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.

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.

• N = 12
• KEY DISEASE CHARACTERISTICS: Consecutive patients with advanced cancer and pain

• LOCATION: Acute pain relief and palliative care unit in Italy

• Open clinical trial

• Pain intensity on a numerical scale from 0–10 and symptoms commonly associated with spinal local anesthetic injection (e.g., hypotension, sensory and motor block, bladder dysfunction) were recorded using a scale of 0--3 (absent, light, moderate, severe) at the time of injection, and then followed at one-minute intervals until pain level was less than 50% of the initial value.
• Assessed for adverse effects of ketamine (e.g., confusion, agitation, drowsiness) graded from 0–3 until pain decreased to 50% of the previous level.

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).

• Data on the treatment of breakthrough pain in patients receiving a spinal treatment are lacking, and the use of spinal route for episodic (breakthrough) pain has never been reported.
• This was an open clinical trial with a very selective population.
• Small sample size
• Further studies need to be performed using a controlled trial with appropriate design.
• Patients were able to choose which treatment they wanted.
• Variability in availability of transmucosal drugs
• Tolerance to ketamine could be an issue long-term.

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).

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.

• N = 68 (263 breakthrough episodes)
• MEAN AGE = 62.1 years (SD = 12.3 years)
• MALES: 60.5%, FEMALES: 39.5%
• KEY DISEASE CHARACTERISTICS: Multiple tumor types with lung, gastrointestinal, and urogenital the most frequent
• OTHER KEY SAMPLE CHARACTERISTICS: Patients had controlled background pain and one to three episodes of breakthrough pain per day.

• SITE: Multi-site  
• SETTING TYPE: Inpatient  
• LOCATION: Italy

• APPLICATIONS: Palliative care

Randomized, single-group, crossover study

• 10-point Numeric Rating Scale (NRS) for pain intensity
• Three-point scale for adverse effect severity

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.

• Small sample (< 100)
• Risk of bias (no blinding)

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.

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.

• N = 50
• MEDIAN AGE = 66.3 years
• MALES: 40%, FEMALES: 60%
• KEY DISEASE CHARACTERISTICS: Primary tumors were breast (n = 13), urogenital (n = 10), gastrointestinal (n = 9), lung (n = 7), pancreas (n = 5), and other (n = 6).
• OTHER KEY SAMPLE CHARACTERISTICS: Patients with moderate-to-severe pain (greater than 4 on a 10-point scale); unresponsive to non-opioid drugs; with occasional use of opioids; who had a Karnofsky score of 50 or more; who did not have poor renal or hepatic function, history of substance abuse, cognitive failure, brain metastasis, or brain damage; who did not have a short anticipated survival

• SITE: Single site 
• SETTING TYPE: Not specified 
• LOCATION: University of Palermo, Italy (assumed to be a teaching facility but not clearly identified)

• PHASE OF CARE: End-of-life care
• APPLICATIONS: Palliative care

• Prospective, single-arm intervention study

• Pain on a 0–10 scale
• Symptoms related to opioid therapy
• Quality of life measured with Spitzer scale
• TP escalation index percent ([TP maximum dose - TP starting dose] / TP starting dose / days x 100)
• PainDETECT to determine prevalence of neuropathic pain

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.

• Small sample (less than 100)
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Findings not generalizable
• Intervention expensive, impractical, or training needs
• Number of patients lost to follow-up

TP is not widely used in the United States and will require education of nurses on its use and side effects.