Gabapentin Monotherapy

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

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.

• 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%.

• Single-site outpatient setting
• Japan

Randomized, controlled trial

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

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.

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

• 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.

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

The purpose of the study was to evaluate the effect of gabapentin on chemotherapy-induced peripheral neuropathy (CIPN).

Patients were assigned to either one of two groups: gabapentin followed by placebo or placebo followed by gabapentin. Doses of both capsules were incrementally increased during the course of three weeks to a target does of 2,700 mg. Patients were treated for six weeks and then had a two-week washout period. After the washout period, patients were treated for another six weeks in the crossover. The sample size was determined by power analysis and study measures were obtained weekly.

• The sample consisting of 68 participants with a mean age of 59 years and a range of 25–84 years.
• Women outnumbered men, 73%–27%, respectively.
• Specific diagnoses were not described by the authors, but 50% of the participants were on active treatment at the time of the study.
• All patients had symptom severity of 4 or greater on a numerical rating scale for peripheral neuropathic pain.
• Patients were receiving vinca alkaloids, taxanes, cisplatin-based compounds, or some combination of these.

The study was conducted at multiple outpatient settings in the north-central region of the United States.

• A numeric rating scale of 0-10 for pain.
• The World Health Organization classification scale for neuropathic symptoms (parasthesias, tendon reflexes, weakness, motor loss included).
• The short form McGill pain questionnaire.
• The Brief Pain Inventory.
• A symptom distress scale (five point).
• The Profiles of Mood States.

The McGill pain rating questionnaire at six weeks indicated lower pain in the gabapentin-treated groups. No other differences were noted between groups at any point in time during the study. On the numerical scale, a slight reduction in pain was seen in all participants. Improvement was highest in patients who had higher baseline average pain and in those currently in active chemotherapy treatment.  Most frequent adverse events were dizziness and fatigue and no differences in adverse events were noted based on gabapentin treatment.

The findings failed to demonstrate any benefit in using gabapentin for CIPN.

• Limitations included a sample size of less than 100 participants.
• A 41% dropout rate occurred, which was not discussed.
• Because of the dropouts, the sample size in the final analysis was underpowered.
• No intention-to-treat analysis was reported and no mention was made of other medications used to treat pain.

The findings do not support the use of gabapentin for the management of CINV.

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

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.

• 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.

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

This was an open-label, prospective study.

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.

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.

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

• 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.

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

This study outlines the common antineoplastic agents known to cause neuropathy and provides information on incidence, onset dosages, the signs and symptoms, and general course and patterns of resolution. Agents identified include platinum compounds, vinca alkaloids, taxanes, bortezomib, ixabepilone, thalidomide, and lenalidomide. In addition to outlining the mechanisms of neuropathy development in cancer, the study discusses neurophysiologic and objective testing, noting that findings on electromyographic (EMG) and nerve conduction studies (NCS) can lag behind clinical symptoms. The study also identifies commonly used physician-based grading systems, including the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) and Eastern Cooperative Oncology Group (ECOG) systems, and notes that these two grading systems lack inter-rater reliability. Patient-based instruments for assessment include the Functional Assessment of Cancer Treatment (FACT) and the Patient Neurotoxicity Questionnaire (PNQ). The authors note that the routine assessment of pain secondary to neuropathy, using instruments such as the Brief Pain Inventory (BPI), is useful.

Routine assessment should be conducted and continued throughout therapy. Key points in assessment that should be included are:

• History, related comorbid conditions, alcohol use, symptoms, pain assessment, time course, and treatment delays or discontinuation from CIPN
• Physical examination
• Patient interview questions regarding sensation of numbness or tingling, pain, bothersome sensations, weakness, difficulty walking, falls, and interference with activities of daily living
• Functional skills testing, such as straight-line walking, name writing, buttoning, pegboard tests, and timed pellet retrieval.

Proposed agents for prevention of CIPN identified include:

• Agents with positive findings: vitamin E, calcium, magnesium, glutamine, glutathione, N-acetylcysteine, oxcarbazepine, xaliproden
• Agents with negative findings: amifostine, nimodipine, Org2766, rhuLIF
• Agents being tested in trials: vitamins B12, B6, acetyl-L-carnititne, alpha lipoic acid

Agents used for pain management:

• Those with negative results in CIPN, including gabapentin, amitriptyline, notriptyline
• Other agents commonly used include duloxetine, 5% lidocaine patch, opioids, tramadol

Current literature is inconclusive on the benefits of neurostimulation in treating CIPN. The authors note that evidence is scarce on efficacy of complimentary and alternative medicine (CAM) therapies and the need for appropriately powered and controlled studies in this area. However, acupuncture was identified as a promising adjunct option. The article also provides safety tips and issues for management of functional deficits in PIN, including situations in which to avoid or discontinue physical training, footwear selection, orthosis, and safety aspects of the household environment. Finally, the article addresses how autonomic neuropathy from chemotherapy occurs, but has not been well documented or studied.

• Limitations include a significant lack of evidence regarding effective management and prevention in this area.
• The review did not describe a search strategy or process to determine the quality of evidence used.

The article provides a comprehensive review of current knowledge about CIPN and common approaches toward assessment, prevention, and management. The authors do not make specific recommendations for treatment, research to validate evaluation tools, and exploration of combinations and scheduling of pain medications. In addition, testing of the safety and effectiveness of therapeutic interventions and dietary supplements are needed.