To evaluate the effectiveness of probiotic supplementation for the prevention and treatment of radiation-induced diarrhea

Databases searched were PubMed, EMBASE, Cochrane Library, Google Scholar, and online clinical trials registers (Cochrane Central Register of Conrolled Trials, metaRegister of Controlled Trials, National Institutes of Health) until January 2009. Other relevant trials were identified from the reference list of selected articles. Abstracts presented up to 2008 at the United European Gastroenterology Week meetings, American Society for Therapeutic Radiology and Oncology Annual Meetings, and American Gastroenterological Association Digestive Disease Week were searched manually.

Search keywords were diarrhea, probiotics, radiotherapy, radiation therapy, Lactobacilli, Bifidobacteria, Enterococci, VSL no. 3, pelvic tumors, and abdominal tumors.

Studies were included in the review if they were randomized, controlled trials with at least two parallel groups that evaluated the effectiveness of probiotic supplementation to prevent or treat radiation-induced diarrhea.

Studies were excluded if they were review articles, involved nonradiation-induced diarrhea, or covered radiation-induced gastrointestinal (GI) symptoms other than diarrhea.

The abstracts of 58 articles were reviewed. Fifty evaluated the effects of probiotic supplementation for conditions other than radiation therapy and were eliminated. Of the remaining eight, three were duplicate reports and one studied radiation-induced chronic bowel discomfort rather than diarrhea.

The remaining four studies were selected for this review. Three were randomized controlled trials evaluating probiotic supplementation for the prevention of radiation-induced diarrhea, and one trial evaluated probiotic supplementation for the treatment of radiation-induced diarrhea.

Three studies evaluated the use of probiotic supplementation to prevent radiation-induced diarrhea. A total of 632 individuals initially were randomized to the studies; the final sample sizes were 21, 85, and 482. The study using probiotic supplementation to treat radiation-induced diarrhea had a sample size of 205 patients, with 102 receiving the intervention and 103 receiving a placebo.

• Probiotic supplementation was well-tolerated in the prevention and treatment trials.
• The three trials addressing probiotic supplementation for the prevention of radiation-induced diarrhea did not collectively show significant differences between the intervention and control groups.
• The study addressing treatment also did not show significant differences between the intervention and placebo groups.

The few available studies on the use of probiotics to prevent or treat radiation-induced diarrhea do not allow for firm conclusions to be drawn regarding the benefits of this intervention.

The studies included in the systematic review and meta-analysis used different single strains and different doses of probiotics.

More studies using preparations containing several strains of probiotics and studies looking at comparisons between different probiotics are needed.

To determine the effectiveness of topical rectal beclomethasone dipropionate (BDP) in the prevention of rectal proctopathy, which can lead to rectal bleeding, in patients undergoing radiation therapy for prostate cancer

The treatment arm consisted of a 3 mg BDP enema each evening before radiotherapy treatments and two 3 mg BDP suppositories (one in the morning and one in the evening daily) over four weeks. The placebo arm consisted of an identical looking enema and suppository given at the same intervals without medication. Time points for clinical evaluation were before radiotherapy, one month after completion of the treatment, and every three months thereafter. Time points for endoscopic evaluation were before treatment, at three months, and at 12 months postradiotherapy. The patients self-administered the treatment, and they were asked to hold the medication in for as long as they could and return the unused materials at the end of the study to assess compliance.

• N = 110  
• AGE = Not collected
• MALES: 100%         
• KEY DISEASE CHARACTERISTICS: Prostate cancer 
• OTHER KEY SAMPLE CHARACTERISTICS: N/A

• SITE: Single-site
• SETTING TYPE: Not specified  
• LOCATION: S.Orsola-Malpighi University Hospital in Italy

• PHASE OF CARE: Active treatment 
• APPLICATIONS: Elder care 

Double-blind, placebo-controlled, randomized trial

• The endoscopic evaluation consisted of a flexible sigmoidoscopy procedure. The findings were measured using World Organisation of Digestive Endoscopy language and were evaluated using the Vienna Rectoscopy Score (VRS).
• Simple Clinical Colitis Activity Index (SCCAI)
• Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer acute and late toxicity scales (RTOG/EORTC)
• Inflammatory Bowel Disease Questionnaire quality of life Index (IBDQ)

With respect to bleeding rate, the BDP group showed a statistically significant lower amount of blood in stools (OR = 0.38; 95% CI 0.17–0.86). The patients in the BDP arm showed a later onset of blood in stools overall (p = 0.032). The quality of life IBDQ score was significantly lower in patients randomized to BDP who reported rectal bleeding (p < 0.001). Severe hemorrhagic proctopathy, defined as anemia with a drop in hemoglobin of at least 1.5 g/dL, was found in 10 patients (four in the BDP group and six in the placebo group).

The BDP therapy arm of this study seemed to fair better with respect to bleeding risk postradiation and the prevention of some of the mucosal changes that lead to significant complications. It does not seem to affect other quality of life issues like continence and diarrhea. Changing the formulation of the BDP and/or its frequency of usage may improve outcomes for patients. Since the treatment did not cause harm to patients, it seems to be a good recommendation for patients to try.

It would be best for nurses to train patients on the usage of BDP during and following radiation therapy. A nursing study to evaluate methods of application and quality of life for patients would be the next step to further improve this research.

To evaluate the safety, feasibility, and acceptability of the Optimal-Lymph-Flow™ program for patients with breast cancer and to evaluate its benefit when introduced presurgically

The Optimal-Lymph-Flow™ (OLF) program is a patient self-care program designed to reduce the development of lymphedema through specific exercises and behaviors to improve lymph flow and reduce or maintain body mass index (BMI). Participants were recruited preoperatively and followed prospectively for 12 months after surgery. Trained nurses provided each participant with the study intervention through a 30-minute face-to-face meeting. Participants were trained in various exercise techniques and then did a return demonstration (shoulder, breathing, and pumping exercises). They also were instructed in a nutrition-balanced and portion-appropriate diet to maintain preoperative BMI. Participants’ limb volume was measured with a Perometer, and BMI was measured with bioimpedance presurgery, two to four weeks after surgery, and at 6–12 months. Any patient with a limb volume measurement ≥ 10% was referred for complete decongestive therapy. If a 5% increase in limb volume occurred, patients were instructed to increase OLF activities, and limb volume was rechecked a few weeks later.

• N = 140
• AVERAGE AGE = 56 years (SD = 11.8 years, range = 25–84 years)
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: First-time diagnosis of breast cancer (stages 1–3)
• OTHER KEY SAMPLE CHARACTERISTICS: Women aged greater than 21 years and scheduled for surgical treatment including lumpectomy, mastectomy, sentinel lymph node biopsy, or axillary lymph node dissection; excluded stage 4 breast cancer, preexisting lymphedema, patients with a history of breast cancer, and bilateral breast cancer

• SITE: Single site    
• SETTING TYPE: Other  
• LOCATION: New York, United States

• PHASE OF CARE: Multiple phases of care

Prospective, longitudinal, quasi-experimental design with repeated measures

• The safety of the OLF program was assessed by asking participants if the program created any discomfort or injury at each follow-up visit.
• The feasibility of the program was evaluated in terms of intervention delivery time by the trained nurses.
• The acceptability of the program was assessed by asking the participants if the program helped the them to (a) understand how to reduce the risk of lymphedema, (b) reduce the fear and anxiety of developing lymphedema, and (c) develop a plan to reduce the risk of lymphedema.
• Lymph volume changes were measured by an infrared Perometer, and BMI was measured by a bioimpedance device.

One-hundred and thirty-four participants completed the study. At each follow-up visit, no participants reported injury or discomfort associated with the OLF program, making it safe. It took about 30 minutes for the trained nurses to deliver the program, making it feasible. Greater than 90% of the patients reported that the OLF program helped them reduce their fear and anxiety of developing lymphedema, making it acceptable.

The majority (97%) of patients maintained or improved their preoperative limb volumes and BMIs at the study endpoint of 12 months following surgery.

All four women who experienced a 10% lymph volume increase two to four weeks post-surgery and at six months decreased their lymph volume to less 5% at the 12-month visit. BMI did not change significantly. No control group was used, so the benefits of this treatment could not be determined.

This educational and behavioral program may be effective to enhance lymphedema risk reduction. The study provided initial evidence for an emerging change in lymphedema care from treatment focus to proactive risk reduction.

• Baseline sample/group differences of import
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment) 
• Other limitations/explanation: Single-site study

Studies with more rigorous research designs (i.e., randomized, controlled trials) are needed to replicate the findings from this study, evaluate the effectiveness of the OLF program, and determine the dosage and contribution of individual components of the program.

To evaluate the effectiveness of electroacupuncture (EA) and hormone therapy (HT) on health-related quality of life (HRQoL) and sleep in breast cancer survivors with vasomotor symptoms.

Women who had completed treatment for breast cancer were randomized to receive EA for 12 weeks or HT for 24 months. They completed the Psychological and General Wellbeing Index (PGWI) and Women’s Health Questionnaire (WHQ) pretreatment for vasomotor symptoms; during treatment; and at 6, 9, 12, 18, and 24 months after the start of treatment.

• The sample was comprised of 18 female patients.  
• Mean age was 54.1 years (range 47–69). 
• Patients had completed treatment for breast cancer in situ for a T1 or T2 tumor with a maximum of four metastatic lymph nodes or T3 tumors without metastatic lymph nodes.
• Patients also had:
  • Vasomotor symptoms 
  • Been seen by a breast surgeon or oncologist within the last three months and were not receiving active treatment for breast cancer  
  • No clinical or mammographic signs of recurrence.

Women were excluded if they were receiving ongoing breast cancer treatment other than tamoxifen; had other malignancies; or had a history of thromboembolic, cereverbrovascular, or liver disease; porphyria; or active cardiovascular disease.

• Multisite   
• Outpatient
• Sweden

• Patients were undergoing the long-term follow-up phase of care.
• The study has clinical applicability for late effects and survivorship and elderly care.

The study was a multicenter, randomized, prospective trial.

• WHQ
• PGWI
• Log books for hot flushes and for sleep data, specifically the number of hours slept and times woken

Nineteen women completed 12 weeks of EA. Eleven women were excluded due to changes in treatment. About 40% of the patients had no other treatment. The HT group had 11 women complete the 24 months of treatment. In both groups, reduction of hot flushes was noted. The EA group had a decrease in the median number of flushes/24 hours of 55% (p < 0.001) after 12 weeks. The decrease was 29% (p = 0.026) after 24 months. In the HT group, the median number of hot flushes/24 hours decreased by 100% (p = 0.001) after 12 weeks of treatment with no further changes. Sleep parameters improved significantly in both groups from baseline, with a WHQ sleep score in the EA group at baseline of 0.50 and at 24 months 0.33; in the HT group, the baseline score of 0.33 to declined 0.00 at 24 months.

The study showed improvement in sleep scores of both groups up to 21 months. The numbers of hours slept per night did not increase, but the numbers of flushes and distress caused by them decreased, resulting in fewer times woken, with overall improvement in HRQoL. Both groups also showed a significant decrease in the number of HF experienced, which was maintained up to 21 months after treatment was stopped.

EA, compared to HT for management of hot flashes in breast cancer survivors, shows some potential benefit in reducing numbers of hot flashes/24 hours, improving overall WHQ scores.

• The study had a small sample size, with less than 30 patients.
• There was a high number of drop-outs in EA group.

HT is not recommended as a safe treatment for vasomotor symptoms for breast cancer survivors. Thus, the value of using that group to compare with a group that received EA is of concern. EA needs further investigation in larger sample sizes. Further research is needed for efficacy of EA in hot flash management for breast cancer survivors and in women treated with aromatase inhibitors experiencing hot flash distress, as this study did not address that phenomenon. 

To describe hot flushes in men with prostate cancer and their treatment methods.

TYPE OF STUDY Systematic review

DATABASES MEDLINE, ISI Web of Knowledge, Cinahl & PsycINFO

KEYWORDS  Prostate cancer, androgen deprivation therapy, vasomotor symptoms, hot flashes treatment

INCLUSION CRITERIA All studies were randomized controlled studies (RCT) that addressed hot flashes (HF) in men with any stage of prostate cancer, treated with androgen deprivation therapy either medically or surgically. The studies addressed treatment for hot flashes where the main outcomes were frequency of hot flushes, distress from hot flushes, or hot flash score.

EXCLUSION CRITERIA Studies were limited to human studies and publications appearing between 1966 - 2009. Excluded were reviews & meta-analysis.

TOTAL REFERENCES RETRIEVED: 252

METHOD OF STUDY EVALUATION The Jadad score was used to assess the quality of the randomized controlled trial (RCT), on a five-point scale, and the QUORUM guidelines for systematic review were considered.

This summary did not include the measures that were used by the participants in reporting their hot flashes: i.e, diaries, skin temperature measurements, QOL surveys.
 

FINAL NUMBER STUDIED INCLUDED; N = 5   TOTAL SAMPLE SIZE: N = : 328 men were analyzed.   SAMPLE RANGE ACROSS STUDIES : Sample sizes ranged from 12 - 177.

KEY SAMPLE CHARACTERISTICS: Samples included men with prostate cancer who had undergone surgical or medical castration and were currently experiencing hot flushes.
 

PHASE OF CARE Active Treatment

APPLICATIONS Late Effects and Survivorship; Elderly Care

In the five studies analyzed, the treatments that were studied included cyproterone acetate (CA), megestrol acetate (MA), gabapentin, transdermal clonidine, and diethylstilbestrol (DES). Unfortunately, none of the studies analyzed the same treatment. Because the studies looked at different interventions to relieve hot flushes (HF) in castrated men with prostate cancer, it was not possible to combine the studies to strengthen the outcomes. The studies' outcomes demonstrated varying degrees of success in relieving the hot flushes: Cyproterone acetate 100 mg, once per day, yielded 75% fewer HF than placebo  (p<0.001), and 100% of men on CA had a 50% or greater reduction of mean number of HF, compared to placebo group. Megestrol acetate  20 mg, twice per day, yielded an 80% reduction of the  median number of HF compared to a 19% reduction in the placebo group (p<0.001), an 87% reduction of median HF score vs. a 16% reduction for placebo (p<0.001), and a 50% or greater reduction of median number of HF (p<0.001) reported by 79% of MA group and 12% of placebo group. Gabapentin (4 schedules) achieved a 45.5% reduction of the median number of HF with 900mg gabapentin per day vs. 21.5% with placebo (p=0.02). Transdermal clonidine demonstrated no difference between the  treated group and placebo. Diethylstilbestrol (1 mg) yielded a 100% reduction in the median number of HF vs.13% with placebo. 100% of DES and 14% of placebo reported a 50% or greater reduction of the median number of HF.

The systematic review of studies on treatment approaches to managing hot flushes in men after castration for prostate cancer showed very few such studies. Only five RCT studies were identified, and none of them analyzed the same treatment approach. Several of the studies that were presented demonstrated successful treatment approaches, including DES as the most effective, followed closely by MA and CA. However, these medications are linked to side effects that are not well tolerated by all patients.

Only five RCT studies were identified, and none of them analyzed the same treatment approach. 

Large randomized placebo controlled studies are needed to clarify the data and provide clearer direction to managing HF in men who have been castrated as a treatment for prostate cancer. The summary, although providing insight for possible medical management, addressed only briefly the drop-out rates due to side effects. Further investigations of the drop-out subgroup could explore correlations among the medications to reveal unacceptable side effects  in managing the participants’ hot flash symptoms. Further investigations comparing medications used and providing more specific information about measurements of QOL and hot flash reporting by participants are warranted.

To evaluate the effects of electro-acupuncture (EA) and hormone therapy (HT) on vasomotor symptoms in women with a history of breast cancer

Twenty-seven women were randomized to EA for 12 weeks, 18 received  HT for 24 months. The total population was 45.

This was an international, multicenter study, HABITS19, involving patients from three centers in Sweden between April 1998 and December 2002.

Randomized, controlled study

The patients were monitored with daily entries made in a log book, recording the numbers of hot flashes during day and night and how disturbing they were (range 0 for no distress to 10 for worst possible distress). The log books were completed daily for 1–3 weeks before treatment, continuously during the first 12 weeks of treatment, and thereafter for 1 week per month; altogether for 24 months. The measuring points were baseline, the 12th week of treatment, and at 1 week and 6, 9, 12, 18, and 24 months after start of treatment.

In 19 women who completed 12 weeks of EA, the median number of hot flashes per 24 hours decreased from 9.6 at baseline to 4.3 at 12 weeks of treatment. At 12 months after start of treatment, 14 women with only the initial 12 weeks of EA had a median number of flashes per 24 hours of 4.9, and at 24 months 7. Women with no other treatment than EA had 2.1 hot flashes per 24 hours.

Limitations included small sample size and relatively large attrition rate.

Repifermin (keratinocyte growth factor-2)
25 or 50 micrograms/kg
IV for 3 days prior to conditioning regimen and continued after transplant for up to 10 days.

Assessments before HSCT regimen, day of transplant, and 3x/wk until mucositis resolved.
 

The study was comprised of  42 patients (8 sites), with a mean age of 50.
21 each dose level – 14 study agent, 7 placebo
Auto HSCT
 

Multi-center

Randomized, double blind, placebo-controlled, phase I/II study

• NCI-CTC mucositis toxicity scale for BMT OMAS
• Severity of pain (0-10)
• Severity of pain while swallowing
• Duration of pain
• Ability to eat score (1 = normal, 2 = soft solids, 3 = liquids, 4 = nothing)
• Narcotic use for pain
• Frequency, severity, and duration of diarrhea
   

• Grade 2 – 4 mucositis
• Placebo 100%, 64.2%
• 25 mcg  p = 0.041
• Placebo vs 50 mcg  (50%) p = 0.006

Effectiveness not established; study was not designed to have sufficient statistical power in identifying differences in efficacy between groups.

Number of end points suggest better outcome for 50 mcg group (mean duration, pain on swallowing, days on narcotic pain medication).

• Study predominantly designed for “safety” not “efficacy”.
• Small sample group used (n = 42)
• Multiple conditioning regimens were used; this may affect final outcome as far as efficacy.
• Auto HSCT population only
• Multiple doses were used in study.

Number of post-transplant doses required was unclear.

Larger trial is needed.

To prevent the recurrence of neutropenic events (NEs) in patients with solid tumors and identify potential predictive factors of recurrence of NEs

The study was a prospective, multi-center, observational study to describe prophylactic strategies, including cycle delay, dose reduction, and granulocyte colony-stimulating factor (G-CSF), that were developed to prevent the recurrence of an NE subsequent to a previous episode in patients with solid tumors, and to evaluate their respective efficacy (primary endpoint). Secondary objectives assessed the recurrence rate of NEs and factors predictive of recurrence.

• N = 548  
• MEDIAN AGE = 63 years (range: 18–92 years)
• MALES: 31%, FEMALES: 69%
• KEY DISEASE CHARACTERISTICS: 40% were patients with breast cancer; no hematologic malignancy
• OTHER KEY SAMPLE CHARACTERISTICS: 43.6% of patients were older than 65 years; 59.9% were treated for metastatic disease

• SITE: Multi-site   
• SETTING TYPE: Outpatient   
• LOCATION: 62 cancer centers in France

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Elder care

• Observational

• Incidence of febrile neutropenia, treatment delays, and chemotherapy dose reductions
• Neutropenic events defined as any episode of febrile neutropenia (single temperature elevation over one hour) or any episode of neutropenia with a significant impact in terms of cycle delay or dose reduction

During cycle A, 16.1% experienced febrile neutropenia, 7.7% experienced neutropenic fever, and 76.3% experienced all-grade neutropenia. Cycle B was delayed in 44.5%, dose reductions occurred in 22.3%, and prophylactic G-CSF was given to 85% (59.7% received pegfilgrastim). The incidence of cycle delay and chemotherapy dose reduction decreased with further cycles of chemotherapy. The median number of G-CSF administrations with subsequent cycles, excluding pegfilgrastim, was five. The proportion of patients who experienced an NE was 29% when receiving G-CSF versus 68% for patients who did not. Only use of G-CSF was associated with a lower recurrence rate of febrile episodes (p < .001). In multivariate analysis, factors associated with a greater rate of NE occurrence were prior episode of febrile neutropenia, lung or colorectal cancer, metastatic disease, and prior radiotherapy.

Only the prophylactic administration of G-CSF was found to be an independent predictor of lower recurrence rate of NEs.

• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Risk of bias (no appropriate attentional control condition)

Teaching needs to be done related to G-CSF administration and the necessity of use. Further research is needed in G-CSF prophylaxis and the quality-of-life impact of other methods such as delay/dose reduction.

To investigate if Ruta graveolens 9c can improve quality of life and reduce tumor progression in patients with advanced disease.

Ruta graveloens is a medicinal plant that has been historically used to treat various inflammatory conditions Ruta graveloens was given at a 9c dilution in 1 ml ampules. The extract was taken orally twice daily for eight weeks. Patients continued treatment until there was tumor or clinical progression. Study data were obtained on day 1 and at weeks 8, 16, 28, 40, and 52. Examination and tumor markers were evaluated every four weeks.

• N = 31
• MEAN AGE = 64.3 years (range = 44-87)
• MALES: 33%, FEMALES: 77%
• KEY DISEASE CHARACTERISTICS: Various tumor types, breast cancer most predominant; 64.5% had progressive disease
• OTHER KEY SAMPLE CHARACTERISTICS: Most had performance status lower than 1. At baseline, 70% had clinically relevant anxiety scores and 63% had relevant depression scores

• SITE: Single site  
• SETTING TYPE: Not specified  
• LOCATION: France

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

• Quasi-experimental, open label

• EORTC QLQ-C30
• Hospital Anxiety and Depression Scale 
• Tumor markers and imagery 
• NCI CTCAE version 4

Quality of life improved by week 8 (p < 0.001) and week 16 (p = 0.035). There were no significant changes in anxiety or depression scores. Mean duration of treatment was 3.3 months and median progression free survival was 1.9 months. Ninety percent had at least one adverse event, with an average of nine events per patient. Most comment symptoms were abdominal pain, fatigue, musculoskeletal pain, and headaches. None of the events were considered to be related to the study treatment.

Treatment with Ruta graveolens 9c did not have a demonstrable effect on anxiety or depression.

• Small sample (less than 100)
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment) 
• Unintended interventions or applicable interventions not described that would influence results
• Other limitations/explanation: It is not stated whether any patients were receiving antidepressants or anti-anxiety medications or other interventions that could have impacted quality of life and symptoms

Ruta graveolens did not have an effect on anxiety or depression in this study.

To compare effervescent morphine to immediate release (IR) during breakthrough pain

Dosage adjustments of fixed schedule opioid could be made at the discretion of the investigator. Patients documented onset time, efficacy, and side effects of IR morphine given for breakthrough pain for one month. They were to take it within five minutes of breakthrough pain and titrate until sufficient relief, starting at 20 mg (equivalent to one effervescent tab). For the second month, the patients took effervescent morphine. They were instructed to take it within five minutes (they could take an additional one after 10 minutes) up to a max of four tabs for a single breakthrough pain episode. Patients could take non-investigational drugs for control of adverse effects (e.g., nausea, constipation, sedation). This was a long-term study that lasted up to six months.

• N = 76
• MALES: 41, FEMALES: 35
• KEY DISEASE CHARACTERISTICS: Patients with cancer with chronic pain being treated for breakthrough pain
• OTHER KEY SAMPLE CHARACTERISTICS: 86% of breakthrough pain was related to tumor, 5.3% of patients had neuropathic pain. For primary pain treatment, multiple sustained-released (SR) opioids were used—fentanyl patch, 38.2%; morphine SR, 32.8%; transdermal buprenorphine, 11.8%; oxycodone SR, 14.4%; and hydromorphone, 5.3%.

• LOCATION: Germany and the United States

• Open-label safety and efficacy study

• Time until pain relief, global satisfaction, side effects, efficacy, and long-term safety of effervescent formulation
• An episode was treated sufficiently when adequate pain relief occurred, defined as a visual analog scale (VAS) score of 3 on a 0–10 scale.
• Patients completed questionnaires and kept daily diaries.
• Number of breakthrough pain episodes
• Pain relief using VAS
• Global satisfaction scale using a five-point Likert scale from 0 (poor) to 4 (excellent)

During the IR morphine month, the mean VAS score was 8 and decreased to 3. During the effervescent morphine month, the mean VAS score of 7.8 decreased to 3.2. No statistically significant difference was seen between IR morphine and effervescent morphine; however, the difference was significant (p < 0.001) when comparing pain intensity prior to taking effervescent morphine. The time to relief with effervescent morphine was 13 minutes and 27 minutes with IR morphine (statistically significant, p < 0.001). Effervescent morphine decreased the number of breakthrough pain episodes from a mean of 3.3 per day to 2 per day. This was statistically significant (p < 0.01).

• Dosage adjustments of fixed-schedule opioids could be made at the discretion of the investigator. No formal guidelines were used to make these adjustments.
• The definition of pain relief was VAS of 3. This may not be an adequate pain relief level for all patients.
• The non-investigational drugs given to treat adverse effects were not standardized or monitored.
• Only opioid-responsive patients were included in the study.
• Historical data was used for the IR morphine month and was compared to the effervescent morphine month. The study should have used a concurrent, double-blinded, randomized, cross-over design.

Although effervescent morphine had a faster onset, it does not compare with the onset of transmucosal fentanyl citrate (7–10 minutes).