Mercadante, S., Ferrera, P., & Arcuri, E. (2011). The use of fentanyl buccal tablets as breakthrough medication in patients receiving chronic methadone therapy: An open label preliminary study. Supportive Care in Cancer: Official Journal of the Multinational Association of Supportive Care in Cancer, 19(3), 435–438.
To assess the efficacy of fentanyl buccal tablets (FBTs) for the treatment of breakthrough cancer pain in patients who receive methadone as a background analgesic
Palliative care inpatients receiving 12 mg morphine received 100 mcg FBTs. Proportionally higher doses of FBTs were given according to background methadone dose. Patients requested pain medication from the nurse for breakthrough episodes. Nurses graded pain scores when called and after 15 minutes.
Prospective trial
In the majority of events, 15 minutes after administration of an FBT, evidence showed a decrease in pain intensity greater than 33% and greater than 50% (n = 20, 31.5% and n = 26, 40.6%, respectively). Nine events (14%) were unsuccessfully treated and required IV methadone injection. In all patients, the level of adverse effects after FBT administration was mild and indistinguishable from the level of adverse effects associated with baseline opioid analgesia.
Patients who receive methadone can achieve analgesic effect when FBT is administered for breakthrough cancer pain.
The study had a small sample size, with fewer than 30 patients.
An FBT lozenge must be rubbed gently against the buccal mucosa until it dissolves completely. For FBT treatment to be effective, patients must be instructed how to do this and they must have the ability to do it. For patients receiving methadone, FBTs may be an effective alternative for treating breakthrough cancer pain.
Mercadante, S., Villari, P., Ferrera, P., Mangione, S., & Casuccio, A. (2010). The use of opioids for breakthrough pain in acute palliative care unit by using doses proportional to opioid basal regimen. The Clinical Journal of Pain, 26(4), 306–309.
To determine the efficacy and safety of different opioids, used in doses proportional to basal opioid regimen, for the management of breakthrough pain (BTP)
The choice of opioids was based on clinical judgment. BTP dose was calculated at 20% of the daily dose. Opioids for BTP included IV morphine, oral transmucosal fentanyl citrate (OFTC), oral morphine, IV methadone, oral methadone, and oral oxycodone. Assessment was of pain intensity (PI) at baseline and at 15 minutes after administration.
Prospective descriptive study
Verbal rating scale, 0–10 points
Administration of 20% of the basal dose was effective in controlling BTP.
Results support mathematical calculation of the BTP dose to control BTP adequately. Nurses working in pain management and palliative care should be educated regarding equianalgesic conversion methods.
Mercadante, S., Radbruch, L., Davies, A., Poulain, P., Sitte, T., Perkins, P., . . . Camba, M.A. (2009). A comparison of intranasal fentanyl spray with oral transmucosal fentanyl citrate for the treatment of breakthrough cancer pain: An open-label, randomised, crossover trial. Current Medical Research and Opinion, 25(11), 2805–2815.
To compare the effectiveness of intranasal fentanyl spray (INFS) with that of oral transmucosal fentanyl citrate (OTFC) for relief of breakthrough pain in patients with cancer
The study had three phases. In the screening phase, patients recorded pain intensity, characteristics of breakthrough episodes, and use of rescue medications. Then they received a test dose of INFS. If the patients had no reactions to the dose, they were randomized to receive INFS followed by OTFC or vice versa. In the titration phase, the study drug was used to treat four breakthrough pain episodes, to determine effective dose. In the efficacy phase, six episodes of breakthrough pain were treated with the effective dose of the study drug. The efficacy phase lasted two weeks or less. Following the efficacy phase, the titration and efficacy phases were repeated, with the patient using the alternate study drug. In the efficacy phase, the patient recorded, for each episode of breakthrough pain, time to onset of meaningful pain relief, pain intensity, and use of rescue medication. To measure time to relief, the patient used a stopwatch. Doses of INFS were 50, 100, or 200 micrograms taken as a single dose in one nostril. If a second dose was required, it was allowed after 10 minutes and administered in the other nostril. OTFC doses of 200, 400, 600, 800, 1200 or 1600 micrograms were in the form of a single compressed lozenge. If required, a second dose of OTFC was used 30 minutes after the first. Patients could use rescue analgesics as needed, 45 minutes after one OTFC dose or 60 minutes later, if a second OTFC dose was used. Up to four episodes of breakthrough pain per day were treated with the study drugs. Pain intensity was recorded at multiple time intervals for each breakthrough episode.
Open-label crossover trial
More patients experienced faster relief of cancer-related breakthrough pain with INFS than with OTFC.
Study results show INFS to be an effective treatment for the short-term management of breakthrough cancer-related pain; INFS is associated with rapid relief. Potential adverse events with long-term use and more frequent daily use are unknown. Further study, involving long duration and frequent use, are needed to determine the optimal role of INFS in a comprehensive pain management plan.
Mercadante, S., Porzio, G., Ferrera, P., Fulfaro, F., Aielli, F., Verna, L., . . . Mangione, S. (2008). Sustained-release oral morphine versus transdermal fentanyl and oral methadone in cancer pain management. European Journal of Pain (London, England), 12(8), 1040–1046.
To compare, in patients with advanced cancer, the analgesic efficacy, adverse effects, and effect on quality of life of morphine, fentanyl, and methadone
Patients were randomized to morphine, fentanyl, or methadone. Morphine was offered as breakthrough pain medication at one-sixth the equianalgesic 24-hour dose. Adjuvant medications were allowed. If the patient experienced poor opioid response or uncontrolled adverse events, he or she switched to another opioid. Data were collected at four weekly intervals.
Randomized controlled trial
All three opioids were effective in controlling cancer pain in some patients. Adverse event profiles were similar. Methadone was less expensive than fentanyl or morphine but required clinical expertise in dosing. (The doses of some patients had to decrease and then increase.)
Long-acting morphine, fentanyl, and methadone are effective in controlling the pain of advanced cancer. Methadone is an option for patients for whom cost is a concern. Prescribing methadone requires clinical expertise.
Mercadante, S., Intravaia, G., Villari, P., Ferrera, P., Riina, S., & Mangione, S. (2008). Intravenous morphine for breakthrough (episodic-) pain in an acute palliative care unit: A confirmatory study. Journal of Pain and Symptom Management, 35, 307–13.
To perform a prospective cohort study to confirm the safety of intravenous morphine (IV-M) used in doses proportional to the basal opioid regimen to manage breakthrough pain; to record nurse compliance to data-recording regimen regarding treatment with IV-M
In the course of 116 admissions during one year, 99 patients received IV-M for breakthrough pain.
Italy
Prospective cohort study
IV-M given at doses proportional to basal dose provided prompt analgesia and was effective in most cases.
Mercadante, S., Ferrera, P., & Casuccio, A. (2010). Effectiveness and tolerability of amidotrizoate for the treatment of constipation resistant to laxatives in advanced cancer patients. Journal of Pain and Symptom Management, 41, 421–425.
To evaluate the effectiveness of amidotrizoate by the percentage of patients unresponsive to their current laxative regimens who had a bowel movement within 24 hours after administration.
All patients with cancer admitted to an acute pain relief and palliative care unit during a one-year period were surveyed. If patients had no bowel movement for three consecutive days despite receiving regular doses of senna, lactulose, or a combination of both, they were consented to participate in the study. Patients were hydrated via IV and then given 50 ml of amidotrizoate orally. A repeat dose could be given the next day, based on clinical judgment or patient preference.
The study has clinical applicability for end-of-life and palliative care.
This was a prospective trial.
Amidotrizoate is an effective and well-tolerated alternative therapy for patients with advanced cancer and constipation.
Amidotrizoate is used in radiology as a contrast media. Additional research is needed on the use of this agent as a laxative before it can be considered for patients with constipation.
Mercadante, S., Ferrera, P., Villari, P., & Casuccio, A. (2005). Rapid switching between transdermal fentanyl and methadone in cancer patients. Journal of Clinical Oncology, 23, 5229–5234.
To evaluate whether patients on either transdermal fentanyl or oral methadone required switching opioid therapy because of ineffective analgesia or adverse effects
The ratio between patients receiving fentanyl and methadone was 1:20. Patients who started with fentanyl patches and were switched to oral methadone had the patch removed with the first dose of methadone (n = 24). Patients who started on oral methadone and were switched to patches received the patch immediately after the last dose of methadone (n = 7). Rescue doses of oral or IV morphine were given using 1/6 of the daily dose.
The study consisted of 31 consecutive patients admitted to an acute palliative care unit for a one-year period.
The study was conducted in an acute palliative care unit in Italy.
This was a prospective study.
A switch was considered successful when the pain intensity or distress score decreased by at least 33%.
Eighteen patients benefited from switching, as confirmed by significant changes in pain intensity and distress scores. In those who switched from fentanyl to methadone, the mean time to dose stabilization was 4.3 days. In those who switched from methadone to fentanyl, mean time to stabilization was 2 days. The switch was considered unsuccessful In six patients.
Rapid titrations need to be closely monitored in an acute care setting.
Mercadante, S., Arcuri, E., Ferrera, P., Villari, P., & Mangione, S. (2005). Alternative treatments of breakthrough pain in patients receiving spinal analgesics for cancer pain. Journal of Pain and Symptom Management, 30, 485–491.
Patients with advanced cancer and pain were selected for intrathecal pain management after receiving different trials of systemic opioids. All consecutive patients with cancer pain receiving spinal analgesics were surveyed. They had unsuccessfully received different opioid trials (at least two routes—oral and IV—and two drugs, including fentanyl, morphine, or methadone) resulting in poor analgesia and adverse effects. They were selected for intrathecal treatment versus SL ketamine after receiving different trials with systemic opioids.
Patients received spinal treatment and presented with breakthrough pain, requiring alternative methods, including SL ketamine or intrathecal boluses of local anesthetics. Patients were able to choose between SL ketamine or intrathecal boluses of local anesthetic. Nine patients received intrathecal levobupivacaine boluses. Three patients received ketamine SL.
Nineteen patients who experienced a mean of 2.4 breakthrough pain episodes per day responded to a mean of 27 mg of morphine IV per episode. Twelve subjects required an alternative treatment. No specific differences were found between these two groups in terms of previous systemic opioid doses or pain mechanisms. In the spinal anesthetic group, the median Karnofsky status at the time of admission was 40. The median breakthrough pain intensity was 9 (range 7--10). All patients received an adequate pain relief (less than 50% of initial pain) within five minutes. In the ketamine SL group, pain was controlled in almost all patients within five minutes. Adverse effects were of low intensity (0–1 of scale used).
The administration of these drugs may pose some problems associated with sympathetic block and motor or urinary impairment. Local anesthetics typically have an individualized dose-effect relationship with a narrow therapeutic window. These intensive treatments should be reserved for a very select population and initiated in an appropriate setting with frequent monitoring facilities and skilled nursing. Spinal anesthesia should be reserved for a select number of patients with the best methods to prevent infection (increased manipulation of catheter).
Mercadante, S., Adile, C., Cuomo, A., Aielli, F., Cortegiani, A., Casuccio, A., & Porzio, G. (2015). Fentanyl buccal tablet vs. oral morphine in doses proportional to the basal opioid regimen for the management of breakthrough cancer pain: A randomized, crossover, comparison study. Journal of Pain and Symptom Management, 50, 579–586.
To compare the safety and effectiveness of fentanyl buccal tablets and oral morphine for breakthrough cancer-related pain
After ensuring stable background pain control with severity less than or equal to four on a 10-point scale, patients were instructed to call for breakthrough medication when pain became severe or was distinguishable from chronic background pain. Patients randomly received either fentanyl buccal tablets or oral morphine in does proportional to doses used for ongoing analgesia. After receiving one medication per breakthrough, patients were crossed over to receive the alternative medication. Patients received each drug for two breakthrough episodes. Nurses recorded pain intensity just before drug administration, at 15 minutes, and at 20 minutes. The intensity of adverse effects was recorded.
Randomized, single-group, crossover study
Both medications resulted in significant pain reductions (p = 0.0005). Pain intensity at 15 and 30 minutes was significantly lower with fentanyl buccal tablets (p < 0.0005) compared to oral morphine. There were no differences between groups in the severity of adverse effects. The most common adverse effect was nausea and vomiting, and these events were not severe. Of the patients who received both treatments, twice as many patients preferred the fentanyl tablets.
The analgesic effect for breakthrough pain was greater with the use of fentanyl buccal tablets compared to oral morphine, and the tablets were well-tolerated.
Fentanyl buccal tablets were shown to have greater analgesic effects for breakthrough pain than oral morphine when both medications were given at doses proportional to background analgesia. Some studies suggested that transmucosal opioids need to be titrated, which can delay efficacy, but this study showed that proportional dosage administration was effective. Pain can be one of the most debilitating and problematic symptoms to manage, and it is important that patients have rapid and effective interventions for breakthrough pain. Nurses can advocate for the use of the most effective medications for pain management and the approaches that are preferred by patients. Significant differences in efficacy may justify the use of more expensive drugs.
Mercadante, S., Porzio, G., Ferrera, P., Aielli, F., Adile, C., Ficorella, C., . . . Casuccio, A. (2012). Tapentadol in cancer pain management: A prospective open-label study. Current Medical Research and Opinion, 28, 1775–1779.
To evaluate the efficacy and tolerability of tapentadol (TP) in the management of cancer pain
Fifty consecutive patients with advanced cancer and moderate-to-severe pain initially were given 50 mg doses of slow-release TP twice a day, along with oral morphine 5 mg (initial dose) as breakthrough medication. Doses were managed to provide adequate pain relief or dose-limiting toxicity. Non-opioid medications were continued, provided they were tolerated. Adjuvant symptom relief medications were continued. Patients were visited or contacted at least weekly in order to change therapy. Parameters were assessed before starting therapy and at weekly intervals for four weeks. Parameters included pain intensity (0–10), symptoms associated with pain therapy, quality of life using the Spitzer scale, TP escalation index percent at week 4 ([TP maximum dose - TP starting dose] / TP starting dose / days x 100), and the presence of neuropathic pain using the PainDETECT questionnaire.
Pain intensity significantly decreased from baseline to all week intervals. Some symptoms varied in intensity during the study. Drowsiness increased in week 1 and decreased at week 4. Dry mouth increased from weeks 1–3 and decreased from weeks 1–4. No significant changes were seen in intensity of confusion, nausea, or constipation. Quality of life increased each week. TP escalation index (TPEI) percent and TPEI in mg were 1.78 and 2.26, respectively. No relationship was found between TPEI indexes and primary tumor, pain mechanism, PainDETECT, age, or gender. TPEI was lower in this study than in prior studies with a similar design. This may reflect less tolerability of TP in this study. TP had low discontinuation levels and was well tolerated.
Pain levels significantly decreased during the study. TPEI in this study was lower than in prior studies with a similar design that may reflect less tolerability of TP. TP was well tolerated with low discontinuation levels.
TP is not widely used in the United States and will require education of nurses on its use and side effects.