1. Fentanyl (Dosage)

Adults

Fentanyl oral transmucosal lozenges and buccal tablets are FDA-approved for managing breakthrough cancer pain in patients already receiving and tolerant to opioid therapy for persistent cancer pain^1-4. Fentanyl transdermal patches are approved for the management of pain in opioid tolerant patients, severe enough to require daily, around the clock, long term opioid treatment and for which alternative treatment options are inadequate^1,2,5. Patients are considered opioid tolerant if they are taking around-the-clock opioids consisting of at least 60 mg of oral morphine daily, 25 mcg of transdermal fentanyl/hour, 30 mg of oral oxycodone daily, 8 mg of oral hydromorphone daily, 25 mg of oral oxymorphone daily, 60 mg of oral hydrocodone daily, or an equianalgesic dose of another opioid daily for a week or longer^1-5.

Because of the risk of abuse, addiction, misuse, and overdose, oral fentanyl dosage forms are obtained solely through a restricted distribution program, the Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Management Strategy (REMS) Access program, in which only outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors who have registered for the program can prescribe, dispense, and/or obtain intranasal and oral fentanyl¹⁴.

Due to pharmacokinetic differences between oral transmucosal, buccal, and transdermal fentanyl formulations, these products are not interchangeable on a mcg per mcg basis and should not be substituted on a mcg for mcg basis as enhanced or attenuated pharmacologic effects could occur^1-5.

Transmucosal Lozenges (Actiq, generic)

Patients receiving fentanyl oral transmucosal lozenges for breakthrough pain are prescribed an initial dose of 200 mcg with instructions to allow the lozenge to dissolve over 15 minutes as the product is not designed to be chewed. Until the appropriate dose is reached, patients may find it necessary to use an additional oral transmucosal unit during a single episode. Re-dosing may begin 30 minutes after the start of the previous unit. During the titration phase, no more than two units should be administered for each individual cancer breakthrough pain episode. Patients must wait at least 4 hours before administering fentanyl oral transmucosal lozenges for another episode of breakthrough pain. To limit the number of units during the titration period, patients should be prescribed a maximum supply of six 200 mcg fentanyl oral transmucosal lozenges. At each new dose of oral transmucosal lozenge required by a patient, it is recommended that no more than six units of the titration dose be prescribed. Once a successful dose is identified for a patient, the quantity of lozenges utilized by a patient should be limited to 4 or fewer units per day. If consumption increases to greater than 4 units per day, the dose of the long-acting opiate should be re-evaluated. To discontinue use of fentanyl oral transmucosal lozenges, a downward titration is recommended to minimize potential withdrawal adverse effects^{1, 7-15}.

Buccal Tablets (Fentora, generic)

Patients prescribed fentanyl buccal tablets for breakthrough pain should begin therapy with an initial dose of 100 mcg, with the exception of those previously treated with fentanyl oral transmucosal lozenges^{2, 7-11}. Dose conversions between fentanyl oral transmucosal lozenges and buccal tablets are summarized in Table 1.

The tablet is placed in the buccal cavity (the space between the upper cheek and rear molar) or under the tongue and should be allowed to dissolve completely over a period of 30 minutes. Tablets should not be split, crushed, chewed or swallowed whole. If there are any tablet pieces remaining after 30 minutes, the patient may swallow them with a glass of water. The same dosage strength may be repeated once during a breakthrough pain episode, administered no sooner than 30 minutes after initiating buccal fentanyl tablet therapy, if pain is not relieved by the first buccal tablet dose. Patients must wait at least 4 hours before administering a fentanyl buccal tablet dose for another episode of breakthrough pain. The fentanyl buccal tablet dose should be increased in patients requiring greater than one breakthrough dose for several consecutive episodes. Patients requiring fentanyl buccal tablet doses higher than 100 mcg should be titrated in multiples of 100 mcg. Patients may receive up to four 100 mcg tablets at one time placed on each side of the mouth in each buccal cavity (2 tablets per side). Fentanyl buccal tablet dosages greater than 400 mcg should be titrated in 200 mcg increments. Doses should be titrated to achieve adequate analgesia with acceptable side effects, but no more than 4 tablets should be used concurrently for a breakthrough episode. Patients should receive only one buccal tablet dosage strength at a time to minimize confusion and the possibility of overdose. If more than four breakthrough pain episodes happen per day, the long-term opiate maintenance dose should be re-evaluated. To discontinue fentanyl buccal tablet use, a downward titration is recommended to minimize potential withdrawal adverse effects.

Transdermal Patch (Generics)

To initiate fentanyl transdermal patch therapy in patients prescribed other opioids, discontinue all other around-the-clock opioid therapy. Short-acting opioid agonists may be used as needed for the first 24 hours after initial application. Breakthrough pain may require supplemental doses even after a transdermal dose is established. Conversion doses from an oral or parenteral fentanyl preparation to fentanyl transdermal patches is summarized in Table 4. Conversion doses from daily oral morphine dosages to fentanyl transdermal patches is provided in Table 5. This table does NOT represent equianalgesic doses and is only intended to provide dosage conversions from other opioids to fentanyl transdermal patches but does NOT provide dosage conversions from fentanyl transdermal patches to other fentanyl/opioid dosage forms as the new opioid dose would be overestimated and may potentially result in a fatal drug overdose.^1,2,5.

Patients requiring fentanyl transdermal patch therapy and taking an opiate not listed in Table 4 should calculate the previous 24-hour analgesic requirement and convert the quantity to an equianalgesic oral morphine dose and use Table 4 or an additional dosage conversion chart such as the “Table. Morphine Milligram Equivalent Doses for Commonly Prescribed Opioids for Pain Management” table provided in the CDC Clinical Practice Guidelines for Prescribing Opioids for Pain – United States, 2022^5,6. The fentanyl transdermal patch dose should be titrated to a dose that provides adequate analgesia and minimal adverse reactions. The patch should be changed every 72 hours. If adequate analgesia is not achieved, the initial dose can be titrated after three days; subsequent dosage titrations should not be made more frequently than every six days. In the event that breakthrough pain occurs, a dosage adjustment may be necessary as well as rescue medication administration with an immediate-release analgesic. A small percentage of adult patients may not have adequate pain control with an every 72 hour dosage scheme and may require an every 48 hour dosing regimen. The patch should be applied to non-irritated, non-irradiated skin on a flat surface; avoid exposing the patch to external heat sources^1,2,5.

Off-Label Uses

Additional outpatient off-label use has been investigated in opioid-naïve patients with cancer, moderate to severe osteoarthritis with an inadequate response to weak opioid analgesic therapy, and pain associated with sickle cell anemia. The use of fentanyl patches in opioid-naïve patients with cancer is contraindicated, but two studies demonstrated successful use in this patient population^2,7,8. Short-term treatment with transdermal fentanyl significantly improved pain and functionality in patients with moderate to severe pain due to knee or hip osteoarthritis in two trials^2,9,10. However, opioid medications are conditionally recommended against for use in patients with osteoarthritis of the knee, hand, or hip while recognizing use may be appropriate when alternative options have failed^2,11. Current recommendations for the management of pain in sickle cell disease recommend against the use of chronic opioid therapy (COT) in children and adults unless the pain is refractory to multiple other therapies. Shared decision making should be used to determine the continuation of COT in patients who are well functioning and receiving a perceived benefit in therapy. Continuation of COT is not recommended in patients who are functioning poorly or are at high risk for opioid abuse or toxicity¹².

Dosage Limits

The lowest effective fentanyl transmucosal, buccal, or transdermal dose should be administered to patients with renal or hepatic dysfunction, as well as those patients receiving concurrent CYP3A4 inhibitor drugs^1-5.

Patient profiles containing prescriptions for greater than 6 units of fentanyl oral transmucosal lozenges during a transition phase will be reviewed. Patient profiles containing prescriptions for more than one strength of buccal or transmucosal fentanyl concurrently for greater than two months will be reviewed. Patient profiles documenting treatment of more than 4 breakthrough episodes daily with fentanyl buccal or transmucosal forms will be reviewed (see Table 6)^1-4.

Pediatrics

Fentanyl citrate transmucosal lozenges are FDA-approved for use in adolescents 16 years and older^1-3. Fentanyl transdermal patch is FDA-approved for use to manage chronic severe pain in opioid-tolerant pediatric patients 2 years of age and older requiring around-the-clock opiate therapy^1,2,5. The safety and efficacy of fentanyl buccal tablets has not been established in patients below 18 years of age^1,2,4. Pediatric fentanyl maximum dosage recommendations are summarized in Table 7.

Opioid Reversal Agents

Naloxone is an opioid receptor antagonist that is FDA approved for reversal of opioid-induced respiratory and central nervous system depression. Naloxone is supplied as Narcan® 4 mg/0.1 mL nasal spray, Kloxxado® 8 mg/ 0.1 mL nasal spray, Zimhi® 5 mg/ 0.5 mL pre-filled injection, and generic formulations of nasal sprays and solutions for injection are available^1,2,13-15.

In July of 2020 the U.S. Food and Drug Administration made the recommendations that healthcare professionals should discuss the availability of naloxone products and consider prescribing naloxone to patients who are prescribed opioid pain relievers and are at increased risk of opioid overdose. Patients at risk of opioid overdose include patients who are co-prescribed benzodiazepines or other drugs that depress the central nervous system, patients with a history of opioid use disorder (OUD), or who have experienced a previous opioid overdose. Healthcare professionals should also consider prescribing naloxone to patients who have other household members, including children, or other close contacts at risk for accidental ingestion or opioid overdose²⁰¹⁶. In 2016, the state of Texas, in association with the Texas Pharmacy Association, obtained a physician-signed standing order that allows pharmacists to dispense naloxone products to patients after completing Texas-accredited training. This allows for the sale and possession of naloxone products without a prescription in the state of Texas¹⁷.