Naloxone: Indications, Dosage, and Adverse Effects

Overview

Naloxone is an FDA (Food and Drug Administration) approved medication that got approval in 2015 to reverse the action or effects caused by opioid overdose. Naloxone is an opioid antagonist and works by binding to the opioid receptor sites, which reverses and blocks the effects of opioids.

Although Naloxone is not a complete treatment, it is a temporary treatment for opioid overuse and requires a complete treatment after its use. It is available as nasal sprays or injections administered intravenously, intramuscularly, or subcutaneously.

What Are the Indications of Naloxone?

• Naloxone injections are used in the emergency treatment of patients 12 years of age or older when high-potency opioids like Fentanyl have been used and where it works as a chemical weapon for them.

• It is also used as a temporary prophylaxis for respiratory or central nervous system depression as a chemical incident responder contaminated with high-potency opioids like Fentanyl analogs.

Dosage and Administration:

• Dosage Form: Injections.

• Dosage Strength: 10 milligrams per 0.4 milliliters solutions in a single dose.

Administration:

• Naloxone injections are administered according to instructions.

• Administration of injection is done soon after knowing the opioid exposure and when going for emergency medical assistance after use.

• The injection is administered in the anterolateral aspect of the thigh.

• If the respiratory or central nervous system depression occurs after the first dose, then administer an additional Naloxone injection.

• The patient is kept under supervision after the injection is administered.

Contraindications:

• If the patient is suffering from any hypersensitivity reaction from Naloxone or its ingredients, then it is contraindicated.

Warning and Precautions:

• Precipitation of Severe Opioid Withdrawal: When Naloxone is administered to opioid-dependent patients, then it may cause abrupt opioid withdrawal symptoms. The patient should be under the supervision of the medical staff. And the lower dosage of Naloxone injection is given lower than 10 mg in these opioid-dependent patients.

• Recurrence of the Respiratory and Central Nervous System Depression: After administering the Naloxone injection, There is a chance the patient can develop respiratory or central nervous system depression. So, it is important to monitor the patient and keep the patient under surveillance and provide Naloxone injections as necessary.

Adverse Reactions:

• Dizziness.

• Feeling hot.

• Headache.

• Redness or erythema over the injection site.

Special Considerations:

• Pregnancy: There is not adequate data available on the Naloxone injection use in pregnant women. However, cohort studies performed have provided no effects like miscarriage or fetal defects. There are no estimated outcomes for using Naloxone injections in pregnant women. So, it is used cautiously in pregnant women.

• Lactation: There is no available data present to define any changes in the breastfed child. As Naloxone is taken very minimally in oral forms. But few articles have described that there are no effects of Naloxone on the prolactin or oxytocin hormones.

• Pediatric Use: Pediatric patients 12 years old or older are given a lower dosage of less than 10 mg. But the safety and effectiveness of the Naloxone injection through intramuscular or subcutaneous injection have not been defined. After the administration, the patient should be under complete surveillance to avoid opioid withdrawal syndrome.

• Geriatric Use: The safety and effectiveness of Naloxone has not been determined in the geriatric patient as there is no adequate data present. As these patients have higher chances of getting decreased hepatic or renal functions so systemic exposure to Naloxone can be higher in them.

For Patients:

When Is Naloxone Prescribed?

Naloxone is an opiate antagonist. It mainly works by stopping the effects of opiates to overcome the symptoms formed by increased levels of opioids. Naloxone is used as an emergency medical treatment to overcome the life-threatening effects of opioids being overdosed. It is also used after the surgery to reverse the effects of opioids given during the surgery. It is used during the delivery of the baby as it was given to pregnant women before the delivery to decrease the opioid effects.

How and When to Use Naloxone Injections Used?

Naloxone injections are available as vials, ampules, or prefilled syringes, which are injected into the veins (intravenously), into muscles (intramuscularly), or under the skin (subcutaneously). These injections may not reverse the actions of a few opioids at once so they require an additional dose for opioids like Buprenorphine.

The patient should know what happens if an opiate overdose occurs. The patient should also be aware of the Naloxone injections and when to call for emergency help. Before administering the injection, the administrator should read the instruction provided over the device. In an emergency condition, even an untrained person should inject Naloxone injection to overcome the life-threatening effects of opioid overdose.

Symptoms to identify that the patient is under opioid overdose.

• Excessive sleepiness.

• Unaware and not awakened to loud voices or when the chest was rubbed.

• Shallow breathing rate.

• Small pupils.

If such symptoms are noticed, then Naloxone injections are injected under the skin of the thigh or into muscles as a first dose of Naloxone. And then call for emergency medical help.

And if such symptoms reappear, then go for the second dose of Naloxone. Then further, additional injections can be given every two to three minutes. Every time single-dose injection syringes are used and then discarded on using once.

What Are the Precautions Taken While Injecting Naloxone?

• If the patient is allergic to Naloxone injection or any other ingredient in the Naloxone injections. This patient should avoid having Naloxone injections.

• Inform the doctor, before injecting, about the vitamins and supplements and any other herbal products if a patient takes them.

• Inform the doctor if the patient has a heart, kidney, or other medical disease.

• Inform the doctor if the patient is pregnant or planning to get pregnant or breastfeeding the child. Then cautious use of Naloxone injections is done. And should be kept under medical supervision.

What Are the Side Effects Related to Naloxone Injections?

• Pain.

• Burning sensation.

• Redness over the site of injections.

• Hot flushes.

There are a few side effects that are serious and require medical attention.

Some of them are:

• Irregular heartbeat.

• Hallucinations.

• Signs of opiate withdrawal like diarrhea, fast heartbeat, fever, sneezing, sweating, yawning, etc.

• Loss of consciousness.

• Crying unusually.

• Reflexes are stronger.

How to Store and Dispose of the Naloxone Injections?

The injections are kept in tight containers and at room temperature. It is kept away from extreme heat and moisture. The injections do not require freezing. The injections are specially kept out of the reach of children. It is very important as children can easily get poisoned after intaking such injections or medications. So, all the medications are placed safely, tightly capped, and away from the reach of children.

The unrequired injections are disposed of in a very special way, as suggested by the Food and Drug Administration (FDA). Special take-back programs are available to dispose of the medicines, which are not required as no pet, child or person unknowingly takes the medicine or injections.

For Doctors:

Naloxone:

Naloxone is used to treat opioid overuse as it is an opioid antagonist. It is available as nasal sprays and injections. In naloxone injections, the main ingredient is Naloxone hydrochloride which is given intramuscularly or subcutaneously. It is available in the pre-filled forms as a single dose which is an auto-injector that is 10 mg of Naloxone hydrochloride in 0.4 mL solution.

Naloxone hydrochloride is a salt with 17-Allyl-4,5α-epoxy-3,14-dihydroxy morphinan-6-one chemical name. Its chemical formula is C19H21NO4 HCl, and its pH is 3 to 4.5.

It has a white to slightly off-white powder and is easily soluble in water, strong alkali, or diluted acids. However, it is slightly soluble in alcohols and not soluble in ether and chloroform. All the 0.4 mL Naloxone hydrochloride injections have 10 mg of Naloxone HCl, nearly 3.34 mg of Sodium chloride, and hydrochloric acid, which can adjust its pH and water also present in it.

Clinical Pharmacology:

• Mechanism of Action: As Naloxone is an opioid antagonist, it reverses the effects like respiratory depression and hypotension, which are formed on its overdosage. It does the reversing effects by competing with the opioid receptor sites and attaching to the opioid sites. It can also reverse psychotomimetic and dysphoric effects formed by the agonist-antagonists like Pentazocine.

• Pharmacodynamics: Intravenous administration of Naloxone starts its action in two minutes. On comparing the onset of action, the intravenous step is shorter than the subcutaneous or intramuscular. So, the duration of action of Naloxone injections depends upon the route of administration and the dosage. However, studies have shown that even a single infusion of Naloxone (10 mg) can reverse the depressed ventilation rate, which was started by opioids like Morphine, Buprenorphine, and Fentanyl.

• Pharmacokinetics: A study with 24 healthy subjects was performed with 2 mg Naloxone injections and 10 mg Naloxone injections which were administered to the anterolateral aspect of the thigh. And then, plasma tests were taken after 12 hours of dosages. The results depict the 10 mg Naloxone injections have better parameters of Tmax, Cmax, and AUC.

• Absorption: The median time for Naloxone injections is 15.6 minutes and it ranges from 5.4 to 40.2 minutes.

• Distribution: Naloxone is distributed all over the body and even can cross the placenta. But plasma protein binding is very weak. It has a major binding constituent which is plasma albumin. There is no suspicion till now that Naloxone is present in breastmilk or not.

• Elimination: Naloxone has a plasma half-life of 1.46 hours.

• Metabolism: Naloxone is metabolized by the liver, mainly by the glucuronide forming the conjugation as Naloxone-3-glucuronide metabolite.

• Excretion: Naloxone is excreted around 25 % to 40 % in the urine in 6 hours and 50 % in about 24 hours, and 60 % to 70 % in about 72 hours

Nonclinical Toxicology:

• Carcinogenesis: The studies performed on animals regarding Naloxone use have not been completed till now. So, no suspects of carcinogenesis are present.

• Mutagenesis: Naloxone injection, when injected, showed a weak positive action in Ames mutagenicity and in vitro human lymphocyte chromosome aberration test but showed a negative response in vitro Chinese hamster (V79 cell HGPRT mutagenicity assay) and in vivo rat bone marrow aberration study.

• Impairment of Fertility: When a dose of four to eight times more was injected into mice or rats showed no effects on the fertility or the reproductive organs.

Dosage and Administration:

Important points while administrating the dose:

• Read the instructions before using them.

• Administer the injections soon after noticing the opioid overdose effects like respiratory depression.

• The injection can be administered subcutaneously or intramuscularly as the injection contains 10 mg/0.4 mL Naloxone hydrochloride.

• Do not reuse the injection again.

• Observe the injection before injecting, as it contains cloudy contents or glass is damaged, then go for a replacement of injection.

• If the red safety guard is removed, then the injection is injected immediately, and do not try to replace the red safety guard after removing it.

Dosage in 12-Year-Old Children and Adult Patients:

Naloxone injection is injected into the anterolateral aspect of the thigh.

While injecting a few points to keep in mind are:

• Be careful and ensure that the injection site is free of all materials.

• Just before injecting, pull off the red safety guard.

• Do not touch the black side or base of the auto-injector used to inject.

• The black side or base of the autoinjector is placed against the anterolateral aspect of the thigh.

• Press it firmly until a sound like a hiss is heard.

• When actuation occurs, the injection itself inserts the needle intramuscularly or subcutaneously and delivers the Naloxone, and then retracts its back into the device.

• After injection, the black side gets locked in place, and a red safety indicator also appears on the viewing window.

• This injection can be self-administered or with someone else's help too.

• It can be injected through clothing.

Emergency treatment in 12 years old or adult patients, where opioid use of Fentanyl had occurred.

Such patients should go for:

• Immediate medical help after administering the first dose of Naloxone by any non-trained personnel.

• The patient is kept under complete surveillance until medical care comes.

• If such patients have relapses of the opioid overuse symptoms like respiratory or central nervous system depression, then administer an additional Naloxone injection to overcome the symptoms.

• If the patient showed no improvement in the condition after administration of the dose then it is depicted that the respiratory depression is because of some non-opioid etiology.

• Temporary prophylaxis of respiratory or central nervous system depression in personnel or chemical incident responder who enters the contaminated opioid (Fentanyl) overdose area. Such a person should administer an injection before entering an area of contamination as one injection is used at once and provide temporary protection. If exposure to such areas is more than an additional injection of Naloxone is administered to protect.

Dosage Form: Injection.

Dosage Strength: 10 mg/0.4 mL in a single dose pre-filled auto-injector.

Clinical Trial:

78 healthy adults were subjected to the Naloxone injection (0.4 mg) auto-injector, two Naloxone injections (0.8 mg), some were exposed to 2 mg injection, and some to 10 mg Naloxone injection. And the adverse refraction noticed in these people were dizziness, feeling hot, headache, and erythematous reaction over the injection site.

Storage and Handling

• Keep the injections at 15 to 25 degree Celsius (59 to 77 degrees Fahrenheit).

• Excursions are to be maintained between 4 degree Celsius and 40 degrees Celsius (39 degrees Fahrenheit and 104 degrees Fahrenheit).

• Avoid freezing the injections.

• Protect these injections from heat.

Storage:

• Store the Naloxone injection in the case provided.

• If the injection is frozen, do not wait to thaw or use it as such; instead, go for emergency help. Only after the injection gets thawed, then it can be used.