Gabapentin and Opioid Combination

Gabapentin and Opioid Combination

PEP Topic 
Peripheral Neuropathy
Description 

Gabapentin is in a class of medications called anticonvulsants. Gabapentin treats seizures by decreasing excitement in the brain. Gabapentin has been studied for its effect in patients with cancer who have neuropathic pain or symptoms of peripheral neuropathy. Its effect occurs by changing the way the body senses pain. It has also been studied for its effect on anxiety and hot flashes. Gabapentin in combination with other medications such as opioids and impramine have been studied for effects on neuropathic pain and other symptoms.

Effectiveness Not Established

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 evaluate the effectiveness of low-dose gabapentin combined with imipramine, in treating cancer-related neuropathic pain

Intervention Characteristics/Basic Study Process:

Patients were allocated to four groups. Group 1, consisting of 14 patients, received gabapentin 200 mg and imipramine 10 mg orally every 12 hours; Group 2, consisting of 14 patients, received gabapentin 200 mg orally every 12 hours; Group 3, consisting of 12 patients, received gabapentin 400 mg orally every 12 hours; and Group 4, consisting of 12 patients, received imipramine 10 mg orally every 12 hours. The average intensity of total pain over the past 12 hours was assessed, and the number of paroxysmal pain episodes in the past 24 hours were recorded. Pain was assessed at the first visit and seven days after the beginning of the regimen. Opioid rescue doses were available if needed.

Sample Characteristics:

  • The sample consisted of 52 patients with solid tumors and neuropathic pain from nerve compression or spinal cord invasion.
  • The mean age across groups was 65–69 years, range was 58–79 years.
  • Men outnumbered women, 65% to 35%.

Setting:

  • Single-site outpatient setting
  • Japan

Study Design:

Randomized, controlled trial

Measurement Instruments/Methods:

Pain was measured on a numeric scale, 1–10.

Results:

The total pain scores and daily paroxysmal pain episodes of the patients taking the low-dose gabapentin-imipramine combination (Group 1) decreased significantly (p < 0.05). The combination significantly decreased the previous 24-hour opioid rescue dose. Researchers observed mild adverse symptoms in all four groups. Symptoms included drowsiness, dizziness, and nausea. Note: Three patients dropped out of Group 3 because of adverse effects.

Conclusions:

The combination of gabapentin and imipramine in low doses offers a means of successfully treating neuropathic pain, with minimal side effects.

Limitations:

  • The small total sample size (< 100 participants) and the use of a single pain measurement scale are limitations.
  • The results may not be reproduceable.
  • Generalizing results to chemotherapy-induced neuropathic pain may be inappropriate.

Nursing Implications:

The gabapentin-imipramine combination is effective in treating neuropathic pain caused by nerve compression or invasion of the spinal cord.

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:

The objective of this study was to compare the safety and efficacy of gabapentin with opioid versus opioid monotherapy for the management of neuropathic pain.

Intervention Characteristics/Basic Study Process:

Patients were randomized to one of two groups: Group GO included gabapentin added to ongoing opioids, gabapentin titrated to pain, and opioids kept constant; group OO saw the continuation of opioid monotherapy using the World Health Organization ladder approach.

Regarding dosing, gabapentin was initially given at 100 mg three times daily for patients aged 60 and older and 300 mg three times daily for those younger than age 60. Doses were titrated over the three days—up to 3,600 mg per day according to response. Patients in the GO group also could take gabapentin as a rescue drug.

Sample Characteristics:

  • Seventy-five patients who were receiving opioids with minimal opioid side effects and had unrelieved neuropathic pain were enrolled in the study.
  • A total of 63 patients completed the trial.
  • Patients had a Karnofsky score higher than 60 and pain intensity rated as 4 or greater.
  • Potential participants were excluded 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:

The study was conducted in Turkey.

Study Design:

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

Measurement Instruments/Methods:

  • Pain intensity, specifically burning and shooting, was recorded with a numeric rating scale.
  • The mean absolute change in pain intensity was recorded at day 13.
  • Allodynia and analgesic drug consumption, including rescue, were evaluated at days 4 and 13. Side effects also were recorded.
  • Allodynia was assessed by a light cotton material being stroked on painful and non-painful areas. Allodynia was said to be present if a normal response was noted in non-painful areas but pain or an unpleasant sensation was noted in the painful area.

Results:

Both groups (GO and OO) saw a significant reduction in pain intensity on days 4 and 13 compared to baseline. The mean pain intensity for burning or shooting pain was significantly higher in group OO compared to group GO at both assessment times (p = 0.0001); however, a clinically meaningful reduction was noted in group OO. In addition, a significant decrease in allogynia was seen in the GO group at day 4 (p = 0.002) and the rate of side effects was significantly lower in GO (p = 0.015). Of note, one patient in the GO group withdrew from the study due to respiratory depression. The patient was taking gabapentin and SR morphine and was age 66. Depression occurred three days after gabapentin was added.

The most frequent causes of pain included malignant sacral plexopathy (32%) in group GO and brachial plexopathy (28%) in group OO. Patients in the GO group remained at the same step of the ladder at day 4; group OO patients who took weak opioid at the second step all progressed to the third step. This may explain less SE in the GO group.

Conclusions:

The findings suggest that gabapentin added to opioids provides better relief than opioid monotherapy alone and may represent a potential first-line treatment for these patients. Gabapentin added to opioids may create a synergistic effect. Gabapentin also may extend opioid efficacy.

Limitations:

  • The measurement of allodynia was seen as a limitation, as were the primary neuropathic syndromes being different in each group.
  • The World Health Organization ladder has been abandoned by many practitioners in favor of National Comprehensive Cancer Network or American Pain Society guidelines.

Nursing Implications:

Nurses should be aware of possible respiratory depression when patients are treated with gabapentin and morphine, particularly older adult patients.

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, 40–45.

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Study Purpose:

The purpose of the study was to evaluate the effects of gabapentin with nonsteroidal anti-inflammatory drugs (NSAIDs) and morphine versus gabapentin alone.

Intervention Characteristics/Basic Study Process:

Participants were randomized into three groups. Group 1, consisting of 25 participants, received gabapentin alone, titrated weekly from 300 mg per day to 3,600 mg per day in divided doses. Group 2, consisting of 25 participants, received gabapentin 1,200 mg per day and diclofen 100 mg per day, also titrated over the first week. Group 3, consisting of 25 participants, received gabapentin 900 mg per day, diclofen 100 mg per day, and morphine 60 mg per day all in divided doses. Patients were treated for six weeks and assessed on a weekly basis.

Sample Characteristics:

  • Seventy-five participants, all women aged 23–74 years (with a median age of 44 years), took part in the study.
  • Participants were patients with breast cancer who were previously treated with any combination of chemotherapy, radiation therapy, and surgery, with neuropathic pain occurring post-treatment.
  • Additional eligibility requirements included participants having a pain intensity rating of 5 or higher on a visual analog scale, having pain duration of at least three months, being older than age 18, being cognitively intact, having normal renal function, and having no gastrointestinal issues.

Setting:

This single-site study was conducted in an outpatient setting in Serbia.

Phase of Care and Clinical Applications:

Phase of care

  • Transition
  • Long-term follow-up

Applications

  • Late effects
  • Survivorship

Study Design:

This study was quasiexperimental.

Measurement Instruments/Methods:

  • Measurement tools included a visual analog scale, a modified Brief Pain Inventory, and the Pain Intensity Difference scale.
  • Side effects from the medications used were assessed using a four-point Likert-type scale (0–3), with 0 indicating no side effects and 3 indicating severe side effects.

Results:

Participants in all three groups saw diminished pain and diminished influence of pain on their daily activities. No significant difference was noted between groups (p = 0.05).

Conclusions:

Although all groups achieved significant pain control, the authors concluded that the multimodal therapy used in group 3 provided the best pain relief with the fewest side effects. However, inconsistency existed regarding doses between groups and, although differences in pain levels in each group diminished over time, between-group differences were not significant. No firm conclusions can be made.

Limitations:

  • Limitations include a lack of control group, the potential for bias with no blinding method enacted, and that no valid measure of neuropathy was used.
  • Actual dosages used varied from group to group, so clear conclusions are difficult.

Nursing Implications:

The results support a multimodal approach to pain management in patients with breast cancer with neuropathic pain, but are not specific to peripheral neuropathy. The findings do not suggest any difference between the treatments tested in terms of efficacy; however, multiple limitations did exist in the study.

Systematic Review/Meta-Analysis

Hershman, D.L., Lacchetti, C., Dworkin, R.H., Lavoie Smith, E.M., Bleeker, J., Cavaletti, G., . . . American Society of Clinical Oncology. (2014). Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. Journal of Clinical Oncology, 32, 1941–1967.

doi: 10.1200/JCO.2013.54.0914
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Purpose:

STUDY PURPOSE: To provide evidence-based guidance on optimum prevention and treatment approaches in the management of chemotherapy-induced peripheral neuropathy in adult cancer survivors

TYPE OF STUDY: Systematic review

Search Strategy:

DATABASES USED: Ovid Medline (1946–April, week 2, 2013); EMBASE (1980–2013, week 16); AMED Allied and Complementary Medicine (1985–April 2013)

KEYWORDS: chemotherapy-induced peripheral neuropathy; adult cancer survivors; randomized clinical trials

INCLUSION CRITERIA: Adult cancer survivors with chemotherapy-induced peripheral neuropathy; randomized trials

EXCLUSION CRITERIA: Phase 1 trials; published in a language other than English; less than 10 patients; focused on radiation or stem cell transplant neuropathy; animal studies

Literature Evaluated:

TOTAL REFERENCES RETRIEVED = 1,252

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: An expert panel representing neurology, nursing, medical oncology, community oncology, pain research, and genetics met through teleconference and emails to review and develop the American Society of Clinical Oncology guidelines.

Sample Characteristics:

  • FINAL NUMBER STUDIES INCLUDED = 48
  • TOTAL PATIENTS INCLUDED IN REVIEW: Treatment studies: 780; prevention studies: 3,741

Phase of Care and Clinical Applications:

  • PHASE OF CARE: Active antitumor treatment

Results:

Forty-two randomized clinical trials involved 19 various interventions for prevention of chemotherapy-induced peripheral neuropathy. These agents included anticonvulsants, antidepressants, vitamins, minerals, and other chemoprotectant drugs. Only six randomized clinical trials discovered six different drugs, such as antidepressants, anticonvulsants, and a topical gel, for the prevention of chemotherapy-induced peripheral neuropathy. The following are not recommended for use: acetyl-l-carnitine, amifostine, amitriptyline, calcium and magnesium, glutathione, nimodipine, ORG 2766, trans retinoic acid, rhuLIF, and vitamin E. Venlafaxine is not recommended for routine use in clinical practice. Although data support potential utility, evidence is not strong enough to suggest use. For treatment of chemotherapy-induced peripheral neuropathy, clinicians can offer duloxetine. No recommendation is made regarding ALC. Tricyclic antidepressants or gabapentin through trial use may be reasonable.  The panel felt that trying topical gel containing baclofen, amitriptyline, and ketamine would be reasonable. 

Conclusions:

No agents were recommended for the prevention of chemotherapy-induced peripheral neuropathy, but duloxetine is moderately recommended for the treatment of chemotherapy-induce peripheral neuropathy. Even though conclusive evidence is lacking to recommend tricyclic antidepressants such as nortriptyline, gabapentin, and a topical gel containing baclofen,amitriptyline, and ketamine for treatment of chemotherapy-induced peripheral neuropathy, the expert panel agreed that offering these agents based on treatment for neuropathic pain is reasonable. The panel also recommended that patients be counseled regarding the lack of evidence in treating chemotherapy-induced peripheral neuropathy with these agents.

Limitations:

  • Small, insufficient sample
  • Inability to compare studies because of different outcomes
  • Measurements and instruments used at different points in treatment

Nursing Implications:

Nurses are at the frontline in assessing patients who are receiving agents with the potential for chemotherapy-induced peripheral neuropathy. Nurses should be aware of the standard of care in treating this population. Many drugs prescribed have no evidence in preventing or treating these patients. However, with these American Society of Clinical Oncology guidelines, a role for duloxetine is clear and a role for tricyclic antidepressants is possible. Nurses need to be knowledgeable about this information to better inform patients.

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.

Guideline/Expert Opinion

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/f_guidelines.asp

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Type of Resource/Evidence-Based Process:

NCCN categories of evidence and consensus are described. Unless otherwise stated, all recommendations are reported to be category 2A, indicating a low level of evidence and uniform NCCN consensus. Specific process for evidence rating and consensus development is not described in the document. In addition, a search strategy was not described.

Guidelines & Recommendations:

The NCCN guidelines document recommends universal screening for pain and provides an algorithm for comprehensive assessment and management approaches based on etiology of pain and current status with regard to pharmacologic management.

For opioid-naïve patients:

  • Rapidly titrate short-acting opiods for moderate and severe pain, and consider for mild pain.
  • Consider nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen for mild pain.
  • Consider addition of co-analgesics for all pain levels based on the specific pain syndrome.

For opioid-tolerant patients:

  • An algorithm is provided for dose increases based on timing of peak effect and patient response. Initial calculation for titration is 10%–20% of the previous 24-hour dose, and if pain is unchanged or increased, an increased dose of 50%–100%.

For all cases, recommendations include:

  • Regular pain medication dosing with rescue medications as needed
  • Ongoing reassessment and regimen modification to manage pain and minimize adverse effects

For specific pain syndromes:

  • Inflammation–A trial of NSAIDS or glucocorticoid
  • Nerve compression or inflammation–A trial of glucocorticoid
  • Bone pain without emergency–NSAIDS titrated to effect, consideration of nerve block or local radiation therapy for local pain, trial of biphophonates, hormonal or chemotherapy, and radioisotopes for diffuse bone pain
  • Neuropathic pain–A trial of antidepressants, anticonvulsants, or topical agents

Limitations:

The major limitations of these guidelines are:

  • Recommendations are mainly consensus based
  • Recommendations are associated with low levels of evidence

Nursing Implications:

The NCCN guidelines document provides comprehensive decision making algorithms for assessment, severity grading, and management of cancer-related pain. The guidelines also provide assessment tools, titration schedule examples, and conversion tables for medications and conversion to transdermal fentanyl. An additional offering are suggestions regarding the management of a variety of opioid adverse effects. (A trial of adjunctive medications are suggested for neuropathic pain as a pain management approach.)


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