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.

• Twenty-four patients completed all four weeks.
• Mean patient age was 67.2 years (SD = 11.9 years).
• Of all patients, 41% were female and 59% were male.
• The sample included multiple cancer types; gastrointestinal, breast, and lung cancers were the most frequent.

The setting type was unspecified. The site was Palermo, Italy.

Open-label observational trial

• Numeric scale, 0–10, to measure pain intensity
• Scale (0 = not at all, 3 = severe), to measure multiple symptoms
• Spitzer Quality of Life Index

• Pain intensity scores declined by 50% over the four-week period (p < 0.001).
• Transdermal buprenorphine dose increased significantly and had doubled by the end of the study. 
• Dry mouth and drowsiness were the most severe side effects.
• Of all patients, 15% discontinued the study because of poor compliance or the need for different pain management.

For the patients in this study, transdermal buprenorphine was effective for pain management and well tolerated.

• The study had a risk of bias due to no appropriate control group.
• The study had a relatively small sample.
• The duration of the study was very short; long-term effectiveness and side effects were not evaluated.
• The report provides mean scores regarding treatment side effects but does not provide the prevalence rates of the effects.

Authors pointed out that the World Health Organization analgesic ladder suggests a dose equivalent of approximately 35 mcg/hour.

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.

• The sample was composed of 39 patients, of which 17 patients completed the eight-week extension.
• Mean patient age was 63.2 years (SD = 9.48 years).
• Of all patients in the initially randomized group, 58.7% were female and 41.3% were male.
• All patients had pancreatic cancer. The study excluded patients with bone metastases.

• Single site
• Palliative care, home, and outpatient care
• Italy

Randomized controlled trial

• Numeric rating scale (0–10), to measure pain
• Rating scale (0–3), to measure side effects and symptoms

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.

• The study had a small sample, with fewer than 100 patients.
• The study had a risk of bias due to no blinding.

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.

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.

• The study reported on 55 patients with advanced cancer. Complete data was available for 45 patients.
• The mean age was 60 years with a range of 33–82 years.
• The sample was 42% female (n = 23) and 58% male (n = 32).
• Patients had undergone previous pain management trials with at least three opioids and two routes of administration (including IV).
• Oral morphine equivalents at baseline averaged 466 mg/d.

This was a single-site study conducted at La Maddalena Cancer Center in Palermo, Italy.

This was a prospective trial.

• Pain intensity was measured using 0–10 numerical scale.
• Opioid-related symptoms, such as nausea and vomiting, drowsiness, confusion, constipation, and dry mouth, were measured using a numerical scale of 0–3 (not at all, slight, a lot, and awful).

• Statistical differences in pain intensity were found with daily dose escalation of intrathecal morphine doses. At the time of hospital discharge and by six months, pain intensity had gone from a mean of 7.98 to 3.0 (p < 0.0002).
• Systemic use of opioids significantly decreased along all measured points of time, up until death, following intrathecal catheter placement for pain control (p < 0.029).
• Symptoms of confusion (p < 0.0001) and constipation (p < 0.008) declined with intrathecal pain management. Early complications, occurring during the hospitalization period, included mild bleeding, headache, and urinary retention requiring bladder catheterization.
• One patient died unexpectedly during admission, and a second patient died after suffering a stroke. No relationship with the use of spinal analgesia was found.
• Two patients developed late complications of local infection. One of these patients required removal and replacement of the catheter.
• One patient developed spinal cord compression and did not proceed with intrathecal treatment.
• Overall, treatment was discontinued in 10 patients for different reasons, but these were not all described.

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.

• The sample size was small, with fewer than 100 patients.
• Patient and caregiver education was not documented.
• No comparison or control group was included.
• The authors did not discuss breakthrough pain, explain the reasons for all of the discontinuations, or describe the methods of measurement and analysis of complications.

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.

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.

• The sample was composed of 13 patients.
• Mean patient age was 58.1 years (SD = 9.9 years). The age range of the sample was 43–75 years.
• Of the 13 patients, 4 were female and 9 were male.
• Seven patients had lung cancer, two had pancreas cancer, one had kidney cancer, one had breast cancer, one had prostate cancer, and one had ovarian cancer.
• All patients were receiving stable doses of oral methadone.
• All patients were inpatients receiving palliative care.

• Single site
• Inpatient
• Italy

Prospective trial

• Numeric pain scale, 0–10
• Numeric pain intensity scale, 0–10, to measure changes of pain intensity

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.

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.

• The sample was composed of 66 patients and involved 503 episodes of BTP.
• Mean patient age was 66.7 years (SD = 12.2 years).
• The sample included 24 females and 42 males.
• Authors did not include information about diagnoses.
• Patients had been admitted to a pain relief and palliative care unit and were receiving opioids equivalent to morphine 60 mg/day or more.

• Single site
• Inpatient
• Italy

Prospective descriptive study

Verbal rating scale, 0–10 points

• Patients experienced a mean of 8.7 BTP episodes during hospitalization—a median of 2/day.
• Of 503 episodes of BTP, 427 were treated without making a further request for pain control; 76 patients (15%) required an additional BTP dose within two hours.
• IV morphine and OTFC were administered most frequently. In 99.2% of patients, IV morphine resulted in a decrease in pain intensity of greater than 33%. In 97.6% of patients, OTFC resulted in a decrease in pain intensity of greater than 97.6%.
• No adverse effects were severe enough to require intervention.

Administration of 20% of the basal dose was effective in controlling BTP.

• The study had a small sample size, with fewer than 100 patients.
• The sample was a convenience sample.
• Patients were not blinded to intervention.
• Patients were in one unit only.
• The study comprised various opioids.

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.

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.

• Eighty-six patients completed all phases. INFS efficacy data were for 101 patients; OTFC efficacy data, for 100 patients.
• Mean patient age was 62 years. The age range was 22–94 years.
• Of all patients, 43.2% were female and 56.8% were male.
• All patients were Caucasian.
• Authors did not provide information about specific diagnoses.
• Patients had a life expectancy of three months or longer and were receiving stable opioid therapy for background pain, at a dose equivalent to 60–500 mg/day morphine, for at least one month prior to the study.
• Patients were excluded if they had had recent cancer treatment or if treatment was scheduled within the next eight weeks.

• Multisite
• Inpatient and outpatient
• Europe

Open-label crossover trial

• Stopwatch, to measure time to onset of meaningful pain relief
• 11-point numeric scale, to measure pain intensity
• Five-point Likert-type scale, to rate general impression of efficacy
• Five-point Likert-type scale, to rate ease of drug administration

• Authors reported that 85.1% of patients achieved an effective INFS dose and 87.9% achieved an effective OTFC dose in titration.
• Results revealed that 73.6% obtained faster onset of pain relief with INFS (p < 0.001) than with OTFC.
• After onset of the breakthrough pain episode, INFS produced a significantly larger mean decrease in pain intensity (p < 0.001) in the first 15 minutes and the first 60 minutes. Compared to OFTC, INFS was associated with a higher rating of efficacy (p < 0.001).
• Onset of relief was faster with INFS; however, at 60 minutes results tended to converge.
• The majority of adverse events were not considered to be related to the study drugs. Prevalence of adverse events of the nasal cavity was low, with one patient experiencing a nasal ulcer. General adverse events were similar in both groups. The most frequent adverse events were nausea, vomiting, and constipation. These occurred in less than 9% of patients.

More patients experienced faster relief of cancer-related breakthrough pain with INFS than with OTFC.

• Duration of INFS use was two weeks or less; potential adverse events of the nasal cavity, related to long-term use of INFS, are unknown.
• Although INFS was associated with faster onset of pain relief, the difference in the effect of the two drugs became less clear at 60 minutes. The percentage of patients who used rescue medication was higher with INFS than with OTFC. Whether these facts were due to real differences in effect or to the study design, which allowed patients taking INFS to take rescue medication earlier than patients taking OTFC, is unclear.
• Patients used the study drugs to treat up to four episodes daily. Authors provided no information about how many daily episodes total that patients experienced or how either study drug might fit into a comprehensive pain management plan.

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.

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.

• The sample was composed of 108 patients, 36 in the morphine group (22 patients in this group completed the study), 36 in the fentanyl group (25 completed the study), and 36 in the methadone group (23 completed the study).
• In the morphine group, mean patient age was 59 years; in the fentanyl group, 57 years; and in the methadone group, 61 years.
• In the morphine group, 10 patients were female; in the fentanyl group, 14 were female; and in the methadone group, 12 were female. In the morphine group, 12 patients were male; in the fentanyl group, 11 were male; and in the methadone group, 11 were male.
• Patients had advanced cancer with pain and required first-line opioids for pain control. Patients were excluded from the study if they had liver or renal disease, cognitive impairment, or expected survival of less than three months; if they were undergoing radiation therapy or a new course of chemotherapy; or if they had prevalent incident pain, mixed pain, or nociceptive and neuropathic pain. Breast cancer was the most frequent diagnosis.

• Multisite
• Outpatient
• Multiple sites in Italy

Randomized controlled trial

• Scale (0 = not at all, 3 = severe), to measure adverse events 
• Number of passages per day, to measure constipation
• Scale, 0–10, to measure pain intensity (PI)
• Number of daily dose changes to stabilization
• Opioid escalation index, or OEI (OMD – OSD/OSD per day x 100, where OMD represents doses administered at four weeks after study initiation and OSD represents the opioid starting dose at study initiation)
• Spitzer Quality of Life Index
• Costs of opioid therapy

• A similar number of patients in each group switched to other opioids.
• No significant differences existed in number of days to achieve dose stabilization.
• No significant differences existed in the number of dose changes needed during titration.
• No differences existed in the PI of the three groups.
• OEI% was highest in the fentanyl group and significantly lower in the methadone group; 14 patients on methadone did not have a dose change, but 8 required a decrease in the dose and then a subsequent increase.
• Authors observed no significant intergroup difference in quality-of-life scores.
• Methadone was less expensive.

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.)

• The study had a small sample, with fewer than 100 patients.
• The sample was a convenience sample; it was not blinded.

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.

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.

• Of the 99 patients, 53 were male and 46 were female.
• Mean patient age was 62; of all participants, 42% were over 65.

Italy

Prospective cohort study

• The measurement instrument was a tool to measure pain intensity.
• Nurses implemented the measurement method. Nurses documented the number of patients who benefited from IV-M within 15 minutes of administration and the number of patients who needed further treatment after 15 minutes. In addition, nurses documented adverse events severe enough to require medical intervention.

• Mean pain intensity decreased from 7.2 to 2.7 within 15 minutes.
• In all, 945 breakthrough events were treated. The mean number of events/patient/admission was eight. The mean dose of IV-M was 12 mg.
• At the end of the study, nurses had collected complete documentation for 49.6% of events. Of the 49.6%, a decrease in pain of greater than 33% was documented in regard to 61.2% of patients. In 24.5% of patients, documentation showed a pain decrease of greater than 50%.

IV-M given at doses proportional to basal dose provided prompt analgesia and was effective in most cases.

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 reported on a sample of 99 patients (63 men and 36 women).
• Mean patient age was 65.7 years (SD = 12.2).
• Cancer sites were lung (n = 30), genitourinary (n = 19), gastrointestinal (n = 11), breast (n = 8), pancreas (n = 8), head and neck (n = 6), and other (n = 17).
• Previous treatments were chemotherapy (n = 29), surgery (n = 23),  and radiation (n = 3).

• Single site
• Inpatient
• Italy

The study has clinical applicability for end-of-life and palliative care.

This was a prospective trial.

• Nausea scale (0 to 3)
• Demographic information: age, gender, primary tumor, previous abdominal surgery, chemotherapy, radiotherapy in the last month, and use of opioids in the last month
• Presence of early satiety
• Reduction of fluid and food intake scale (0 to 3)
• Time to first bowel movement
• Adverse effects from amidotrizoate

• Of the evaluable patients, 80.8% were receiving opioids.
• Within 24 hours after amidotrizoate administration, 44.4% of patients had a bowel movement and patients reported significant improvement in nausea, hydration, and nutrition.
• Early satiety symptoms improved in the amidotrizoate group (p < 0.048).
• The effect of amidotrizoate on bowel movement was independent of age, Karnofsky Performance Status, days of constipation, use or dose of opioids, primary tumor, or concomitant chemotherapy or radiotherapy.
• The treatment was more effective in patients who had a history of abdominal surgery.
• The most frequent adverse effect reported was diarrhea in 19 patients.

Amidotrizoate is an effective and well-tolerated alternative therapy for patients with advanced cancer and constipation.

• The sample was small (less than 100).
• There was no blinding, with potential for bias. 
• The study was performed in a specific setting (an acute palliative care unit) where patients may be at end of life; therefore, other patient populations or settings may need to be considered to avoid bias.

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.

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.

• Few patients switched from methadone to fentanyl.
• The sample size was small.
• Studying patients undergoing palliative care in critical conditions can be difficult because of complex contexts.

Rapid titrations need to be closely monitored in an acute care setting.