia; it has no approved pediatric indications.[6]

When used medically, cocaine requires no renal dose adjusting, including for dialysis patients with no supplement necessary. For patients with hepatic dysfunction, caution is advised with close monitoring.

Adverse Effects

CNS reactions may be excitatory, then depressive. In its mild form, the patient may display anxiety, restlessness, and excitement. Full-body tonic-clonic seizures may result from moderate to severe CNS stimulation. These seizures are often followed by CNS depression, with death resulting from respiratory failure and/or asphyxiation if concomitant emesis is present. Other clinical findings may include hyperreflexia, headache, mydriasis, and abdominal pain. Cocaine-induced central sympathetic stimulation and direct cardiac effects may lead to tachycardia, hypertension, and coronary or cerebral artery vasoconstriction leading to myocardial infarction and stroke.[3] As a potent vasoconstrictor, cocaine may result in hyperthermia from impaired heat loss. Cocaine is not for ophthalmic use. If accidentally introduced into the eye, corneal damage may occur.[7]

Contraindications

Cocaine is contraindicated in patients with a history of allergy or hypersensitivity to the drug or the components of the topical solution. Elderly patients and/or patients with a history of hypertension or cardiovascular disease should not receive the drug. It was an FDA Category C drug in pregnancy under the old pregnancy rating system. It is also unknown whether cocaine can cause fetal harm and should be given to a pregnant woman only if needed.

Monitoring

Patients receiving topical cocaine should have cardiac monitoring in case of dysrhythmia, and frequent vital signs are necessary to check for cocaine-induced hypertension and tachycardia. Clinicians should use the lowest dosage that results in effective anesthesia to avoid high plasma levels from mucosal absorption and potential adverse effects. The fatal dose of cocaine has been estimated to be 1.2 g, but there are reports of severe adverse effects from doses as low as 20 mg.[3] The single-use vial contains four mL of a 40 mg/mL solution, thus 160 mg in total. There is also a multi-use vial containing 10 mL of 4% cocaine. As mucosal absorption is variable, the possibility of receiving the entire amount of cocaine is low, especially when delivered by cotton pledgets or gauze.    

Toxicity

Treatment recommendations for acute cocaine toxicity are based on an extensive systematic review from 2016.[8] Cardiovascular toxicity and agitation are optimally treated first-line with benzodiazepines to decrease CNS sympathetic outflow. However, there is a risk of over-sedation and respiratory depression with escalating and numerous doses of benzodiazepines, which is often necessary. Non-dihydropyridine calcium channel blockers such as diltiazem and verapamil have shown the ability to reduce hypertension reliably, but not tachycardia. Clinicians should avoid using dihydropyridine agents such as nifedipine, as reflex tachycardia may occur. The alpha-blocker phentolamine has been recommended but only treats alpha-mediated hypertension and not tachycardia. It is a rarely-used drug, and most clinicians are unfamiliar with its use and limited titratability. Nitroglycerin and nitroprusside effectively lower blood pressure, but the risk of reflex tachycardia should be recognized. The mixed beta/alpha blocker labetalol is safe and effective for treating concomitant cocaine-induced hypertension and tachycardia without any “unopposed alpha-stimulation” adverse events. A recent AHA/ACC guideline approves the use of labetalol for cocaine and methamphetamine patients with unstable angina/non-STEMI.[9]

The best treatment for agitated patients is benzodiazepines, but antipsychotics such as haloperidol and olanzapine may also be useful. Combination treatment with benzodiazepines and antipsychotics has been demonstrated to be more efficacious than monotherapy.[10] Diphenhydramine is often added to enhance sedation and as prophylaxis against dystonia and akathisia. A typical example of this is the “B-52” with its combination of haloperidol (5 mg), diphenhydramine (50 mg), and lorazepam (2 mg). In several case reports, lidocaine and intravenous lipid emulsion have been successful for serious ventricular tachydysrhythmia.[8] Hyperthermia from cocaine toxicity is best treated with external cooling measures. Tepid water misting with convection cooling from a fan is the easiest and safest method to accomplish this in the field and in all emergency departments.

The phenomenon of “unopposed alpha-stimulation,” in which blood pressure increases or coronary artery vasoconstriction worsens after blockade of beta-2 vasodilation in cocaine-abusing patients, is controversial. This rarely-encountered adverse effect has resulted in some clinicians advocating for an absolute contraindication of the use of all beta-blockers, including specific, non-specific, and mixed. Many clinicians disregard this dogma and administer beta-blockers for cocaine-related chest pain and acute coronary syndrome, especially when there is demand ischemia from uncontrolled tachycardia [4]. Of the 1744 total patients identified in the systematic review, only seven adverse events were from putative cases of “unopposed alpha-stimulation” due to propranolol (n=3), esmolol (n=3), and metoprolol (n=1).[8] The authors of the original “unopposed alpha-stimulation” articles dating back to the 1980s concluded in a 2017 review that the phenomenon might result from the effects of cocaine alone, with or without beta-blockers.[4]

Enhancing Healthcare Team Outcomes

Both the legitimate/clinical use of cocaine and toxicity resulting from illicit use require interprofessional healthcare team coordination.

Cocaine toxicity is managed by an interprofessional team that includes the emergency department physician, poison control, internist, cardiologist, and psychiatrist. The management is strictly supportive, with the treatment of symptoms as needed. Some of these patients may require admission to the ICU and monitoring by nurses. If a patient receives benzodiazepines to treat toxicity, a pharmacist should carefully review the patient's medication record and verify benzodiazepine dosing. Before discharge, patients should be referred to a mental health nurse so that they can receive education regarding the detrimental effects of this agent and how to stop further usage. They can also benefit from ongoing support from a mental health professional such as a social worker or psychotherapist.[11][12]

The use of cocaine as an anesthetic agent will require careful consideration by the clinician, who should involve the pharmacist in dosing and medication reconciliation. If nursing is administering the drug, they should also coordinate with the clinician and the pharmacist to ensure proper administration and patient safety. It can also be important to know whether the patient has ever had an issue with misusing cocaine as a recreational drug, which may prompt the use of a different agent for the procedure.

When using cocaine as a therapeutic agent or when misused by a patient requires full interprofessional team collaboration, open communication channels, and coordination of actions and interventions for safe and effective treatment with minimal adverse effects. [Level 5]

Review Questions

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References

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Donroe JH, Tetrault JM. Substance Use, Intoxication, and Withdrawal in the Critical Care Setting. Crit Care Clin. 2017 Jul;33(3):543-558. [PubMed: 28601134]

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Zimmerman JL. Cocaine intoxication. Crit Care Clin. 2012 Oct;28(4):517-26. [PubMed: 22998988]

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Richards JR, Hollander JE, Ramoska EA, Fareed FN, Sand IC, Izquierdo Gómez MM, Lange RA. β-Blockers, Cocaine, and the Unopposed α-Stimulation Phenomenon. J Cardiovasc Pharmacol Ther. 2017 May;22(3):239-249. [PubMed: 28399647]

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Suen LW, Davy-Mendez T, LeSaint KT, Riley ED, Coffin PO. Emergency department visits and trends related to cocaine, psychostimulants, and opioids in the United States, 2008-2018. BMC Emerg Med. 2022 Feb 04;22(1):19. [PMC free article: PMC8814795] [PubMed: 35120449]

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Reigstad A, Reigstad O. [The history of local anaesthesia – from coca leaves to effective analgesia]. Tidsskr Nor Laegeforen. 2021 Dec 14;141(18) [PubMed: 34911266]

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Ghosheh FR, Ehlers JP, Ayres BD, Hammersmith KM, Rapuano CJ, Cohen EJ. Corneal ulcers associated with aerosolized crack cocaine use. Cornea. 2007 Sep;26(8):966-9. [PubMed: 17721298]

8.

Richards JR, Garber D, Laurin EG, Albertson TE, Derlet RW, Amsterdam EA, Olson KR, Ramoska EA, Lange RA. Treatment of cocaine cardiovascular toxicity: a systematic review. Clin Toxicol (Phila). 2016 Jun;54(5):345-64. [PubMed: 26919414]

9.

Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE, Chavey WE, Fesmire FM, Hochman JS, Levin TN, Lincoff AM, Peterson ED, Theroux P, Wenger NK, Wright RS, Jneid H, Ettinger SM, Ganiats TG, Philippides GJ, Jacobs AK, Halperin JL, Albert NM, Creager MA, DeMets D, Guyton RA, Kushner FG, Ohman EM, Stevenson W, Yancy CW. 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013 Jun 11;61(23):e179-347. [PubMed: 23639841]

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Zun LS. Evidence-Based Review of Pharmacotherapy for Acute Agitation. Part 1: Onset of Efficacy. J Emerg Med. 2018 Mar;54(3):364-374. [PubMed: 29361326]

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Alonso-Matias L, Reyes-Zamorano E, Gonzalez-Olvera JJ. Cognitive functions of subjects with cocaine and crack dependency disorder during early abstinence. Rev Neurol. 2019 Apr 01;68(7):271-280. [PubMed: 30906976]

12.

Lima DR, Gonçalves PD, Ometto M, Malbergier A, Amaral RA, Dos Santos B, Cavallet M, Chaim-Avancini T, Serpa MH, Ferreira LRK, Duran FLS, Zanetti MV, Nicastri S, Busatto GF, Andrade AG, Cunha PJ. The role of neurocognitive functioning, substance use variables and the DSM-5 severity scale in cocaine relapse: A prospective study. Drug Alcohol Depend. 2019 Apr 01;197:255-261. [PubMed: 30875646]

Disclosure: John Richards declares no relevant financial relationships with ineligible companies.

Disclosure: Erik Laurin declares no relevant financial relationships with ineligible companies.