Actiq®, manufactured by Cephalon, is a solid formulation of fentanyl citrate on a plastic stick that dissolves slowly in the mouth for absorption across the buccal mucosa. It is also available as a generic product known as Oral Transmucosal Fentanyl Citrate (OTFC). This lollipop form of fentanyl is one of five prescription dosage forms of the opiate, the others being fentanyl solution for intravenous injection (no brand name), a film for buccal application (brand name Onsolis®), an effervescent lozenge (brand name Fentora®), and a transdermal patch (brand name Duragesic®). All dose forms of fentanyl citrate are listed as Schedule II controlled substances under the Federal Controlled Substances Act.
One Actiq or OTFC lollipop contains 2 grams of sugar in a raspberry flavored additive. It is available in 6 different microgram (mcg) strengths of fentanyl citrate: 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1200 mcg, and 1600 mcg. Each strength is packaged in boxes of 30 lollipops. Given that fentanyl is approximately 100 times more potent than morphine or oxycodon , the 1600 mcg strength (1.6 mg) would be equivalent to taking 160 mg of morphine or oxycodone.
As a result of the repetitive fentanyl dosing using a dose form of high sugar content, Actiq use could cause significant dental problems. Oral adverse reactions reported in clinical trials have included tooth caries, gum hemorrhage, mouth ulceration, oral moniliasis, dry mouth, and cheilitis. Because of the high sugar content (2 grams of hydrated dextrates per unit), frequent consumption may increase the risk of dental decay. The occurrence of dry mouth caused by the fentanyl may add to that risk.
Case Report and Dental Concerns
Gee et al (“Dental Disease and the Use of Oral Transmucosal Fentanyl: A Case Report,” American Academy of Pain Medicine, 23rd annual meeting, February 7-10, 2007, New Orleans Paper # 147) enrolled a 48-year-old male with chronic generalized pain of eight years duration in a rehabilitation program. He had been treated with OTFC for more than three years and during that time developed extensive dental caries, decay, and tooth loss. He was first prescribed OTFC (400 mcg PRN) in November 2002. Dosing increased through June 2004 to a maximum of 600 mcg four times daily. The patient reported annual dental prophylaxis and minimal carious history. Prior records were not available for review. A dental examination in March 2004 identified multiple infected, nonrestorable teeth. By June 2004, he had undergone extraction of eleven teeth. In May 2005, extraction of all remaining teeth was recommended. The authors of the case study proposed that the sugar content of OTFC was causally related to his advanced decay. They suggested that further studies were warranted to discern a correlation, if any, between the use of OTFC in the management of chronic pain and dental disease.
Postmarketing reports of dental decay have been received from patients taking Actiq. In some of these patients, dental decay occurred despite reported routine oral hygiene. Since patients are taking Actiq “as needed” for pain, any given patient could be taking significant numbers of lollipops each day and month. Thus, the risk of dental decay and other dental problems will always be present. This presents a challenge in the proper dental management of the lollipop users. Product labeling has indicated that patients using Actiq should consult with their dentists to ensure appropriate oral hygiene in order to minimize the risk of dental decay.
Attempts were made to develop a sugar-free form of Actiq but studies were halted in favor of the marketing of Fentora, which is a brand name of an effervescent buccal fentanyl tablet having a similar use as the lollipop version. It is not known at this time what the sugar content is, if any, in the Fentora dose form. However, the assumption is it will cause dry mouth because of the fentanyl component.
More on Actiq (oral transmucosal fentanyl)
Actiq gained FDA approval for the management of breakthrough cancer pain in patients with malignancies who are already receiving, and who are tolerant to, opioid therapy, such as the fentanyl transdermal patch, morphine, or oxycodone, for their underlying persistent cancer pain. Actiq achieved off-label status as a powerful pain reliever (80-100 times more potent than morphine) and is used to treat migraine headaches, severe back pain, cluster headaches, bone pain, arthritis, neuropathies, and other situations of severe chronic noncancer pain. It can legally be prescribed for off-label use but cannot be marketed as such. As much as 80% of the prescriptions for Actiq each year are written for off-label use for sufferers of noncancer, chronic pain.
Dosage Forms and Dosing
When the lollipop is placed in the buccal mucosal area, fentanyl is immediately absorbed and rapidly passes into the central nervous system reaching a peak blood level within 20 minutes. Normally 25% of the drug is taken up through the oral mucosa and the remainder swallowed and absorbed through the GI tract. Two thirds of the swallowed fentanyl is metabolized in the liver to inactive compounds leaving only about 33% of the swallowed fentanyl available for pain relief. Thus, the drug is much more effective when absorbed through the oral mucosa. It is most effective when consumed in exactly 15 minutes, as the optimal amount of drug will be absorbed through the mucosa and quickly into the bloodstream. Patients taking Actiq for severe pain are warned not to take more than 120 doses (lollipops) per month. It has been reported that some patients with severe chronic pain may be taking up to 300 doses per month.
Uses for Actiq (oral transmucosal fentanyl) in Noncancer Pain
Actiq and Migraine
In a report by Landy SH (Oral Transmucosal Fentanyl Citrate for the Treatment of Migraine Headache Pain in Outpatients: A Case Series,” Headache, 2004, 44(8):762-6), twenty patients with recurrent acute refractory migraine headaches who had been referred to the headache clinic were reported in this case series. They were prescribed OTFC 400 mcg as rescue treatment for moderate to severe migraine headache pain as outpatients. They were instructed to self-administer at home and complete a diary recording pain intensity (10=worst pain imaginable to 0= no pain) before and 15, 30, 60, and 120 minutes after OTFC. They recorded satisfaction with the effectiveness of OTFC (from 1 to 7 categories) ranging from “very dissatisfied” through “very satisfied” rated at 120 minutes and also recorded any adverse events.
Results of the Landy study: Eighteen patients (13 female) experienced a migraine attack and self-administered OTFC. The drug successfully treated migraine episodes in all 18 patients. The OTFC rapidly reduced pain intensity, with significant improvement within 15 minutes, that was sustained and provided progressively more pain relief at 30, 60, and 120 minutes . Mean pain intensity significantly declined from 8.83 pretreatment to 2.23 at 120 minutes, an average reduction of 75%. Patients satisfaction ratings with OTFC were overwhelmingly positive, with 94% being satisfied and more than half (56%) being “very satisfied”. Three patients experienced nausea, two experienced somnolence, and one each experienced itching, vomiting, and dry mouth.
Conclusion of the Landy study: OTFC rapidly and significantly relieved acute migraine pain in outpatients, and was associated with a high patient satisfaction rating. OTFC may be effective for outpatient treatment of acute, refractory migraine headache pain.
Actiq and Decrease in Emergency Room Visits
Tennant F and Hermann L (Pain Medicine, 3(2): 186-7, June 2002) proposed that self treatment with OTFC use may prevent emergency room visits. Emergency room visits by chronic pain patients who experience pain flare-ups pose an expensive public health problem. To determine if OTFC is effective and safe for at home treatment of emergency pain flares, 90 chronic pain patients with a variety of painful conditions were treated with a long-acting opioid consisting of the fentanyl skin patch, methadone, or a sustained release oxycodone or morphine. All additionally used a short-acting oral opioid, suppository, or injectable opioid for self-treatment of emergency flares. All were given OTFC to alternatively substitute for their current opioid to self-treat emergency flares. Patients were surveyed after three or more months of OTFC use, and 86 (95.6%) believed they could safely and effectively treat their emergency flares with OTFC. Seventy-one (78.8%) believed OTFC had prevented the necessity to attend an emergency room or enter a hospital for pain control. Forty-five (50.0%) patients had collectively used OTFC for 375 months and during that period could specifically estimate, based on previous experience, they had avoided 474 emergency room and 220 hospital admissions. There were no emergency visits in the entire group during the study period, and 76 (84.4%) preferred OTFC over their current emergency opioid.
Actiq’s sweet taste and fast acting effect mean it has become ripe for diversion to the black market, where the lollipops are sold as “perc-a-pops” or “morphine lollipops” (although they do not contain morphine). Prescription fentanyl citrate in all its dose forms is diverted to the street via pharmacy theft, fraudulent prescriptions, and illicit distribution by patients. In order to curb misuse, many health insurers have begun to require precertification of the prescribers and/or quantity limits for Actiq prescriptions. It is claimed that only a small proportion of people will abuse Actiq and that the majority of users really need and use it legitimately for relief of chronic pain.
In summary, Actiq (oral transmucosal fentanyl) offers a dose form of a powerful opioid offering rapid relief of intense pain and is associated with tooth decay. Its high sugar content and repeated use, both for breakthrough cancer pain and noncancer pain, offer optimal conditions for dental problems.