Mercadante, S., Porzio, G., Ferrera, P., Aielli, F., Verna, L., Tirelli, W., . . . Casuccio, A. (2009). Low doses of transdermal buprenorphine in opioid-naive patients with cancer pain: A 4-week, nonrandomized, open-label, uncontrolled observational study. Clinical Therapeutics, 31(10), 2134–2138.
To examine the effectiveness and side effects of transdermal buprenorphine in opioid-naive patients with cancer-related pain
Patients received an initial dose of transdermal buprenorphine: 17.5 mcg/hour, with patch changes every three days. For the treatment of breakthrough pain, patients received 5 mg oral morphine. Every 2–3 days, the transdermal buprenorphine dose was adjusted up to 70 mcg/hour. Each patient received adjuvant symptomatic drugs as needed. Patients were contacted weekly for adjustment of therapy. Patients completed rating scales of side effects and pain intensity at baseline, after 1 week, and at 4 weeks.
The setting type was unspecified. The site was Palermo, Italy.
Open-label observational trial
For the patients in this study, transdermal buprenorphine was effective for pain management and well tolerated.
Authors pointed out that the World Health Organization analgesic ladder suggests a dose equivalent of approximately 35 mcg/hour.
Mercadante, S., Tirelli, W., David, F., Arcara, C., Fulfaro, F., Casuccio, A., & Gebbia, V. (2010). Morphine versus oxycodone in pancreatic cancer pain: A randomized controlled study. The Clinical Journal of Pain, 26(9), 794–797.
To test the hypothesis that oxycodone has advantages over morphine in terms of efficacy and dose escalation in the treatment of pancreatic cancer pain
Patients were randomized to one of two groups: One group took 30 mg/day sustained-release morphine; the other, 20 mg/day sustained-release oxycodone. Clinicians increased doses as needed to treat pain that measured higher than 4 on a 0–10 rating scale or if the patient had more than three episodes of breakthrough pain per day. Patients in both groups used oral morphine, at one-sixth daily dose, to address breakthrough pain. Adjuvants were prescribed at the discretion of the clinician. Investigators collected data for four weeks. Patients could enter an extension phase that lasted eight weeks. Investigators followed patients in inpatient palliative care units, at home, and through outpatient care.
Randomized controlled trial
Authors noted no differences between groups in pain intensity or use of breakthrough medication. Pain decreased in both groups, in a similar pattern of decline. Dose escalation was similar in both groups. In regard to use of adjuvant pain medication, authors noted no differences between groups. Side effects were similar across groups, with the exception that patients receiving oxycodone had a greater increase in confusion over the course of eight weeks (p = 0.011). No difference in confusion was apparent between groups at any other time point.
This study revealed no differences in the analgesia and side effects associated with morphine and oxycodone, delivered according to similar dose escalation, used in the treatment of pancreatic cancer pain.
This study suggests that, over an eight-week period, morphine SR and oxycodone SR provide similar analgesia with similar side effects. Whether differences would become apparent during a longer term is unknown.
Mercadante, S., Intravaia, G., Villari, P., Ferrera, P., Riina, S., David, F., & Mangione, S. (2007). Intrathecal treatment in cancer patients unresponsive to multiple trials of systemic opioids. The Clinical Journal of Pain, 23(9), 793–798.
To evaluate patient response to a combination of opioids and local anesthetics administered intrathecally to patients with advanced cancer and to evaluate treating patients with an oral-to-intrathecal-morphine ratio of 100:1, along with required changes in dosage
A cohort of patients with the indicated inclusion criteria received an intrathecal catheter in the operating room under aseptic conditions. The catheter was tunneled subcutaneously to the anterior abdominal wall and connected to a subcutaneous port. Morphine and levobupivacaine initially were started via a syringe pump to provide an infusion rate of 2 mL/h. Levobupivacaine was started at 12.5 mg/d, and morphine rate was calculated from the patient’s daily systemic dose using an oral-intrathecal ratio of 100:1. Doses of each drug were modified as needed to acceptably control pain (about 4 out of 10 on a numeric pain scale), and patients were monitored for adverse effects. Adjuvants, including clonidine and ketamine, were administered intrathecally as necessary. Patients were discharged seven days after the port implantation and converted to a balloon-type device instead of syringe pump. The balloon-type device was changed every five days. Frequent follow-ups were completed over the phone or in person if possible. Pain and related symptoms were recorded prior to intervention; at hospital discharge; and at one-, three-, and six-month intervals, as well as at least one week prior to death.
This was a single-site study conducted at La Maddalena Cancer Center in Palermo, Italy.
This was a prospective trial.
In patients who have received multiple trials and routes of opioids, intrathecal treatment may provide rapid and long-term relief. An oral-intrathecal morphine conversion ratio of 100:1 and use of local anesthetics may be effective for pain control in highly opioid-tolerant patients with advanced cancer.
This study was able to demonstrate an effective method and ratio for administration of intrathecal opioids for pain relief in patients with advanced disease. This may provide nursing with additional knowledge regarding appropriate dosages for medication administration, opportunities to develop staff educational sessions on the use of intrathecal catheter maintenance, and educational materials for patients and caregivers. This study suggests that this approach has promise; however, shortcomings in reporting all of the reasons for discontinuation in 18% of the initial sample are problematic. Intrathecal treatment is associated with some complications and caregiving needs for monitoring complications.
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.