Gabapentin Combinations

Gabapentin Combinations

PEP Topic 
Chronic Pain
Description 

Gabapentin, an anticonvulsant, treats seizures by decreasing excitement in the brain. The medication works by changing the way the body senses pain. Researchers have studied the effects of gabapentin in patients with cancer who have neuropathic pain or symptoms of peripheral neuropathy. Gabapentin is also used in combination with other medications, such as opioids and imipramine, for the treatment of neuropathic pain and other symptoms. Researchers have also studied the effects of gabapentin on anxiety and hot flashes.

Likely to Be Effective

Research Evidence Summaries

Arai, Y.C., Matsubara, T., Shimo, K., Suetomi, K., Nishihara, M., Ushida, T., . . . Arakawa, M. (2010). Low-dose gabapentin as useful adjuvant to opioids for neuropathic cancer pain when combined with low-dose imipramine. Journal of Anesthesia, 24, 407–410.

doi: 10.1007/s00540-010-0913-6
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Study Purpose:

To determine if low-dose gabapentin, combined with low-dose imipramine, is effective in treating cancer-related neuropathic pain

Intervention Characteristics/Basic Study Process:

Patients were randomly assigned to one of four groups. Patients in group 1 received gabapentin 200 mg and imipramine 10 mg every 12 hours. Patients in group 2 received gabapentin 200 mg every 12 hours. Patients in group 3 received gabapentin 400 mg every 12 hours. Patients in group 4 received imipramine 10 mg every 12 hours. Pain assessment occurred at baseline and at seven days after the start of medication. Opioid rescue medication was available as needed. Nonsteroidal anti-inflammatory drugs (NSAIDs) were continued if used. No other pain medication changes were made.

Sample Characteristics:

  • The study reported on 52 patients.
  • Age range across all groups was 58–79 years.
  • The sample was 52% female and 48% male.
  • Patients had a variety of cancer types, including breast, lung, neck, prostate, pancreatic, gynecologic, and gastrointestinal cancers, as well as sarcoma.
  • All patients had neuropathic pain. At baseline, daily opioid dose was 22.5–120 mg/day; patients were receiving either sustained-release oxycodone or fentanyl patch for pain management. All patients had inadequately controlled neuropathic pain.

Setting:

  • Single site
  • Outpatient setting
  • Japan

Study Design:

The study was a randomized, prospective, parallel-group trial.

Measurement Instruments/Methods:

Numeric rating scale (NRS), 0–10, to measure pain

Results:

Compared to baseline scores, scores relating to low-dose gabapentin-imipramine showed that the combination significantly decreased pain and daily pain episodes (p < 0.05). Compared to the other treatments, gabapentin-imipramine was the most effective (p < 0.001). The drug combination was associated with decreased doses of rescue opioids. Only the scores of the group treated with low-dose gabapentin-imipramine showed a significant reduction in pain.

Conclusions:

The combination of low-dose gabapentin and imipramine was effective in reducing neuropathic pain.

Limitations:

  • The study had a small sample, with fewer than 100 patients.
  • Authors provided no information about analysis of differences in the use of rescue medication.
  • The follow-up period was only seven days.

Nursing Implications:

The use of a combination of low-dose gabapentin and imipramine, as adjuvant analgesia, can improve pain control in patients with neuropathic pain. This study demonstrates that neither of these drugs alone, in different dosages, effected the improvement. Note that this study does not establish long-term efficacy or side effects.

Banerjee, M., Pal, S., Bhattacharya, B., Ghosh, B., Mondal, S., & Basu, J. (2013). A comparative study of efficacy and safety of gabapentin versus amitriptyline as coanalgesics in patients receiving opioid analgesics for neuropathic pain in malignancy. Indian Journal of Pharmacology, 45, 334–338.

doi: 10.4103/0253-7613.115000
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Study Purpose:

To determine the comparative efficacy and safety of gabapentin and amitriptyline as coanalgesics for cancer-related pain

Intervention Characteristics/Basic Study Process:

Patients were assigned randomly to receive oral tramadol 150–200 mg and oral gabapentin titrated from 600–1,800 mg daily, or tramadol 150–200 mg and amitriptyline titrated from 25–100 mg daily. Oral morphine or fentanyl transdermal patch were used as rescue medication. At baseline, if patients were on any coanalgesic, they were entered after a washout period. Patients were followed monthly up to six months. Patients were asked to maintain a diary used for assessment of compliance. Once a patient used rescue medication, the patient was excluded from further efficacy assessment, and last pain scores were carried forward.

Sample Characteristics:

  • N = 76  
  • MALES: 53%, FEMALES: 47%
  • KEY DISEASE CHARACTERISTICS: Tumor types are not stated. Baseline pain scores were 8.425 on average.
  • OTHER KEY SAMPLE CHARACTERISTICS: Patients did not have any disorder of vital organs or bone marrow.

Setting:

  • SITE: Single site   
  • SETTING TYPE: Outpatient   
  • LOCATION: India

Phase of Care and Clinical Applications:

  • PHASE OF CARE: Late effects and survivorship
  • APPLICATIONS: Palliative care

Study Design:

  • Open-label, two-group, randomized trial

Measurement Instruments/Methods:

  • Visual analog scale (VAS)—scored as 0, 1, or 2 if scores decreased, remained the same, or increased
  • Verbal rating scale (VRS)
  • Percentage of pain relief (PPR) calculated
  • Global pain score calculated as the sum of changes in VAS score, VRS score, and PPR
  • MD global impression of efficacy (four-point scale)

Results:

For patients receiving gabapentin, pain scores on the VAS reduced significantly between the first and second month (p < .001). The same timing and pattern of pain reduction were shown in the amitriptyline group (p < .001). No significant differences were seen between groups at any study time point. Six patients on gabapentin and eight patients receiving amitriptyline required rescue medication. Thirty percent of patients in the gabapentin group and 42% of patients in the amitriptyline group had adverse events. These were generally mild. More patients receiving amitriptyline experienced postural hypotension (p = .02) and dry mouth (p = .04). Sedation, dizziness, and dyspepsia were the most frequent side effects.

Conclusions:

Findings suggest that gabapentin and amitriptyline can be effective as coanalgesics for neuropathic pain.

Limitations:

  • Small sample (less than 100)
  • Risk of bias (no blinding)
  • Unintended interventions or applicable interventions not described that would influence results
  • Measurement validity/reliability questionable
  • Findings not generalizable
  • Subject withdrawals 10% or more
  • Other limitations/explanation: Information regarding any changes in opioid medications or lack of change is not provided. No data regarding compliance are provided. Depending on the timing in which patients who used rescue medication had prior pain scores carried forward, this approach could have overestimated or underestimated results. Opioid dosage information is not provided. The sample did not appear to have any significant comorbid conditions, so applicability among patients with other chronic diseases is unclear.

Nursing Implications:

Findings suggest that either gabapentin or amitriptyline can be effective coanalgesics for neuropathic pain, and professional guidelines generally have suggested consideration of such medication. The side effect profiles of the two drugs studied here were slightly different, so individual patient characteristics and risks need to be considered in medication selection. In this study, patients had no significant other disorders, so if similar results would be seen among patients with comorbid conditions is not clear.

Keskinbora, K., Pekel, A.F., & Aydinli, I. (2007). Gabapentin and an opioid combination versus opioid alone for the management of neuropathic cancer pain: A randomized open trial. Journal of Pain and Symptom Management, 34, 183–189.

doi: 10.1016/j.jpainsymman.2006.11.013
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Study Purpose:

To compare a gabapentin-opioid combination to opioid monotherapy, in terms of safety and efficacy, in the management of neuropathic pain

Intervention Characteristics/Basic Study Process:

Patients were randomized to one of two groups. One group received treatment with gabapentin added to ongoing opioids. Gabapentin was gabapentin titrated to pain; in this group (group GO), opioids were kept constant. In the other group (group OO), opioid monotherapy was continued according to the World Health Organization (WHO) ladder approach. The initial gabapentin dose was 100 mg three times daily for patients older than age 60 and 300 mg TID for those younger than age 60. Treatment was titrated to these doses in three days and to 3,600 mg per day according to response. GO patients could take gabapentin as a rescue drug.

Sample Characteristics:

  • The sample was comprised of 75 patients who were receiving opioids with minimal opioid side effects and had unrelieved neuropathic pain; 63 patients completed the trial.
  • All patients had a Karnofsky Performance Status score greater than 60 and a pain intensity score of 4 or higher.
  • Patients were excluded from the study if they were taking adjuvant drugs and nonopioid analgesics.
  • Patients were removed from the study if new pain from disease progression occurred or if intolerable side effects developed.

Setting:

  • Single site
  • Turkey

Study Design:

The study was a randomized, single-site, open trial.

Measurement Instruments/Methods:

  • Numeric rating scale (NRS) to measure pain intensity, specifically burning and shooting
  • Mean absolute change in pain intensity at day 13
  • Allodynia (Allodynia was assessed by stroking painful and nonpainful areas with a light cotton material. If normal response was noted in nonpainful area but pain or unpleasant sensation was noted in painful area, allodynia was said to be present.)
  • Analgesic drug consumption, including rescue, evaluated on day 4 and day 13
  • Side effects

Results:

  • Both treatments resulted in significant reduction in pain intensity on day 4 and day 13, compared to baseline.
  • Mean pain intensity for burning or shooting pain was significantly higher in group OO than in group GO at both assessment times (p = 0.0001). However, there was a clinically meaningful reduction in group OO.
  • Data showed a significant decrease in allodynia (p = 0.002) in group GO at day 4.
  • The rate of side effects was significantly lower (p = 0.015) in group GO.
  • One patient in the group GO withdrew from the study because of respiratory depression. The patient was taking gabapentin and sustained-release morphine and was age 66. Depression occurred three days after the addition of gabapentin. Respiratory depression should be considered when using gabapentin and morphine, particularly in older adults.
  • In terms of the most frequent causes of pain, 32.3% of GO patients had malignant sacral plexopathy, and 28.15% of OO patients had brachial plexopathy.
  • GO patients remained at the same step of the ladder at day 4. Group OO patients, who took a weak opioid at the second step, all progressed to the third step. This may explain why fewer patients in group GO experienced side effects.

Conclusions:

This study suggests that gabapentin added to opioids provides better relief than opioid monotherapy. Gabapentin-opioid treatment may be a first-line treatment for the specified patients.

Limitations:

  • The means of measuring allodynia are questionable.
  • The primary neuropathic syndromes were different in each group.
  • The WHO ladder has been abandoned by many practitioners, who now follow National Comprehensive Cancer Network or American Pain Society guidelines.

Mishra, S., Bhatnagar, S., Goyal, G.N., Rana, S.P., & Upadhya, S.P. (2012). A comparative efficacy of amitriptyline, gabapentin, and pregabalin in neuropathic cancer pain: A prospective randomized double-blind placebo-controlled study. American Journal of Hospice and Palliative Care, 29, 177–182.

doi: 10.1177/1049909111412539
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Study Purpose:

To compare the efficacy of amitryptylline, gabapentin, and pregabalin in patients with cancer experiencing neuropathic pain

Intervention Characteristics/Basic Study Process:

Patients were randomly assigned to amitryptyllin (AT), gabapentin (GB), pregabalin (PG), or placebo. AT was given at 50 mg/day for one week, then increased incrementally to 100 mg/day. GB was given at 900 mg/day for one week in divided doses, then increased to 1,800 mg/day by week 3. PG was given at 150 mg/day for one week, then increased to 600 mg/day by week 3. The control group received placebo capsules. Morphine was used as rescue pain medication as needed. Patients were evaluated weekly for four weeks.

Sample Characteristics:

  • The study reported on 120 patients.
  • Information on patient age and key disease characteristics was not provided.

Setting:

  • Single site    
  • Setting not specified
  • India

Phase of Care and Clinical Applications:

The study has clinical applicability for late effects and survivorship.

Study Design:

The study was a placebo-controlled, randomized trial.

Measurement Instruments/Methods:

  • Visual analog scale (VAS) to measure pain globally as well as burning, lancinating pain and dysesthesia
  • Eastern Cooperative Oncology Group (ECOG) score for functional capacity
  • Global satisfaction rating on a five-point verbal scale

Results:

VAS scores decreased in all groups. In week 4, those on pregabalin had significantly lower VAS scores than other groups, and scores declined by 4–5 points (p < 0.03). By the third visit, the percentage of patients who required morphine rescue increased: 46.7% with AT, 23.3% with GB, 16.7% with PG, and 100% with placebo. Lancinating pain incidence was lowest in the PG group. There were significantly fewer patients with dysesthesia in the PG group (6.7%) compared to the GB and placebo groups after four weeks. The percentage of patients with allodynia declined in all groups. The PG group showed a statistically significant improvement in ECOG score compared to all other groups (p < 0.001). Satisfaction was similar in all groups, and there were no significant differences in adverse reactions, with a gradual increase in all groups over time. Adverse effects were somnolence, dizziness, nausea, constipation, and dry mouth.

Conclusions:

All of the drugs tested here demonstrated some efficacy in improving neuropathic symptoms. In several areas, it appears that pregabalin was more effective than gabapentin, opioid monotherapy, and amitryptylline. All medications were given in combination with opioids for pain management.

Limitations:

  • No information of opioid dosages in each group was provided for comparison.
  • The follow-up period of four weeks was relatively short, given the usual duration of symptoms.
  • No information was provided regarding the causes of peripheral symptoms (whether they were chemotherapy-induced or related to other causes).

Nursing Implications:

All of the medications examined in this study were effective and had a morphine-sparing effect in the treatment of neuropathic pain and other symptoms. Pregabalin was more effective than other alternatives tested in some areas. As all patients in this study received opioids for pain rescue, it should be noted that essentially all medications compared were given in combination with opioids.

Patarica-Huber, E., Boskov, N., & Pjevic, M. (2011). Multimodal approach to therapy-related neuropathic pain in breast cancer. Journal of B.U.ON.: Official Journal of the Balkan Union of Oncology, 16(1), 40–45.

http://www.ncbi.nlm.nih.gov/pubmed/21674848
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Study Purpose:

To evaluate the effects of multimodal therapy on intensity and relief of treatment-related neuropathic pain in patients with breast cancer

Intervention Characteristics/Basic Study Process:

This study consisted of 75 patients with breast cancer who were experiencing neuropathic pain randomly divided into three groups. Group 1 received gabapentin only, starting at 300 mg, titrated up to 3,600 mg/day until an adequate response was obtained. Group 2 received a constant dose of 1,200 mg gabapentin and 100 mg diclofen gradually titrated up. Group 3 received multimodal therapy including 900 mg gabapentin, 100 mg diclofen, and 60 mg M-Eslon. Additional medicine was allowed PRN.

Sample Characteristics:

  • The study reported on 75 patients with breast cancer experiencing neuropathic pain.
  • Median patient age was 44 years.
  • Patient gender was not specified directly, but was assumed to be 100% female due to breast cancer population.
  • Patients underwent different treatments and therapies for breast cancer.
  • At study entry, all patients had pain intensity of at least 5 on a visual analog scale (VAS), and pain duration of at least three months.

Setting:

  • Single site
  • Serbia

Phase of Care and Clinical Applications:

  • Patients were undergoing the transition phase of care after initial treatment.
  • The study has clinical applicability for late effects and survivorship.

Study Design:

A randomized, three-group, parallel study design was used.

Measurement Instruments/Methods:

Modified Brief Pain Inventory questionnaire (VAS/Likert scale)

Results:

Group 3 (which received the combination of three medications) achieved the highest level of pain relief; however, there was no significant difference between groups. There was a statistically significant drop in pain intensity for all groups. The largest decrease was achieved at time of the first visit. Side effects increased in intensity over time, and group 2 experienced the most intense side effects.

Conclusions:

Multimodal therapy seems to have some benefit on neuropathic pain in patients with breast cancer.

Limitations:

  • The study did not include an appropriate control group.
  • The study had a small sample, with less than 100 patients.
  • The study lacked blinding, and confounding variables were present. Patients were to receive morphine as needed for breakthrough pain; however, breakthrough episodes and opioids used were not evaluated.

Nursing Implications:

Patients with breast cancer would appear to benefit from multimodal therapy including different drugs and dosages to treat their neuropathic pain. Nurses should watch for an increase in side effects at subsequent follow-up visits.

Ross, J.R., Goller, K., Hardy, J., Riley, J., Broadley, K., A’hern, R., & Williams, J. (2005). Gabapentin is effective in the treatment of cancer-related neuropathic pain: A prospective, open-label study. Journal of Palliative Medicine, 8, 1118–1126.

doi: 10.1089/jpm.2005.8.1118
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Study Purpose:

To evaluate the effectiveness of gabapentin for cancer-related neuropathic pain

Intervention Characteristics/Basic Study Process:

Gabapentin was administered at a dose of 300 mg/day up to 1.8 g/day over 15 days. Final doses were taken in three divided doses. Two parallel groups were recruited with either treatment-related (n = 25) or tumor-related (n = 37) neuropathic pain. Gabapentin was dose-escalated from 300 mg/day to 1.8 g/day. Median dose was 1,200 mg/day. Patient selection was nonrandomized.

Sample Characteristics:

  • The study reported on 62 patients: 16 males and 46 females, 21 of whom had had breast cancer.
  • A total of 41 patients completed to day 15.
  • Patients were excluded from the study if they had started treatment that was likely to affect their neuropathic pain, such as anticonvulsants (< one month), antidepressants or steroids (< seven days), and anesthetic interventions, such as nerve blocks (< two weeks).

Setting:

Patients were selected from inpatient and outpatient settings in a U.K. tertiary referral center.

Study Design:

Prospective, open-label studies of inpatients and outpatients

Measurement Instruments/Methods:

Patients completed pain and side-effect scores and were evaluated by a clinician on days 0, 8, and 15. In addition, pain scores were obtained on day 4. Pain was assessed using the modified Brief Pain Inventory (BPI) to measure pain on a 0–10 scale. Patient descriptors of pain and scores of activities of daily living (0–10 scale) were collated together with demographic data. Toxicity scores ranged from “not at all” to “a little,” “quite a bit,” or “very much.”

Results:

Baseline and final pain scores were not significantly different between the tumor-related and treatment-related groups. In addition, ANOVA did not show etiology to be a significant predictor of response to gabapentin. Data from both groups were pooled into the primary analysis. A total of 41 patients completed the study, with the median-range dose of gabapentin to be 1,200 mg/day. A total of 28 of 62 patients achieved at least a one-third reduction in their pain score (95% CI); the number needed to treat to obtain this benefit was 2.2. There was a significant reduction in all scores measuring the impact of pain on daily living (p < 0.003). ANOVA suggested that gender and cancer diagnosis, but not etiology of neuropathic pain or type of neuropathic pain, were independent predictors of change in average pain score. There was suggestion that beneficial effect was only in women, not men; men with bowel or lung cancer showed no benefit. This may be a chance subgroup finding. There was significant reduction in worst, average, and current pain scores (p < 0.002), but not in least pain scores. The tumor group described pain as shooting, pins and needles, and the treatment group described pain as hot, burning sensations. There was no significant difference in pain scores on day 8 compared to day 15. No further pain relief was reported from day 8 to day 15—if improvement is not seen in one week, this suggests that an alternative drug should be started. Six patients (10%) discontinued study because of probable drug-related side effects, 14% reported mild/moderate side effects, and 45% were already taking steroids or antidepressants, although doses did not change during the study.

Conclusions:

Gabapentin is an effective treatment for cancer-related neuropathic pain from both tumor and treatment.

Limitations:

  • The study time period was short and therefore may not have given enough time for patients to gain confidence and reduce the amount of opioid use. Further, patients were not randomized, so the placebo effect is not clear.
  • Breakthrough medications were available, but their use was not documented.
  • Women had a better response, which may be a chance subgroup finding or related to diagnosis (21 of 46 female patients had breast cancer).
  • Gabapentin was not used prophylactically.
  • Dose escalation was limited by side effects. Side effects were not clear; 10% left study due to side effects, and 14% had mild/moderate side effects.
  • Of 62 patients, 41 completed study to day 15.
  • Patients in the tumor group were more likely to be on steroids, and patients in the treatment group were more likely to be on antidepressants.
  • This was a single-site study; there was no comparison between methods employed at different radiation centers.

Nursing Implications:

Side effects included drowsiness, unsteadiness, dizziness, nausea, headache, and others. There was no change in opioids during study—one might question whether there could there be a synergistic effect between gabapentin and opioids. Studies need to be performed to determine if the escalation of a dose greater than 1,800 mg/day is beneficial between men and women and different cancer diagnoses.

Takahashi, H., & Shimoyama, N. (2010). A prospective open-label trial of gabapentin as an adjuvant analgesic with opioids for Japanese patients with neuropathic cancer pain. International Journal of Clinical Oncology, 15, 46–51.

doi: 10.1007/s10147-009-0009-1
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Study Purpose:

To assess the usefulness of gabapentin in the treatment of cancer-related neuropathic pain

Intervention Characteristics/Basic Study Process:

Patients who met the eligibility criteria of a score of 5 or greater on a numeric pain rating scale were entered. Gabapentin was begun at baseline at 200 mg and titrated to a maximum dose of 2,400 mg per day. Patients were asked to keep a pain diary and were assessed by a clinician throughout the 15-day study period.

Sample Characteristics:

  • Twenty participants (10 men, 10 women) with a median age of 62 years (range of 31–74 years) were included in this study.
  • Participants had a variety of tumor types, with the most common being colon and lung cancers.
  • Of the total sample, 83% were inpatients, all were on opioids, 46% also were receiving nonsteroidal anti-inflammatory drugs, 79% were taking anticonvulsants, and 67% were on antidepressants.
  • The range of the opioid dose was 6–600 mg.
  • Fifty-four percent had pain from the tumor rather than from the treatment, and only 29% had actual peripheral neuropathy.

Setting:

The study was conducted in a single-site inpatient setting in Japan.

Study Design:

This was an open-label, prospective study.

Measurement Instruments/Methods:

Measurements included a numeric pain rating scale using the Brief Pain Inventory, the McGill Pain Questionnaire, a numeric pain relief scale, and the Patient Global Impression of Change scale.

Results:

A significant reduction was noted at various time points for worst, least, and average pain on the numeric scale (p < 0.004). Mean change in scores from baseline ranged from 0.6 to 1.3. No differences were found in any other outcome measure.

Conclusions:

A statistical reduction in pain occurred as measured on the five-point numeric rating scale; however, the change was relatively small.

Limitations:

  • The study had a small sample size, with less than 30 participants.
  • Neuropathic symptoms were found to be related to treatment in only 46% of patients in the study.
  • Pain was measured by various means, but no direct measures were specific to neuropathy.
  • No discussion took place as to whether there were any changes in analgesic regimens provided during the study.
  • No appropriate control or comparison groups were used.

Nursing Implications:

The study findings do not provide strong support for the effectiveness of gabapentin for the management of cancer-related neuropathic pain or other symptoms.

Guideline/Expert Opinion

Caraceni, A., Hanks, G., Kaasa, S., Bennett, M.I., Brunelli, C., Cherny, N., . . . European Association for Palliative Care (EAPC). (2012). Use of opioid analgesics in the treatment of cancer pain: Evidence-based recommendations from the EAPC. Lancet Oncology, 13, e58–e68.

doi: 10.1016/S1470-2045(12)70040-2
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Purpose & Patient Population:

The guidelines, which relate to the use of opioids to treat cancer pain, are the result of revision of previous European Palliative Care Research Collaborative guidelines.

Type of Resource/Evidence-Based Process:

  • In the development of the revised guidelines, collaborators assigned 22 topics to groups of reviewers, who completed the systematic review using a standardized method. The evidence profile of each relevant outcome was reviewed and became the basis of the final recommendations. The Scientific Advisory Board of the European Palliative Care Research Collaborative and the Board of Directors of the European Association for Palliative Care reviewed the recommendations. Upon revision, the recommendations were again distributed to the groups for comment and/or approval.
  • The data search completed in connection with the project was a systematic retrieval of randomized and nonrandomized trials and meta-analyses that
    • Involved adults with chronic cancer pain
    • Contained data on efficacy, side effects, and the treatments considered
    • Described outcomes.
  • Databases searched were MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL).
  • Search keywords were terms relevant to each outcome. Outcomes related to the following: World Health Organization (WHO) step II opioids, WHO step III opioid of first choice, opioid titration, role of transdermal opioids, role of methadone, opioid switching, relative opioid analgesic potencies, alternative systemic routes of opioid administration, opioids for breakthrough pain, treatment of opioid-related emesis, treatment of opioid-related constipation, treatment of opioid-related central nervous system symptoms, use of opioids in patients with renal failure, role of paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs) in addition to step III opioids, role of adjuvant drugs for neuropathic pain (antidepressants and anticonvulsants), and spinal route of opioid administration.
  • Studies were excluded if they dealt with the role of opioids in liver failure and the use of opioid combinations. (Data were of insufficient quality to support a recommendation regarding these topics.) Reviewers excluded a literature review regarding the treatment of opioid-related constipation; its content completely overlapped that of a Cochrane review. The role of ketamine was not included because resources to complete the work were unavailable.
  • Authors made 16 recommendations based on evidence profiles.

Phase of Care and Clinical Applications:

  • Patients were undergoing multiple phases of care.
  • The study has clinical applicability for palliative care, late effects and survivorship, and elder care.

Results Provided in the Reference:

Findings are submitted as a general framework to help clinicians make informed decisions regarding cancer pain management.

Guidelines & Recommendations:

  • Data reveal no differences regarding the use of morphine, oxycodone, and hydromorphone; any can be used as step III treatment.
  • Guidelines include a weak recommendation regarding oral opioids:
    • Immediate- and slow-release oral opioids can be used for dose titration.
    • Transdermal fentanyl and buprenorphine are step III alternatives, and some patients may prefer them.
    • Methadone can be used as a step III opioid but only by experienced providers, given its complex pharmacokinetic profile.
  • Guidelines include a weak recommendation regarding patients who are not getting adequate analgesia: These patients may benefit from opioid switching.
  • Guidelines include strong recommendations regarding route of administration:
    • The subcutaneous route should be the first choice when alternate routes of administration are needed.
    •  Breakthrough pain can be managed with oral, immediate-release opioids or buccal or intranasal fentanyl.
  • Guidelines include a weak recommendation about additions to step III opioids: Add NSAIDs or paracetamol to step III opioids. However, guidelines note that efficacy is not well documented.
  • Guidelines include a strong recommendation regarding neuropathic pain: Consider using amitriptyline or gabapentin for patients with neuropathic pain that is only partially responsive to opioids. 
  • Guidelines include a weak recommendation regarding epidural and intrathecal opioids: Consider using an epidural or intrathecal opioid with a local anesthetic in cases of intractable pain or intolerable adverse effects.

Limitations:

  • Pharmaceutical industry sponsorships were noted.
  • The guidelines do not evaluate treatment costs.
  • The process evidenced lack of consensus regarding methods of pain assessment.

National Comprehensive Cancer Network. (2011). NCCN Clinical Practice Guidelines in Oncology: Adult cancer pain [v. 2.2011]. Retrieved from http://www.nccn.org/professionals/physician_gls/pdf/pain.pdf

http://www.nccn.org/professionals/physician_gls/pdf/pain.pdf
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Type of Resource/Evidence-Based Process:

These guidelines do not provide any information about search strategy or any specific evaluation of evidence. Notes state that most direct evidence is of low quality, but recommendations do result from unanimous consensus.

Guidelines & Recommendations:

The guidelines provide detailed recommendations regarding:

  • Screening and assessment
  • Management of pain in opioid-naive as well as opioid-tolerant patients
  • Ongoing care of adult patients with cancer and related pain management
  • Comprehensive pain assessment and use of pain ratings
  • Interventions for specific types of pain syndromes
  • Opioid prescribing, titration, and ongoing management
  • Management of adverse effects related to opioids
  • Psychosocial support and patient and family education
  • Nonpharmacologic interventions.

Limitations:

In general, opioids are first-line interventions. The NCCN guidelines suggest that antidepressants and anticonvulsants can be first-line treatments for adjuvant pain, although the recommendation for using them as such is still based on anecdotal experience or guidelines relating to patients who do not have cancer.

Nursing Implications:

The NCCN guidelines provide comprehensive algorithms for pain management, from screening to ongoing maintenance. The guidelines recommend considering a variety of nonpharmacologic interventions. Psychosocial support, including coping-skills training, is recommended, as is comprehensive patient and family education. The guidelines provide useful information and an overview of the full range of pain management. The work points to the ongoing need to consider multiple adjuvant and supportive interventions to achieve pain relief that works for the individual patient.

Systematic Review/Meta-Analysis

Jongen, J.L., Huijsman, M.L., Jessurun, J., Ogenio, K., Schipper, D., Verkouteren, D.R., . . . Vissers, K.C. (2013). The evidence for pharmacologic treatment of neuropathic cancer pain: Beneficial and adverse effects. Journal of Pain and Symptom Management, 46, 581–590.e1.

doi: 10.1016/j.jpainsymman.2012.10.230
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Purpose:

STUDY PURPOSE: To evaluate the evidence regarding beneficial and adverse effects of pharmacologic treatment of neuropathic cancer pain

TYPE OF STUDY: Systematic review

Search Strategy:

DATABASES USED: PubMed and EMBASE before August 2012; additional studies were identified from study reference lists.

KEYWORDS: Complete search terms are provided.

INCLUSION CRITERIA: Studies involving adult patients with cancer receiving oral analgesics

EXCLUSION CRITERIA: Not specified

Literature Evaluated:

TOTAL REFERENCES RETRIEVED = 653

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: American Academy of Neurology evidence classification was used. Authors calculated the absolute risk benefit as the number of patients who received 30%–50% improvement divided by the total number of patients in the treatment group. The fraction of patients who dropped out because of adverse events also was determined. Pain reduction scores were calculated as the percentage of pain reduction from baseline in the study.

Sample Characteristics:

  • FINAL NUMBER STUDIES INCLUDED = 30
  • SAMPLE RANGE ACROSS STUDIES = 1–218
  • TOTAL PATIENTS INCLUDED IN REVIEW = 2,267
  • KEY SAMPLE CHARACTERISTICS: Not provided

Phase of Care and Clinical Applications:

  • APPLICATIONS: Palliative care

Results:

The proportion of patients who obtained improvement of pain with antidepressants was 0.55 (95% CI 0.40–0.69), with anticonvulsants was 0.57 (95% CI 0.44–0.69), with opioids was 0.95 (95% CI 0.93–0.96), and with other adjuvant medications was 0.45 (95% CI 0.33–0.57). Effects for patients with mixed pain were similar. The proportion of patients who withdrew because of adverse effects was 12.6% with antidepressants, 5% with anticonvulsants, 6% with opioids, and 6% with other adjuvant medications.

Conclusions:

A substantial proportion of patients achieved pain reduction with adjuvant pain medications, and the proportion of patients who had benefit was higher than those who had to withdraw from studies because of adverse effects. The highest benefit was seen with opioids.

Limitations:

  • Whether non-opioids were given in combination with opioids is unclear in this review.
  • Controlled and uncontrolled studies were included.
  • Many studies were determined to be of low quality.

Nursing Implications:

Numerous limitations in this review make it difficult to evaluate the relative benefits of various approaches evaluated for management of neuropathic pain. Findings do suggest that results with all types of coanalgesics used appear to have benefits that outweigh the prevalence of adverse effects. Findings continue to support the effect and benefits of opioids as a mainstay of pain management for mixed and neuropathic pain.


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