Oral Transmucosal Fentanyl

Mechanism of Action

OTFC is a solid formulation of lipophilic fentanyl citrate. Its mechanism of action involves acting as an agonist on mu-receptors in the brain and spinal cord, resulting in therapeutic outcomes of sedation and analgesia. As the lozenges of OTFC dissolve, 25% of the total fentanyl is absorbed across the oral mucosa, while the remainder 75% is swallowed. One-third of the 75% escapes the first-pass metabolism and is slowly absorbed in the intestines. OTFC's rapid absorption across the oral mucosa coupled with its fast diffusion across the blood-brain barrier establishes its rapid onset. Delivery of fentanyl as OTFC via the oral mucosa is advantageous due to the nature of the oral mucosa. The oral mucosa is highly permeable and vascular, allowing lipophilic compounds to diffuse across the mucosa into the bloodstream easily. The oral mucosa has a uniform temperature and increased surface area, accentuating the delivery of OTFC.[12][13]

Administration

OTFC is available as a sweetened lozenge with a fentanyl citrate base for oral administration by sucking to facilitate oral transmucosal absorption. OTFC is available in six different dosages based on the strength of the fentanyl citrate base: 200, 400, 600, 800, 1200, and 1600 micrograms. In BTP, it is necessary to initially establish control of chronic pain using long-term opioids. Afterward, OTFC is used to treat the episodic breakthrough pains that occur. It is necessary to titrate under supervision to establish the correct dosage for controlling BTP. Start with 200 micrograms; if the BTP remains uncontrolled after 15 minutes, the patient should wait 15 more minutes and then take another lozenge (30 minutes total after the first lozenge). The patient may receive no more than two lozenges per episode of BTP during the titration period to minimize adverse side effects. If the pain is relieved after the second dose of 200 micrograms, then for the next episode of BTP, one 400 microgram lozenge is used. If pain relief of a BTP episode requires more than two lozenges, an increase of OTFC strength is applied to the next BTP episode. After establishing the correct strength of OTFC for the control of a BTP episode, a limit of 4 units per day is set. OTFC has a rapid onset of analgesia with peak effects occurring at 20 to 40 minutes after administration and lasting 2 to 3 hours.[2][5][14][15]

Adverse Effects

OTFC is an opioid, and its side effects include nausea, constipation, confusion, dizziness, somnolence, addiction, asthenia, and hypotension. The therapeutic range is 1 to 3 nanograms/milliliters. High plasma levels can lead to respiratory depression and death. Concomitant consumption of other central nervous system (CNS) depressants (i.e., alcohol, heroin, benzodiazepines) may contribute to additive adverse effects; hence, patients with multiple CNS depressant medications require careful monitoring. Similar to all opioids, avoid use in the elderly with a history of falls.[5][16]

Contraindications

OTFC should not be administered to opioid intolerant patients to prevent fatal respiratory depression. Clinicians should not use it with patients who have acute or severe asthmatic patients. It is contraindicated in patients with gastrointestinal obstruction and patients with a known history of hypersensitivity (i.e., anaphylaxis) to fentanyl.

Monitoring

Concomitant use of cytochrome P450 3A4 (CYP3A4) inhibitors (i.e., macrolide antibiotics) results in higher fentanyl plasma levels and can contribute to fatal respiratory depression. Patients require close monitoring, and the clinician should consider reducing the OTEC dose. Similarly, discontinuation of CYP3A4 inducer medications (i.e., phenytoin) can increase plasma levels of fentanyl, resulting in prolonged OTFC adverse effects. Therefore, patients receiving OTFC and CYP3A4 inhibitors/inducers must be monitored closely and frequently, along with considering adjusting the dosing of OTFC, as needed.[5]

Toxicity

OTFC toxicity manifests as miosis, somnolence progressing to coma, airway obstruction, and respiratory depression. In overdose situations, the priority is to remove OTFC from the oral cavity, establish a patent and protected airway and administer oxygen. Intubation and mechanical ventilation of the patient are considerations if needed. For clinically significant respiratory depression secondary to OTFC overdose, an opioid antagonist, naloxone, is administered. If the respiratory recovery is suboptimal, additional naloxone is administered, and the patient is monitored until initiating patient-initiated respiration, and appropriate oxygen saturation levels return. Naloxone is FDA approved for the treatment of suspected or known opioid overdose resulting in respiratory depression. Naloxone administration can be intramuscular, intravenous, subcutaneous, or intranasal.[17]

Enhancing Healthcare Team Outcomes

Management of pain in patients with an underlying cause (i.e., cancer) is an important clinical issue since such patients experience relentless pain that is usually not appropriately treated and results in poor life outcomes. Cancer patients in moderate to severe flare-ups of episodic pain in addition to their baseline opioid controlled pain require effective medications to control such episodes. OTFC is an optimal choice to manage these episodic flare-ups of pain in cancer patients due to its pharmacokinetics (short duration and rapid onset) and noninvasive and convenient route of delivery (oral transmucosal).

Physicians prescribing this medication should be familiar with its adverse effects, indications/contraindications, and be vigilant regarding the patient’s concomitant medication use (i.e., other CNS depressants, CYP 3A4 inhibitors/inducers) to prevent toxicity or suboptimal therapeutic outcomes. Physicians are encouraged to screen patients for opioid abuse or misuse before prescribing OTFC. Physicians should educate the patient about increased risks of overdose or death associated with the use of additional CNS depressants (i.e., opioids, benzodiazepines, alcohol) with OTFC. Opioid overdose is a serious medical situation due to the high risk of fatal respiratory depression. Ultimately, the optimal approach to managing opioid overdose situations is to prevent it from happening in the first place. A comprehensive approach to preventing overdose situations involves highly regulated prescribing and dispensing policies, follow-up and monitoring processes, and complete coordination among providers via electronic healthcare records.[18] [Level 3]