STUDY PURPOSE: To evaluate the role of acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) for cancer pain

TYPE OF STUDY: Systematic review

DATABASES USED: MEDLINE, PubMed, CANCERLIT, EMBASE

KEYWORDS: Anti-inflammatory drugs or paracetamol or acetaminophen and/or cancer pain

INCLUSION CRITERIA: Randomized, controlled trial in patients with cancer

EXCLUSION CRITERIA: Not specified, but did exclude several studies in which patients were treated with a combination of hydrocodone or oxycodone and in which patients received transdermal fentanyl or morphine

TOTAL REFERENCES RETRIEVED = 3,703

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: No specific quality rating was applied–study limitations are described in the summary of findings of each study

• FINAL NUMBER STUDIES INCLUDED = 9
• TOTAL PATIENTS INCLUDED IN REVIEW = 175
• SAMPLE RANGE ACROSS STUDIES: 22–172
• KEY SAMPLE CHARACTERISTICS: Studies involved a mix of patients who did and did not also receive morphine for chronic pain management

APPLICATIONS: Palliative care

Five studies evaluated paracetamol. None of these demonstrated a meaningful benefit on pain intensity. Only one study reported a significant difference in pain intensity, but this difference was only 0.4 on a 10-point scale. Four studies evaluated NSAIDs. In all of these, patients were also on opioids. One of these compared two different NSAIDs. In the following three studies, use of NSAIDs appeared to have an opioid-sparing effect. Multiple study limitations were identified.

No proof exists that paracetamol or NSAIDs should be used as the first step of the analgesic ladder. No evidence exists of benefit of paracetamol in combination with opioids. NSAIDs may have benefit in patients receiving opioids; however, further research is needed to confirm this.

• Relatively few studies
• Although one inclusion criterion was randomized, controlled trial, one study included was a non-randomized trial.

Findings show that no evidence exists to show efficacy of the addition of acetaminophen to opioids for cancer pain management. Findings suggest that NSAIDs may provide additional benefit to patients on opioids for cancer pain; however, the evidence is limited, and studies done have not involved prolonged use. Nurses need to be aware of potential complications of long-term use of NSAIDs and educate patients regarding these. Selection of adjuvant pain management approaches needs to be made on an individual basis, and continued use needs to be determined on the basis of patient response.

To assess the tolerability and effectiveness of intranasal fentanyl (INFS) for breakthrough pain in opioid-tolerant patients over six months

Patients receiving INFS for breakthrough pain were recruited and data were obtained from patients via survey and clinical records. Patients were followed at three months and six months in person, and data were obtained monthly for six months.

• N = 34 (three months), 12 (six months)
• MEAN AGE = 64.8 years (SD = 12.7 years)
• MALES:  86.7%, FEMALES: 13.3%
• KEY DISEASE CHARACTERISTICS: Multiple tumor types 
• OTHER KEY SAMPLE CHARACTERISTICS: Mean opioid doses for background analgesia ranged from 111–180 mg per day, and mean INFS doses ranged from 87–119 mcg.

• SITE: Multi-site  
• SETTING TYPE: Not specified  
• LOCATION: Italy

• PHASE OF CARE: Multiple phases of care
• APPLICATIONS: Palliative care 

Observational cohort

• Four-point scale for general impression of efficacy from 1 (poor) to 5 (excellent)
• Adverse reactions graded from 0 (none) to 3 (severe)
• Quality of sleep graded from 0 (disturbed) to 3 (very good)

No patients discontinued treatment because of adverse effects. The high drop-out rate over time was caused by death and loss to follow-up. Only minor adverse effects were reported, and they were considered to be related to the opioid therapy used for background pain. Overall, 22% of participants had moderate adverse effects at one month, and 11% had effects at four months. At other time periods, less than 6% had any adverse effects. The most frequent adverse effect was drowsiness. Most patients were receiving buprenorphine, transdermal fentanyl, or oxycodone for background pain. Sleep scores improved significantly over the first four months (p < 0.05). Efficacy scores improved over the first three months overall (p = 0.0005). After three months, the majority of patients reported efficacy levels at 4 or 5.

The findings of this study suggested that INFS for breakthrough pain was well-tolerated and effective for several months.

• Small sample (< 100)
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment) 
• Measurement/methods not well described
• Measurement validity/reliability questionable
• Other limitations/explanation: High loss to follow-up with resulting low sample sizes at follow-up periods; measurement methods not validated or shown to be reliable; methods of data collection not clear; not clear if patients were directly surveyed or data were obtained from medical records or provider evaluations

There is little information on the long-term efficacy and side effects of INFS for breakthrough pain. This study provided some information in this area, suggesting that INFS was well-tolerated and continued to be effective for the majority of patients in a four- to six-month timeframe.

To compare the analgesic activity and tolerability of orally administered and rectally administered tramadol

In this crossover trial, 30 patients started with orally administered tramadol and switched to rectally administered tramadol and 30 patients started with rectally administered tramadol and switched to orally administered tramadol.

• The sample was composed of 60 patients, with moderate to severe cancer pain (a score of 4 or greater on a 0–10 scale) of nonneurpoathic origin, who were no longer responsive to nonopioid drugs.
• Of all participants, 36 were female and 24 were male. Forty-four patients completed both periods.
• Mean patient age was 66.1 years.
• The sample contained multiple types of primary tumors.

The study was conducted in Italy.

Multicenter, randomized double-blind, double-dummy crossover trial

• Numeric scale, 0–10, Likert verbal (0 = none, 1 = slight, 2 = moderate, 3 = severe), to measure pain intensity 
• Numeric scale, 0–10, to measure pain relief
• Likert verbal scale (none, slight, moderate, severe), to measure pain relief
• Likert scale, 0–3 (none, slight, moderate, severe), to measure symptoms
• Scale, 0–4 (0 = disturbed, 1 = frequent waking, 2 = not restorative, 3 = good, 4 = very good), to measure sleep
• Whether rectal passage occured within one hour of rectal administration
• Physican's and patient's judgment of efficacy of treatment (0 = absent, 1 = poor, 2 = slight, 3 = good, 4 = excellent), assessed at the end of each crossover phase
• Patients' rating of global satisfaction (0 = absent, 1 = poor, 2 = slight, 3 = good, 4 = excellent) with treatment

• Fifteen patients dropped out because of adverse effects; one patient refused treatment.
• Most physicians and patients favored oral administration.Three patients eliminated suppository within one hour of rectal administration.
• Authors found no differences in the adverse effect profiles of orally and rectally administered tramadol.

Rectal administration of tramadol appears to be a reliable, noninvasive alternative method of pain control for patients who are no longer responsive to nonopioid analgesics and who are unable to take oral tramadol. Rectal administration of tramadol appears to be as safe and effective as oral administration.

The study had a high dropout rate, with 25% of patients dropping out.

Rectal irritation has occurred with rectal administration of tramadol. If the patient is neutropenic or thrombocytopenic, rectal administration may be contraindicated. Patients with diarrhea will have difficulty maintaining and absorbing tramadol. Patients with lack of rectal tone will not be able to keep the suppository in the rectal vault.

IV morphine (IV-MO) and oral transmucosal fentanyl citrate (OTFC) given in doses proportional to basal opioid regimen. 53 couples of breakthrough events each treated with IV-MO and OTFC. Treatments were recorded. Patients were given both IV-MO and OTFC for each couple of breakthrough events. Order of administration was computer generated. Time between both pain flares was at least 6 hours. Doses of IV-MO 4 mg per 60 mg oral morphine basal and OTFC 200 µcg per 60 mg oral morphine basal.

25 patients with cancer receiving stable dose opioid. Patients were receiving doses of more than 60 mg morphine or equivalent, had acceptable pain relief, and had no more than twopain flares / day. Patients had pain flares between 700 and 1,900.

Comparative study

At episode (T0), 15 (T1) minutes and 30 minutes (T2) after treatment, pain intensity, and opioid-related symptoms were recorded. Decrease in pain intensity of at least more than 33% at T1, not requiring further treatment for next 2 hours was considered effective.

Episodes treated with IV-MO or OTFC showed a decrease in pain intensity. Statistical significance between interventions occurred at T1. AE were comparable

IV-MO and OTFC in doses proportionate to daily scheduled dose are safe and effective. IV-MO may have a shorter onset than OTFC.

Lack of blindness. No placebo control was considered. Double dummy was not feasible. Low number of participants is of concern and most likely due to drop out rates. However, strict inclusion criteria limit this bias.

OTFC given in doses proportionate to basal morphine was effective and safe. It is recommended to research this further.

To evaluate the effectiveness of intrathecal thoracic analgesia compared to continuous epidural analgesia for postoperative pain management

One group of patients received continuous epidural analgesia started prior to surgery, and the other group received an intrathecal catheter that was placed prior to surgery. Data for pain levels, vomiting, and drowsiness were obtained at discharge from the recovery room and at one, two, four, eight, 12, 24, and 48 hours. In both groups, the continuous infusion was of levobupivacaine, which was preceded by a morphine bolus preoperatively.

• N = 48  
• MEAN AGE = 63.7 years
• MALES: 56.4%, FEMALES: 43.6%
• KEY DISEASE CHARACTERISTICS: Disease types were not reported, but most patients had colorectal surgery. All patients were undergoing elective abdominal surgery.

• SITE: Single site  
• SETTING TYPE: Inpatient  
• LOCATION: Italy

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

Randomized, parallel-group trial

• Numeric Rating Scale (NRS) for pain
• Side effects were scored on a three-point Likert scale.
• Vital signs
• Motor blockade (modified four-point Bromage scale)
• Four-point sedation level scale

There were no significant differences between groups in pain intensity or total morphine consumption. There also were no significant differences between groups in Bromage scores, sedation scores, or vital signs.

Continuous intrathecal analgesia provided similar analgesic effects as continuous epidural infusion in the first two postoperative days.

• Small sample (< 100)
• Risk of bias (no blinding)
• Subject withdrawals ≥ 10%  
• Other limitations/explanation: A percentage of patients was not included in the final analysis because of protocol violations or missing data. No intention to treat analysis was done.

Intrathecal analgesic infusion provided results similar to those of continuous epidural analgesia in terms of postoperative pain relief and side effects of pain management. This approach provides an alternative mechanism for acute pain management.

To explore research literature related to the use of guided imagery as an intervention for fatigue.

Databases searched were MEDLINE, CINAHL, PsycARTICLES, PsycINFO, and Psychology and Behavioral Sciences Collection from 1980 through 2008, as well as the Cochrane Database of Systematic Reviews and a review of reference lists.

Search keywords were fatigue, tiredness, imagery, guided, and guided imagery.

Inclusion critieria were not specified.

Studies were excluded if they

• Were dissertations
• Used music alone or in combination with guided imagery
• Used hypnosis
• Had relaxation as a keyword.
   

A total of 5,968 references were retrieved. No quality rating was used. A narrative approach was used.

• A total of eight studies were included in the final analysis, with 364 patients (223 in three studies involved patients with cancer).
• The sample range across studies was 8 to 139 patients.
• Of the studies included, two included women with breast cancer, one included patients with colon cancer prior to surgery, one included patients with HIV, one included patients with asthma, one included patients with multiple sclerosis, and one included patients with chronic obstructive pulmonary disease (COPD).
   

Five studies showed no effect, one showed mixed effect, and two demonstrated a statistically significant positive effect in patients with asthma or HIV. Effect sizes from the studies were not reported. Studies varied in measures of fatigue used and intensity of the intervention. The types of images used also varied substantially, which can be expected to influence the results. Study lengths ranged from a single session to multiple daily use for six weeks. The authors noted that the studies that demonstrated significant improvement included the greatest total duration of exposure to guided imagery.

The findings were inconsistent across the studies, and those including patients with cancer did not show a significant effect. Duration of exposure may influence effectiveness. This review did not support the effectiveness of guided imagery alone for fatigue in patients with cancer. 

• The study included a small number of studies with varied sample characteristics, different study measures, and intensity of interventions studied.
• Studies were eliminated that included relaxation because guided imagery and progressive muscle relaxation often are used together.

Insufficient evidence exists from this review to recommend use of guided imagery alone. Additional well-designed research and evidence synthesis encompassing the combination of relaxation and guided imagery are needed.

The trial had three arms: Group 1 – chemotherapy control, Group 2 – chemotherapy plus midazolam, and Group 3 – chemotherapy plus propofol.

The study reported on a sample of 45 patients with breast cancer (s/p mastectomy, second chemotherapy).

Turkey

A randomized controlled trial design was used.

Clinical Global Impression Scale (CGI) for anxiety

Midazolam and propofol significantly decreased anxiety, with propofol being better.

It is unclear which groups completed the CGI measure.

• FINAL NUMBER STUDIES INCLUDED = 9
• TOTAL PATIENTS INCLUDED IN REVIEW = 788 
• SAMPLE RANGE ACROSS STUDIES = 22–235 patients
• KEY SAMPLE CHARACTERISTICS: Age ranged from 46–60 years with a mean of 55.5 years; 54.2% were female and were receiving treatment; most common treatment was chemotherapy; average months since diagnosis was 8.2 months; most common diagnoses were breast and prostate cancers

PHASE OF CARE: Active antitumor treatment
 
APPLICATIONS: Palliative care

Supervised multimodal exercise programs resulted in an overall reduction of fatigue in cancer survivors (SMD = –0.23, p = 0.001) with low statistical heterogeneity. Slight evidence of publication bias was noted. Length (weeks of training), frequency (sessions/week), and duration (minutes/session) were linearly associated with overall improvement in CRF (Tau squared = 0.04, p = 0.04). Aerobic exercise, resistance training, and stretching were implemented in seven of the nine studies, and the pooled effect estimate showed significant reductions in CRF (SMD = –0.35, p = 0.01). Two studies used resistance training, and the pooled effect estimate showed no significant reductions in CRF (SMD = –0.17, p = 0.3). Reported adverse events occurred infrequently (n = 7 events, one requiring hospitalization). Most studies were conducted during treatment (chemotherapy) and resulted in significant reductions of CRF (SMD = –0.23, p < 0.0001). No significant reductions in CRF were reported after anticancer treatment (p = 0.1).

Supervised multimodal exercise programs implemented during treatment are supported as an intervention for reducing CRF.

• Considerable statistical heterogeneity in effect estimates existed.
• Risk of bias was evaluated by a single investigator.

Supervised multimodal exercise programs are safe and beneficial for patients receiving anticancer therapy. Referrals to exercise professionals to plan a personalized exercise program for patients with cancer is recommended.

• Randomized, controlled trials
• Participants: Patients with any type of cancer without restriction to a particular stage of diagnosis or treatment
• Intervention: Supervised physical activity interventions (i.e., aerobic, resistance, stretching)
• Outcome measures: Cancer-related fatigue (primary outcome), physical wellbeing, and functional wellbeing
• Comparisons: Supervised physical activity versus conventional care

PHASE OF CARE: Active

The interventions had a mean duration of 17 weeks (SD = 12) with an average of three sessions (SD = 1) per week. The mean session duration was 45 minutes (SD = 29). The interventions included aerobic exercise (i.e., walking, stationary cycling) in all trials, resistance training in six trials (55%), and stretching/flexibility exercises in four trials (36%). Training intensity varied considerably among studies, ranging from 50%–90% of maximum heart rates. All studies reported pre-exercise screening before high intensity physical training. The overall meta-analysis showed that supervised physical activity had a favorable effect on cancer-related fatigue when compared to conventional care. The final analysis of the results revealed that supervised physical activity interventions were effective in the management of cancer-related fatigue for all types of cancer. The favorable effect was no longer significant at the six-month follow-up. However, more participants in the intervention group continued to exercise.

This study provides additional support for exercise in management of cancer-related fatigue during active treatment, in this case supervised activity. It reinforces the role of physiotherapy in the management of cancer-related fatigue.

Publication bias may have been present, but it was not possible to test for it because of the small number of included studies. Heterogeneity was present in most of the meta-analyses. This may be because of the range of sample sizes, the diverse exercise regimens (in terms of length, duration, and intensity) evaluated, and the wide variety in outcome measurement tools used in the included studies

Nurses can continue to recommend exercise as an intervention for cancer-related fatigue. However, additional research is still needed on the type, frequency, intensity, and duration of exercise.

• FINAL NUMBER STUDIES INCLUDED = 9 
• TOTAL PATIENTS INCLUDED IN REVIEW = 1,156
• KEY SAMPLE CHARACTERISTICS: Of the trials, 67% were conducted during active treatment. The mean age was 55.2 years, and the studies were mainly of non-Hispanic Caucasians.

PHASE OF CARE: Multiple phases of care

All trials included aerobic training, and six included resistance training. The average duration of training was 21 weeks, and the average sessions per week was 2.5. Supervised aerobic exercise was more effective than usual care in improving fatigue (SMD = –0.51, 95% confidence interval [CI] [–0.81, –0.21]). SMD for resistance training was –0.41 (95% CI [–0.76, –0.05]). No dose response for training intensity was seen. Studies conducted during active treatment showed a significant benefit in reducing fatigue (SMD = –0.66, p < 0.05). In four studies conducted after cancer treatment, the effects of exercise on fatigue were not significant. Exercise improved physical well-being, but no significant effects were observed for social and emotional domains.

Supervised aerobic training during cancer treatment was associated with a significant improvement in fatigue.

• High heterogeneity among the studies
• The analysis was limited to the use of supervised exercise compared to only usual care.
• The number of studies reporting emotional and psychosocial outcomes was small.

Exercise during cancer treatment has been shown to reduce fatigue. This study suggests that the results may be best with aerobic exercise. The optimum intensity and “dosage” of exercise at various time points in cancer treatment remain unclear.