Fentanyl Formulations Research Articles

Pharmacokinetics, safety and tolerability of a novel 100 ?g/h transdermal fentanyl patch co-administered with 100 mg oral naltrexone in healthy males

Background/Aims Recommended initial dose of fentanyl (FEN) in opioid-naive patients is 25μg/h with upward titration. The aim was to assess the pharmacokinetics (PK), safety and tolerability of a FEN patch given with naltrexone (NAL), an opioid receptor antagonist. Methods In a randomized crossover study, healthy male subjects (n=24) received a single 72h application of two formulations of FEN (100μg/h) given with oral NAL (100mg) in a clinical setting. Blood samples were collected and serum FEN was assayed using a LC/MS/MS method. Results Mean (CV%) for AUC and Cmax were 142.7ng·h/mL (25.0) and 2.35ng/mL (34.8), respectively. PK parameters of FEN were similar for the reference product with and without NAL. Even though a high dose of FEN was administered, oral NAL prevented the occurrence of opioid adverse events (AEs). Of the 281 AEs, 139 were drug-related with 100 specific to the patch application site. Most AEs were mild and none were severe. Conclusions Co-administration of oral NAL did not affect the PK of FEN and prevented the occurrence of opioid AEs. Results from this study confirm that a 100μg/h dose of FEN was well tolerated and safe when given with NAL in healthy males. Clinical Pharmacology & Therapeutics (2005) 77, P76–P76; doi: 10.1016/j.clpt.2004.12.181

Pharmacokinetics and tolerability of different doses of fentanyl following sublingual administration of a rapidly dissolving tablet to cancer patients: a new approach to treatment of incident pain

It is estimated that two-thirds of cancer patients will at some point during their illness experience breakthrough pain. In this study, the pharmacokinetics of a novel sublingual dosage form of fentanyl developed for breakthrough pain was evaluated. Eleven Caucasian patients (seven male and 4 female, aged 34-75 years, median 60 years) with metastatic malignant disease were recruited initially, but three patients withdrew. Prior to the study all patients were on continuous nonfentanyl opiate medication. The study was a double-blind, cross-over trial, consisting of three 1-day treatment periods. A new rapidly dissolving preparation of fentanyl, was administered sublingually in single doses of 100, 200 and 400 microg, respectively, on three separate occasions. Plasma fentanyl concentrations were determined using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Pharmacokinetic parameters were calculated by noncompartment analysis. Tolerability and the occurrence of adverse events were monitored throughout the study by patient questionnaire. The data from nine subjects who completed at least two periods were used in the analysis of variance. There were no significant differences between doses (100, 200 and 400 microg) for dose adjusted AUC (F = 0.42, P = 0.6660), dose adjusted C(max) (F = 0.08, P = 0.9206) and Tmax (F = 0.94, P = 0.4107). Thus, these parameters showed dose proportionality. The differences (400-100microg) in dose adjusted AUC from the three-period crossover analysis was -0.016 min.ng/ml (t = 0.71, P = 0.8718). Interindividual variability in systemic exposure to fentanyl was fairly small (25-40%), which may be related to a good in vivo biopharmaceutical performance of the sublingual tablet, and a relatively small fraction of the dose being swallowed. The first detectable plasma concentration of fentanyl was observed between 8 and 11 min after administration. t(max) increased from 39.7 +/- 17.4 to 48.7 +/- 26.3 and 56.7 +/- 24.6 min for the 100, 200 and 400 microg doses, respectively. Adverse events were few and did not increase with increasing dose. With this rapidly dissolving fentanyl formulation, the first detectable plasma concentration of fentanyl was observed at 8-11 min after administration. The pharmacokinetics of the drug showed dose proportionately. This formulation of fentanyl seemed to be well tolerated by the patients.

The Pharmacokinetics of the Intravenous Formulation of Fentanyl Citrate Administered Orally in Children Undergoing General Anesthesia

The bioavailability of oral transmucosal fentanyl citrate (OTFC) in children is similar to that of fentanyl solution administered orally to adults. We hypothesized that administering an oral fentanyl solution to children would result in similar fentanyl plasma concentrations and pharmacokinetic variables as administering comparable doses of OTFC. In this pilot study, 10 healthy children requiring postoperative analgesia were enrolled. Each received the undiluted IV fentanyl formulation orally (approximately 10-15 microg/kg; maximum, 400 microg). Venous blood samples were collected from 15 to 600 min after administration. Pharmacokinetic variables were determined using noncompartmental analysis and were compared with a previously studied population of children who received a similar dose of OTFC. Pharmacokinetic variables for the orally administered IV fentanyl formulation were as follows: time to reach peak concentration = 1.7 +/- 1.6 h, peak concentration = 1.83 +/- 1.19 ng/mL, half-life = 4.7 +/- 2.8 h, area under the plasma concentration time curve = 6.46 +/- 3.96 h . ng(-1) . mL(-1), apparent oral volume of distribution (V/F) = 17.5 +/- 7.2 L/kg, apparent oral clearance (CL/F) = 3.33 +/- 2.25 L . kg(-1) . h(-1). Although both OTFC and orally administered IV fentanyl resulted in similar pharmacokinetic variables and plasma concentrations for a given dose, there was marked interpatient variability, particularly in the early hours after oral administration of the IV formulation of fentanyl. This suggests that this method of administration be used with caution until further data are available.

Clinical effects and plasma concentrations of fentanyl after transmucosal administration in three species of great ape.

Fentanyl is approved for transmucosal use in the United States as a preanesthetic agent in human pediatric patients and in adults for breakthrough cancer pain. Using this formulation in three species of great ape, including eight orangutans (Pongo pygmaeus), nine chimpanzees (Pan troglodytes), and two gorillas (Gorilla gorilla), fentanyl was offered transmucosally at an intended dose of 10-15 microg/kg based on estimated body weight. The animals were trained to accept and suck slowly on a piece of placebo candy, given as a treat, after an overnight fast. On the day of the study, the animals were given the lollipop formulation of fentanyl. The resulting plasma concentrations of fentanyl supported transmucosal absorption, similar to that reported in humans. This study provides an alternative sedative regimen and yielded half-life data of transmucosal fentanyl in great apes. Although transmucosal fentanyl was a useful adjunct for sedating orangutans and gorillas, its acceptance by chimpanzees before chemical immobilization was suboptimal and unpredictable.

Practice Guidelines for Transdermal Opioids in Malignant Pain

Patients with moderate-to-severe malignancy-related pain require opioid pharmacotherapy. Many cancer patients continue to be prescribed subtherapeutic doses of pain medications resulting in undue suffering and diminished quality of life. Pain associated with malignancy and its treatment may exacerbate other symptoms associated with cancer, including nausea, fatigue, weakness, dyspnoea, constipation and impaired cognition. The choice of analgesic pharmacotherapy should be individualised and based on the intensity of pain reported by the patient, rather than its specific aetiology. When selecting pain management pharmacotherapy, the healthcare provider should consider the patient's pain level, activity level and any comorbid illness. Intolerable adverse effects, ineffective pain relief or a change in the patient's clinical status can dictate the need for a new pain management regimen. Healthcare providers must be able to readily quantify the relative analgesic potency when converting from one opioid to another or from one route of administration to another. Transdermal formulations of fentanyl and buprenorphine are effective pharmacotherapy that can be safely used for cancer patients with pain. However, clinicians need to be cognisant that the US/UK manufacturer's recommendations for equianalgesic dose administration of transdermal fentanyl may result in initial doses that produce subtherapeutic concentrations and unrelieved pain in some patients. A less conservative dose administration algorithm for transdermal fentanyl using a 2:1 (mg/day of oral morphine : microg/h of transdermal fentanyl) conversion ratio that considers both a review of the literature and clinical experience should help clinicians individualise cancer pain pharmacotherapy.

Palliative care in the past decade and today

The essence, principles, and philosophy of palliative care are timeless. However, the evolution of new concepts and the development of new therapeutic approaches have enhanced our ability to translate the principles of palliative care into practice. For example, new insights into the different pathways of action of the two variants of the cyclo-oxygenase enzyme may ultimately permit the development of non-steroidal anti-inflammatory drugs with minimal adverse gastrointestinal events. In addition, we now understand that the different clinical effects of various opioids reflect the different affinities of these drugs for occupying and activating μ, κ, and Δ-opioid receptors. Antagonists and blockers of the N-methyl- d-aspartate glutamate receptor-channel show promise for treating neuropathic pain. The introduction of modified-release opioids and of new devices that permit the long-term delivery of spinal analgesia have also opened up new possibilities in the management of pain. A transdermal formulation of fentanyl, which causes less constipation and possibly less nausea than morphine, may have the potential to enhance the quality of life for patients with terminal disease.

FDA panel approves lollipop painkiller

A new, faster-acting formulation of the opioid analgesic fentanyl may soon be available. On Sept 17, a US Food and Drug Administration advisory committee voted to approve Actiq (oral transmucosal fentanyl citrate), despite reservations that the drug, a lollipop-like raspberry-flavoured form on a stick, might be mistaken for candy by children.

The transdermal administration of fentanyl in the treatment of postoperative pain: pharmacokinetics and pharmacodynamic effects

A transdermal formulation of fentanyl (TTS-fentanyl, Alza Corp., Palo Alto, CA) was evaluated in 13 surgical patients after an abdominal operation. An intraoperative dose of fentanyl (100–200 μg i.v.) was administered at the same time as the TTS-fentanyl systems (50–125 μg/h) were applied to the antero-lateral chest wall. The TTS-fentanyl systems remained in situ for 24 h and were then removed and a second lot of systems were applied to the contra-lateral chest wall. There was a mean (S.D.) delay time of 12.7 (9.6) h before minimum effective blood fentanyl concentrations (MEC) were obtained from the systems and pseudo-steady state was reached between 36 and 48 h. There was a decay time of 16.1 (7.1) h after the systems were removed for the blood fentanyl concentration to decrease to less than the mean MEC for the control of postoperative pain. There was marked variability between patients in the actual hourly fentanyl dose rate determined from the residual amount of fentanyl remaining in the system and the duration of application. Significantly more supplementary pethidine was administered for inadequate postoperative analgesia between 0 and 12 h compared to the 12–24, 24–36 and 36–48 h periods; this was consistent with the observed delay time. Three patients required a reduction in the hourly fentanyl dose rate because of bradypnoea while 1 patient required an increase in dose because of inadequate pain relief. Nausea was the most frequently reported side effect (85% of patients) while bradypnoea, drowsiness, unpleasant dreams and headache were also reported. These effects were due to the combined effects of a sustained blood fentanyl concentration and the intermittent supplementary pethidine doses. Side effects due to the topical formulation were transient and included erythema (8 patients) and a minor rash (2 patients) in the area occluded by the systems. The TTS-fentanyl systems provided a significant contribution to postoperative pain control but, at the TTS dose rates used, supplementary doses of pethidine were required by all patients probably to control ‘incident’ pain.