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Gabapentin for Neuropathic Cancer Pain: A Randomized Controlled Trial From the Gabapentin Cancer Pain Study Group

From the Rehabilitation and Palliative Care Unit, National Cancer Institute of Milan, Milan; Pain Therapy and Palliative Care Unit, Salvatore Maugeri Foundation, Pavia; Pain Therapy and Palliative Care Unit, Oncological Center, Regina Elena Institute IFO, Rome; Palliative Care Unit and Oncology Unit, Forli; Pain Therapy and Palliative Care Unit, S. Bortolo Hospital, Vicenza, Italy; and Foundation Instituto Valenciano de Oncologia, Valencia, Spain

Address reprint requests to Augusto Caraceni, MD, Rehabilitation and Palliative Care Unit, National Cancer Institute of Milan, via Venezian 1, 20133 Milan, Italy; e-mail: augusto.caraceni{at}istitutotumori.mi.it

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
PURPOSE: To determine the analgesic effect of the addition of gabapentin to opioids in the management of neuropathic cancer pain.

PATIENTS AND METHODS: One hundred twenty-one consecutive patients with neuropathic pain due to cancer, partially controlled with systemic opioids, participated in a multicenter, randomized, double-blind, placebo-controlled, parallel-design, 10-day trial from August 1999 to May 2002. Gabapentin was titrated from 600 mg/d to 1,800 mg/d in addition to stable opioid dose. Extra opioid doses were available as needed. Zero to 10 numerical scale was used to rate average daily pain. The average pain score over the whole follow-up period was used as main outcome measure. Secondary outcome measures were: intensity of burning pain, shooting/lancinating pain, dysesthesias (also scored on 0 to 10 numerical scale), number of daily episodes of lancinating pain, presence of allodynia, and daily extra doses of opiod analgesics.

RESULTS: Overall, 79 patients received gabapentin and 58 (73%) completed the study; 41 patients received placebo and 31 (76%) completed the study. Analysis of covariance (ANCOVA) on the intent-to-treat population showed a significant difference of average pain intensity between gabapentin (pain score, 4.6) and placebo group (pain score, 5.4; P = .0250). Among secondary outcome measures, dysesthesia score showed a statistically significant difference (P = .0077; ANCOVA on modified intent-to-treat population = 115 patients with at least 3 days of pain assessments). Reasons for withdrawing patients from the trial were adverse events in six patients (7.6%) receiving gabapentin and in three patients receiving placebo (7.3%).

CONCLUSION: Gabapentin is effective in improving analgesia in patients with neuropathic cancer pain already treated with opioids.

	INTRODUCTION

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Neuropathic pain is frequently diagnosed as a complication of cancer pain.¹ While opioids are the mainstay of cancer pain management, their efficacy in neuropathic pain seems to be less then optimal,^2,3 and adjuvant drugs, mainly anticonvulsants and antidepressants, are often combined with opioids in the analgesic regimen of patients with neuropathic cancer pain.⁴ This approach is suggested by well-established guidelines,⁵ but the analgesic benefit of this practice is poorly documented.^6,7 Among new-generation anticonvulsants, gabapentin has been used in anecdotal experiences as adjuvant treatment for cancer pain with a neuropathic component, in combination with opioid analgesics.^8,9

Gabapentin is an anticonvulsant structurally related to gamma aminobutyric acid, which has analgesic effects in several experimental^10,11 and clinical models of nonmalignant chronic neuropathic pain.^12-17 These effects seem to be as a result of a specific antihyperalgesic activity. Experimental and clinical data also suggest that gabapentin can be used to enhance morphine analgesia.^18-20

The aim of this study was to assess the efficacy and safety of the addition of gabapentin to opioids in the treatment of patients with neuropathic pain due to neoplasm that was not completely controlled by systemic opioid administration.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
Patients from 11 palliative care and oncology units (eight Italian and three Spanish) participated in this trial from August 1999 to May 2002. The protocol was approved by the ethics committees of each participating center. The study consisted of a 10-day screening and treatment phase with a double-blind, placebo-controlled, randomized parallel-group design.

Patients’ Characteristics
Patients with cancer pain were enrolled if they had an active cancer lesion causing pain by infiltration or compression of nervous structures, and at least one of the following symptoms or signs referred to the pain area: burning pain, shooting/lancinating pain episodes, dysesthesias, or allodynia. Imaging studies (computed tomography, magnetic resonance imaging, ultrasound, or others as judged appropriate by the investigator) documenting a neoplastic lesion compatible with the neurological pain syndrome were required for all patients.

Inclusion and Exclusion Criteria
Inclusion criteria were: age 18 years; pain intensity 5 on a numerical rating scale from 0 to 10, in the 24-hour period preceding the screening visit, referred to the neuropathic pain syndrome as defined above; regularly scheduled systemic opioid therapy without sufficient analgesia with significant opioid-related side effects; stable dose of opiod medication for at least 24 hours; life expectancy 30 days; and Karnofsky performance status (KPS) 40. Exclusion criteria were: plasma creatinine > 1.5 mg/mL in association with creatinine clearance < 60 mL/min; previous or current gabapentin use; chemotherapy from 3 days before screening throughout the study; and radiotherapy to the pain-producing lesion from 15 days before screening throughout the study. Hormone therapy could be started before the study, but the dose could not be changed afterwards.

Study Design
Patients were randomly assigned to placebo or gabapentin with a 1:2 ratio. A nonstratified, block-of-three randomization list was used. Study medications were provided as identical capsules containing 300 mg of gabapentin or placebo in numbered containers and allocated in random sequence by the pharmacy department of the sponsor’s laboratories. All study participants were blinded to allocation sequence.

During the study, the patients were seen on two scheduled appointments: a screening and randomization visit (visit 1) and after 10 days, or at any time during the double-blind treatment phase if the patient had to discontinue study treatment (visit 2).

Eligible patients gave their written informed consent and were given a physical examination. The treatment phase started on the day of the screening visit; therefore, the 10-day treatment phase overlapped with the screening on day 1.

At visit 2, the patients underwent another physical examination and daily pain diaries were collected.

Pain Assessment at Baseline
Average pain intensity during the 24 hours preceding the screening visit was assessed on a 0 to 10 numerical scale (0 to 10 NRS) with 0 corresponding to "no pain" and 10 to "the worst possible pain".^21,22 In case of multiple pain sites, it was required that the neuropathic pain was the worse problem, and initial and subsequent assessments specifically addressed this pain. Shooting/lancinating pain and/or burning pain and/or dysesthesia intensities were also assessed on a 0 to 10 NRS.

Dysesthesias were described in the study chart with four different types of sensations (pins/needles, cold, numbness, tension/constriction)²³ and the patient had to choose which one of these symptoms better described his or her sensation.

Allodynia (pain following nonpainful stimulation) was assessed at visit 1 and 2 by gently stroking the cutaneous area to which pain was referred with a cotton swab, and then recording the pain as present or absent.

A cancer pain syndrome checklist¹ was used by the investigators to complete the description of the patient’s pain.

Pain Intensity Follow-Up and Pain Diary
At visit 1, patients were instructed on how to complete a daily pain diary which included (on each page) four different 0 to 10 NRSs assessing previous 24-hour average intensity of global pain, shooting/lancinating pain, burning pain, and dysesthesias. The patient was also required to record in the diary the number of lancinating pain episodes experienced during the previous 24 hours, and the use of rescue analgesic doses. The pain diary had to be filled in daily by the patient. The investigator called the patient every morning to check compliance with pain diary completion, pain intensity, and adverse events.

Pain and Antineoplastic Therapies and Causes of Treatment Interruption
Previous analgesic (opioids and nonsteroidal anti-inflammatory drugs) and adjuvant therapies (ie, steroids, antidepressants, anticonvulsants, anxiolitics, or muscle relaxants) were unchanged throughout the study. One extra dose of opioid medication was available as needed (p.r.n.) and it was prescribed at visit 1 based on the previous opioid regimen. Patients needing more than one daily p.r.n. opioid dose during the treatment phase were withdrawn from study. Antineoplastic therapies were prohibited; in the case that chemotherapy, radiotherapy, or surgery was needed during the treatment phase for disease control, the patient was withdrawn.

Study medication was administered orally starting with two capsules per day (300 mg gabapentin every 12 hours or placebo). If the 24-hour global pain score was 3, and if the patient had no significant side effects, the dose could be increased to four capsules per day (300 mg + 300 mg + 600 mg gabapentin or placebo), and subsequently to six capsules per day (600 mg gabapentin every 8 hours or placebo). The dose could be increased on any study day.

Efficacy and Safety Outcomes
The aim of the study was to compare the two groups for average response to treatment over the whole follow-up period; therefore, the primary efficacy variable was defined as the average follow-up pain score. Secondary efficacy parameters were the average of the subjective rating scale scores for lancinating/shooting pain, burning pain, dysesthesias, the number of daily lancinating pain episodes, presence/absence of allodynia, and the use of p.r.n doses of analgesics.

Drug safety was assessed by evaluation of the type, frequency, and intensity of any reported adverse event,²⁴ and by reporting changes on physical examination.

Statistical Methods
A sample size of 80 and 40 patients, respectively, for gabapentin and placebo was determined on the basis of the primary efficacy variable analysis.²⁵ This sample size gives the trial a power of 90%, setting a two-tailed at 0.05, to detect a minimum difference between the two groups of 1 on a 0 to 10 NRS, assuming a common within-group standard deviation (SD) of 3.0. The computation also assumes that the correlation between repeated measurements is 0.65, which is an appropriate choice in many situations.²⁵

Analysis of the primary and secondary efficacy longitudinal measures was performed by an analysis of covariance (ANCOVA) summary statistic approach as suggested by Frison and Pocock.²⁵ The method consists in averaging the post-treatment values on each patient and then using this as a dependent variable in an ANCOVA model with baseline pain data as covariate, as well as fixed terms of treatment and country (Spain-Italy).

The main analysis was performed on the intent-to-treat (ITT) population (all patients who received at least one study medication),²⁶ imputing missing longitudinal data with the average of observed data. In order to evaluate the robustness of the results obtained, a sensitivity analysis was conducted using different criteria for missing data imputation—last observation carried forward and worst value observed. All the remaining analyses were conducted on a modified ITT set of data, defined as all patients who received at least one study medication and compiled at least 3 days of the diary. The choice was made to have the minimum treatment duration be 3 days, allowing for an eventual maximum gabapentin dose of 1,800 mg per day.

In order to complete the description of the response to treatment, (1) pain control was defined as a pain reduction of at least 33% with respect to baseline pain (33% pain intensity difference = 33% PID);^27,28 (2) then two different summary measures were calculated for each patient: the percentage of the follow-up period during which PID was at least 33% controlled (according to this analysis, a patient reporting 33% PID for 7 days over 10 days of follow-up would be classified to have 70% pain response); and the time needed to reach PID 33% for the first time, which was analyzed by Kaplan-Meier survival curves.

To show how pain scores changed over time, the percentage of patients achieving 33% PID was plotted by day and treatment, along with 95% CIs. Safety data analysis was performed on the ITT population, and frequency distributions were used to present the results.

	RESULTS

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Study Profile
Figure 1 reports the trial implementation profile according to the Consolidated Standards of Reporting Trials statement.²⁶ Of 691 cancer patients with neuropathic pain screened, 121 were randomly assigned (80 patients to gabapentin and 41 patients to placebo), with a ratio of about 1:6 for randomized versus screened patients. One patient in the gabapentin group withdrew his consent before taking the first dose of medication and was not considered further in the analysis.

View larger version (61K): [in this window] [in a new window]   Fig 1. Progress through the stages of trial. *Intent-to-treat (ITT) analysis; **patient withdrew just after randomization and did not take any study medication; ***modified ITT population = patients who received at least one dose of study medication and completed at least 3 days of pain diary.

Eleven patients in the gabapentin group did not conclude the study because of intervening prohibited therapies. Four because of recourse to chemotherapy (two patients) or surgery (two patients) for disease control and all of them had good pain control at the moment of dropping out. Seven patients (8.8%) were withdrawn because of increased daily opioid dose for insufficient pain relief. In two of these last patients, disease progression with increasing new pain could be definitely demonstrated (vertebral collapse in one patient and deep venous thrombosis in the second). In the placebo group, six patients (14.6%) dropped out because they needed to increase their opiod consumption as a result of worsening pain.

Patient Demographics and Baseline Clinical Characteristics
Demographic characteristics of patients and baseline pain characteristics are shown in Table 1. The placebo and gabapentin groups were comparable as to age, sex, KPS, stabilized opioid daily dose (expressed in oral morphine daily equivalent milligrams), while baseline global pain intensity was higher in the placebo group.

The presence of shooting pain, burning pain, and dysesthesias was similar for the two treatment groups, while allodynia and the number of daily shooting pain episodes were more frequent among patients in the placebo group (Table 1). Ninety-two patients (79.9%) reported more than one symptom.

The most frequent neuropathic pain syndrome (Table 2) was malignant brachial and lumbosacral plexopathy (49.1% of patients). Five patients had more than one neuropathic pain syndrome.

Primary Efficacy Outcome
The mean (model adjusted) follow-up global pain score (ITT population = 120 patients) was lower for patients taking gabapentin (pain score = 4.6) than for patients receiving placebo (pain score = 5.4; ANCOVA, P = .0250; Table 3). Sensitivity analysis showed that the result obtained was robust when different criteria were used for missing data imputation (P = .0527 using last observation carried forward imputation, and P = .0304 with worst value imputed). Also the analysis on the modified ITT set confirmed this result (P = .0257). Globally, there were 94 missing data (11.8% of potential data) in the gabapentin group (mean data missing per patient ± standard deviation (SD) = 1.18 ± 2.3) and 59 missing data (14% of potential data) in the placebo group (mean ± SD = 1.43 ± 2.75). Data were missing for patients interrupting the study, and for only two patients who failed to complete one entry in their pain diary.

The use of additional analgesic doses was higher in the placebo group (64.7% of patients) than in the gabapentin treated group (47.1% of patients), though the difference did not reach statistical significance (P = .0999, Wilcoxon test), and patients receiving placebo also used p.r.n opioid doses more frequently (35.8% v 21.6% of follow-up days; P = .0559, Wilcoxon test).

Other Pain Response Analyses
The average percentage of follow-up days per patient with PID 33% was 51.6% (SD = 36.5%) in the gabapentin group and 37.8% (SD = 38.8%) in the placebo group (Kruskall Wallis test, P = .039). Only 15% of patients in gabapentin group versus 40% of placebo-treated patients never reached 33% PID.

Kaplan-Meyer curves in Figure 2 show the time needed to reach PID 33% for the first time. A higher number of patients reached 33% PID in the first days of treatment in the gabapentin group than in the placebo group (P = .0048, log-rank test).

View larger version (17K): [in this window] [in a new window]   Fig 2. Kaplan-Meier curves showing the probability of reaching pain control ( 33% pain intensity difference) over 10-day follow-up period for the first time (P = .048, log-rank test) on modified intent-to-treat population (115 patients). The figures underneath the plot show the number of patients at each of the censored intervals.

View larger version (49K): [in this window] [in a new window]   Fig 3. Percentage of patients with pain intensity difference 33% from baseline and 95% CI. Squares = gabapentin group; dots = placebo group. The numbers above and below each data point reports the number of patients with data available at each point in time. The figures underneath the plot show the percentage of responders at each study day.

Safety
Six patients in the gabapentin group and three in the placebo group discontinued treatment due to adverse events (Table 4). In four of the patients who discontinued gabapentin, the adverse events were probably related to the drug.

Another patient with a complex pharmacologic regimen (methadone 90 mg/d, morphine p.r.n 10 mg subcutaneously, ketorolac 60 mg/d, lorazepam 2 mg qhs, fluoxetine 20 mg/d, amytriptiline 175 mg/d) and KPS of 50 had respiratory depression and sedation after taking 1,200 mg of gabapentin on the second study day. Naloxone was administered, while methadone and study treatment were discontinued, with prompt recovery of consciousness and respiratory rate. The same patient had already had an episode of respiratory depression before entering the study while on methadone 120 mg/d.

Most frequent side effects, not leading to drug discontinuation, were mild to moderate somnolence and dizziness which were more common in the gabapentin group than in the placebo group (Table 4).

	DISCUSSION

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There is clinical consensus that some cancer pain syndromes, as a result of neurological lesions, are less responsive to opioid analgesia,^2,3,29 and that adjuvant drugs have an indication in these pain syndromes,^4,5,30 although this practice is based only on anecdotal reports^9,31-34 and are not confirmed by controlled clinical trials.^6,7,35 The aim of this study was therefore to demonstrate the clinical usefulness of an adjuvant drug in improving analgesia for patients with neuropathic cancer pain already treated with opioids.

The low rate of accrual in the protocol (Fig 1) was mainly due to concurrent need for chemotherapy or radiotherapy (179 patients), previous exposure to gabapentin (n = 104), and pain already controlled with opiods (n = 131).³⁶

After randomization, the main reasons for dropping out of the study were changes in analgesic or antineoplastic therapy (Fig 1). In some of these cases, changes of pain type and intensity were seen. Similar changes might have also occurred in patients who remained on the study, with clear implications for the possibility of using longitudinal outcome measure analysis.³⁷

Our results showed a difference in mean pain intensity and dysesthesia scores, but this information can be considered of limited clinical value. For this reason, we used recent data^27,28 suggesting that a reduction of pain intensity of 33% or greater can be considered clinically significant, both in cancer and in nonmalignant neuropathic pain studies. By using this cutoff value, the average follow-up period with PID 33% favored gabapentin (51.6%) versus placebo (37.8%). Figures 2 and 3 also help to understand how often 33% PID was achieved by a different proportion of patients, and how fast this pain relief target was achieved for the first time. In Figure 3, the difference between the two groups was evident in the first study days throughout day 5, while results tended to overlap from the fifth day onward. This observation can have different explanations, including pain changes from baseline, as exemplified in some cases, missing data (slightly higher for the placebo group), or reduced drug efficacy in time. It is also possible that in some patients, further escalation of gabapentin dose beyond 1,800 mg/d could be of benefit.

There are very few controlled trials on adjuvant therapies for neuropathic cancer pain. Two trials on brief lidocaine infusions could not show an effect,^35,38 while one trial on ketamine infusion showed analgesic effects.³⁹ The only other experience on an adjuvant oral medication, comparable with the use of gabapentin in this study, is a 2-week cross-over trial of amitriptyline versus placebo on 16 patients, which could demonstrate an effect only on worst pain and not on global pain.⁷

In general, side effects were mild in most cases, with the exception of four patients who discontinued the drug. In two of them, both receiving benzodiazepines at significant doses (and a number of other drugs), and with poor general conditions, CNS depressing effects were observed. Our conclusion is that the association of 300 mg gabapentin to the opioid drug regimen is usually safe, but in frail patients with high opiod doses and complex drug regimens, especially including benzodiazepines, a more cautious titration schedule is recommendable.

The role of gabapentin in expanding the efficacy of opioid analgesia in combined drug regimens has a rational basis,^{10,18,19,40,41} but should be supported by clinical studies in order to document the feasibility and potential therapeutic advantages of such use. Our study could demonstrate a limited role of gabapentin as adjuvant to opioids for neuropathic cancer pain, although significant benefit could be seen in some patients. Certainly better study design, and more efficacious drugs for neuropathic pain, are needed to improve the control of advanced cancer pain.

	Authors’ Disclosures of Potential Conflicts of Interest

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The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: Augusto Caraceni, Pfizer Italy. Received more than $2,000 a year from a company for either of the last 2 years: Augusto Caraceni, Pfizer Italy; Ernesto Zecca, Pfizer Italy; Cinzia Martini, Pfizer Italy.

	Acknowledgment

 
The authors acknowledge the other members of the Gabapentin Cancer Pain Study Group: From the Rehabilitation and Palliative Care Unit, National Cancer Institute of Milan, Italy (Cinzia Brunelli, DrSc); Foundation Instituto Valenciano de Oncologia, Valencia, Spain (Rosana Escriba, RN); Palliative Care Unit and Oncology Unit, Forli’, Italy (Laura Fabbri, MD); Pain Therapy and Palliative Care Unit, S. Bortolo Hospital, Vicenza, Italy (Leonardo Trentin, MD); Pain Therapy and Palliative Care Unit, AOG Salvini PO Garbagnate, Italy (Furio Zucco, MD); Palliative Care Unit Leopoldo Mandic Hospital and Hospice "Il Nespolo" ASL, Merate, Italy (Mauro Marinari, MD); Palliative Care and Pain Therapy Unit, Ospedale S. Croce, Fano, Italy (Alfredo Fogliardi, MD); Instituto Catalàn de Oncologia, Hospital Duran i Reynals, L’Hospitalet Lobregat, Spain (Alicia Lozano Borbalàs, MD); Servicio Oncologia Médica, Hospital Clinico S. Carlos, Madrid, Spain (Antonio Casado Herràez).

	NOTES

 
This study was funded by Pfizer Italy and Pfizer Spain as study sponsors. The work of Drs Caraceni, De Conno, Gorni, Martini, and Zecca has been also partially funded by a grant from the Associazione Italiana per la Ricerca sul Cancro.

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

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Submitted August 21, 2003; accepted April 19, 2004.

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