Many medical situations require knowledge about pain management, especially when dealing with the tormenting chronic pain associated with cancer. Physicians have to provide patients with relief from agonizing pain, along with investigating the underlying cause. Opioids are a recognized class of analgesia for pain management with established therapeutic outcomes and side effects. Fentanyl is a strong synthetic short-acting opioid that acts on mu-receptors with greater than 50 to 100-fold potency than morphine, and its primary use is for analgesia and sedation. Opioids have numerous routes of administration; however, the oral route is a preferred method of delivery due to its noninvasive nature. Oral transmucosal fentanyl citrate (OTFC) incorporates fentanyl citrate into lozenges, which slowly dissolve in the mouth and undergo rapid absorption via the oral mucosa. Breakthrough pain (BTP) is a severe episodic flare-up of pain in cancer patients with long-term opioid controlled baseline pain. BTP is a severe, paroxysmal, and brief episode of pain that peaks in intensity in 3 to 52 minutes. BTP results in daily functional impairment, psychological disturbance, and increased utilization of medical resources. The duration, intensity, and pathophysiology of BTP make it difficult to manage. OTFC has received approval from the Food and Drug Administration (FDA) and indicated specifically for the management of BTP in cancer patients due to its rapid onset and short duration of analgesia, which mimic the characteristics of BTP episodes. Two randomized, double-blinded studies demonstrated that OTFC had superior analgesic effects, greater global satisfaction, and faster onset of action in the management of BTP than the usual BTP medications. A study evaluating the efficacy of OTFC for the management of severe pain crisis in cancer patients reported OTFC treatment resulted in reducing the mean pain intensity of patients from 9.0 to 3.0. This study demonstrated that OTFC prevented the need for hospitalization or parenteral opioids administration for the management of BTP., suggesting that OTFC is an ideal alternative to intravenous opioids for the management of BTP episodes in cancer patients. OTFC rapid onset, coupled with its short duration of analgesia and its noninvasive delivery (oral), makes it ideal to be used for the management of paroxysmal, severe, and brief episodes of BTP.
OTFC can also have a role in non-FDA approved indications in non-cancerous patients as a treatment of moderate to severe postoperative pain. A randomized, double-blinded study investigated potency, pain relief and pain intensity in 133 postoperative patients assigned to one of four treatment groups: high- or low-dose OTFC (800 micrograms vs. 200 micrograms), or high- or low-dose intravenous (IV) morphine (10 milligrams or 2 milligrams). It demonstrated that the higher dosage groups of OTFC and morphine provided superior analgesia than the lower dosage groups of OTFC and morphine. Higher dosage groups of OTFC and morphine produced pain relief with the duration of analgesia lasting 3.5 hours, while lower dosage groups of OTFC and morphine provided pain relief for approximately 2.5 hours. There was no significant difference in pain relief outcomes when comparing similar dosage groups between the two medications. The study demonstrated that the relative potency of OTFC to morphine was between 8 and 14 to 1.
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 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.
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 with the use of 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.
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 another 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.
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.
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 result in increased plasma levels of fentanyl, resulting in prolonging 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.
OTFC toxicity manifests as miosis, somnolence progressing to coma, airway obstruction, and respiratory depression. In situations of overdose, 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, opioid antagonist, naloxone, is administered. If the respiratory recovery is suboptimal, additional naloxone is administered, and the patient 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.
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 outcomes of life. 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. [Level 3]
|||Portenoy RK,Southam MA,Gupta SK,Lapin J,Layman M,Inturrisi CE,Foley KM, Transdermal fentanyl for cancer pain. Repeated dose pharmacokinetics. Anesthesiology. 1993 Jan; [PubMed PMID: 8424569]|
|||Portenoy RK,Payne R,Coluzzi P,Raschko JW,Lyss A,Busch MA,Frigerio V,Ingham J,Loseth DB,Nordbrock E,Rhiner M, Oral transmucosal fentanyl citrate (OTFC) for the treatment of breakthrough pain in cancer patients: a controlled dose titration study. Pain. 1999 Feb; [PubMed PMID: 10068176]|
|||McMenamin E,Farrar JT, Oral transmucosal fentanyl citrate: a novel agent for breakthrough pain related to cancer. Expert review of neurotherapeutics. 2002 Sep; [PubMed PMID: 19810977]|
|||Mystakidou K,Katsouda E,Parpa E,Tsiatas ML,Vlahos L, Oral transmucosal fentanyl citrate for the treatment of breakthrough pain in cancer patients: an overview of its pharmacological and clinical characteristics. Journal of opioid management. 2005 Mar-Apr; [PubMed PMID: 17315410]|
|||Mystakidou K,Katsouda E,Parpa E,Vlahos L,Tsiatas ML, Oral transmucosal fentanyl citrate: overview of pharmacological and clinical characteristics. Drug delivery. 2006 Jul-Aug; [PubMed PMID: 16766468]|
|||Gordon DB, Oral transmucosal fentanyl citrate for cancer breakthrough pain: a review. Oncology nursing forum. 2006 Nov 3; [PubMed PMID: 16518441]|
|||Fine PG,Busch MA, Characterization of breakthrough pain by hospice patients and their caregivers. Journal of pain and symptom management. 1998 Sep; [PubMed PMID: 9769620]|
|||Portenoy RK,Payne D,Jacobsen P, Breakthrough pain: characteristics and impact in patients with cancer pain. Pain. 1999 May; [PubMed PMID: 10353500]|
|||Christie JM,Simmonds M,Patt R,Coluzzi P,Busch MA,Nordbrock E,Portenoy RK, Dose-titration, multicenter study of oral transmucosal fentanyl citrate for the treatment of breakthrough pain in cancer patients using transdermal fentanyl for persistent pain. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1998 Oct; [PubMed PMID: 9779697]|
|||Burton AW,Driver LC,Mendoza TR,Syed G, Oral transmucosal fentanyl citrate in the outpatient management of severe cancer pain crises: a retrospective case series. The Clinical journal of pain. 2004 May-Jun; [PubMed PMID: 15100597]|
|||Lichtor JL,Sevarino FB,Joshi GP,Busch MA,Nordbrock E,Ginsberg B, The relative potency of oral transmucosal fentanyl citrate compared with intravenous morphine in the treatment of moderate to severe postoperative pain. Anesthesia and analgesia. 1999 Sep; [PubMed PMID: 10475315]|
|||Aronoff GM,Brennan MJ,Pritchard DD,Ginsberg B, Evidence-based oral transmucosal fentanyl citrate (OTFC) dosing guidelines. Pain medicine (Malden, Mass.). 2005 Jul-Aug; [PubMed PMID: 16083461]|
|||Harris D,Robinson JR, Drug delivery via the mucous membranes of the oral cavity. Journal of pharmaceutical sciences. 1992 Jan; [PubMed PMID: 1619560]|
|||Gordon D,Schroeder M, Oral transmucosal fentanyl citrate--OTFC (ACTIQ) [PubMed PMID: 18454617]|
|||O'Connor AB, Is actiq use in noncancer-related pain really [PubMed PMID: 18298711]|
|||Lee M,Kern SE,Kisicki JC,Egan TD, A pharmacokinetic study to compare two simultaneous 400 microg doses with a single 800 microg dose of oral transmucosal fentanyl citrate. Journal of pain and symptom management. 2003 Aug; [PubMed PMID: 12906959]|
|||Dolinak D, Opioid Toxicity. Academic forensic pathology. 2017 Mar; [PubMed PMID: 31239953]|
|||Losby JL,Hyatt JD,Kanter MH,Baldwin G,Matsuoka D, Safer and more appropriate opioid prescribing: a large healthcare system's comprehensive approach. Journal of evaluation in clinical practice. 2017 Dec; [PubMed PMID: 28707421]|