A comparative study of efficacy and safety of gabapentin versus amitriptyline as coanalgesics in patients receiving opioid analgesics for neuropathic pain in malignancy.

OBJECTIVE: To assess the efficacy and safety of gabapentin and amitriptyline along with opioids in patients suffering from neuropathic pain in malignancy.
MATERIALS AND METHODS: Eighty-eight adult patients between 18 and 70 years of age with neuropathic pain in stage III malignant disease, matched for baseline charactistics, were randomly assigned to two groups. Group A received oral tramadol and gabapentin and group B received oral tramadol and amitriptyline. The treatment duration of each patient was 6 months. Visual analog scale (VAS) was the primary efficacy parameter. Verbal rating scale (VRS) score, percentage of pain relief (PPR), and global pain score (GPS) were the secondary efficacy parameters. Oral morphine tablets or fentanyl transdermal patch were used as rescue medication. Data analysis was carried out in Graph Pad instat.
RESULTS: There was decline in VAS pain score from baseline in both the groups in the early phase of the study though there was no statistically detectable difference between them at any study point. Similar changes were seen in the secondary efficacy parameters too. Thus both the drugs were effective in providing relief to cancer patients with neuropathic pain though there was no statistically detectable difference in efficacy between them. Six patients in group A and eight patients in group B required rescue medication. A total of 12 subjects in the gabapentin group and 15 subjects in the amitriptyline group experienced adverse events which were of mild to moderate grades.
CONCLUSIONS: Amitriptyline may be a suitable alternative for management of neuropathic pain in cancer patients although gabapentin is widely used for this purpose. The lower cost of amitriptyline may favor patient compliance with lesser number of drop-outs.

RCT Entities:   Population Interventions Outcomes

Introduction

Malignancy is almost always associated with pain of varying severity causing extreme suffering to the patient. The goal of treatment in cancer patients is to integrate palliative care with curative care regardless of prognosis. Relief from chronic pain is essential in order to improve the quality of life, including psychosocial and functional well-being.

Pharmacological interventions follow the World Health Organization three-step approach involving nonopioid analgesics, mild opioids, and strong opioids with or without adjuvant. Adjuvant analgesics are nonopioids that potentiate the analgesic effect of opioids. They are especially important in management of neuropathic pain. Gabapentin, an anticonvulsant, and amitriptyline, an antidepressant, are both used as adjuvant analgesics in cancer patients.[1]

Gabapentin is now the first-line treatment for neuropathic pain.[23] Amityrptiline also potentiates opioid analgesia in pain of malignancy.[4] There are studies involving use of these drugs as coanalgesics with opioids.[5]

Comparative efficacy of gabapentin and amitriptyline has been studied in diabetic peripheral neuropathic pain and postherpetic neuralgia.[6] Data regarding the comparative study of these two drugs as adjuvant analgesics in neuropathic pain of malignancy are sparse, especially in this part of the country. The present study is aimed to assess the comparative efficacy and safety of these two coanalgesics along with opioids in patients suffering from neuropathic pain in malignancy.

Materials and Methods

Patient screening and recruitment were carried out at the Radiotherapy Outpatient Department of a tertiary care hospital in West Bengal from the period Jan 2011 to Feb 2012. The aforesaid department runs a registered “Pain and Palliative Care Unit” with regular supply of Morphine tablets.

A sample size of 76 patients, 38 in each group, was determined on the basis of the primary efficacy variable analysis. This sample size gives the trial a power of 90%, setting a two-tailed α at 0.05, to detect a minimum difference between the two groups of two on a 0—10 visual analog scale (VAS). A pilot study was done on 10 patients to determine the standard deviation which was found to be 7 on VAS. Assuming a dropout rate of 20%, 92 patients were recruited. Four patients refused consent and hence were dropped out before randomization. A total of 88 patients were analyzed for the study.

A total of 88 adult patients between 18 and 70 years of age with neuropathic pain in primary, recurrent, and palliative setting of stage III malignant disease of head, neck, lungs, breast, and cervix were recruited for the study. There was at least one of the following symptoms or signs referred to the pain area: burning pain, shooting/lancinating pain episodes, dysesthesias, or allodynia. Documentation of a neoplastic lesion by histopathology and imaging studies compatible with the neurological pain syndrome were required for all patients.

All recruited patients were required to have a KPS (Karnofsky Performance Score) above 40 and expected life expectancy at least 3 months or more as judged by the clinician. Those who had any significant disorder of liver, kidney, bone marrow or other vital organs were excluded from the study. Pregnant and lactating females were excluded from trial. Patients with significant cardiac conduction defects and those with hypersensitivity to the study drugs were also excluded. Those who had participated in any other clinical trial within the past 1 month were excluded. Patients enrolled for the study were not permitted to concomitantly use nonsteroidal antiinflammatory drugs, sedative-hypnotic or psychotropic drugs, atropine, and its substitutes. Those patients, who satisfied the inclusion and exclusion criteria and gave written consent to participate, were selected for the study. Necessary ethical clearance was obtained from the Institutional Ethics Committee.

Study design: This was a unicentric, open-labeled, randomized, controlled study with two parallel treatment arms. A simple randomization was done on the basis of a computer-generated random number list. Allocation concealment was maintained by an independent unit. The selected 88 patients were randomly assigned to two groups. Group A received oral tramadol and gabapentin and group B received oral tramadol and amitriptyline. For the individual patient, the treatment duration was for 6 months following selection and recruitment. The patients were examined by the investigator nine times during the trial. After the baseline visit, patients were asked to report again after 1 week and then after another 2 weeks. Subsequent visits were at monthly intervals up to 6 months. The final end-of-study visit was after 2 weeks of withdrawal of study medication. Study drugs: patients of group A were given oral tramadol 150—200 mg in divided doses after food and oral gabapentin was titrated from 600 to 1800 mg in daily divided doses. Those of group B received oral tramadol 150—200 mg in divided doses after food and oral amityrptiline titrated from 25 to 100 mg in daily divided doses. Oral morphine tablets or fentanyl transdermal patch were used as rescue medication.

In the first visit (V0), all patients were screened which also served as their baseline visit if they were not receiving any interacting drugs, otherwise a separate baseline visit was advised after a wash-out period of 2 weeks on withdrawal of the interacting drug (if it was permissible clinically). At screening a thorough medical history was taken and clinical examination of the potential subjects was done to assess their stages of malignancy as evidenced from the diagnostic documents and suitability for participation in the study. Written informed consent was obtained. Body weight, body surface area, resting pulse rate, respiratory rate, and blood pressure were recorded. A blood sample was obtained for hemoglobin (%), total count, differential count, platelet count, fasting, and postprandial blood glucose level, urea, creatinine, SGPT, alkaline phosphatase. ECG was done to rule out any cardiac conduction defects.

Assessment of efficacy and safety: Visual analog scale (VAS) pain score was considered as the primary efficacy parameter. Verbal rating scale (VRS) score, percentage of pain relief (PPR), and global pain score (GPS) were the secondary efficacy parameters. At the baseline visit, the patient's pain perception was noted on a 10 cm visual analog scale. The patient's pain intensity was recorded as a VRS score, which is a graded five-point scale from 0 to 4 (none to excruciating pain).

The study medications were prescribed to the subjects following randomization. A trial diary was asked to be maintained by each patient regarding the intensity of pain relief. In the second visit (V1) physical examination was done and compliance was determined from the trial diary. The patient's pain perception was recorded as a VAS score. The patient's new pain perception noted as a VAS score was compared with the previous one (V0). Values of 0, 1, or 2 were assigned if the score decreased, remain unchanged or increased. Pain intensity was also scored as on VRS. The percentage of pain relief (PPR) during current treatment was noted on a scale of 0—4: 0 (100%), 1 (80 to <100%), 2 (50 to < 80%), 3 (30 to < 50%), 4 (0 to <30%).[7] A global pain score (GPS) was calculated as the sum of the change in VAS, VRS, and PPR.[7] The global pain score ranges from 0 (no pain at all) to 10 (maximum/increasing pain). Adverse events if any were recorded.

The same procedures were repeated monthly at each of the subsequent visits (V2–V7) till stoppage of medication after 6 months. The change in VAS pain score, VRS score, and PPR was assessed at each visit and GPS was calculated. At the end-of-study visit (V8), GPS was repeated in order to evaluate the residual efficacy of the study medications, if any. The blood sample was sent for laboratory examination at monthly intervals till discontinuation of study medications. Once a patient had taken rescue analgesic, he/she was excluded from further efficacy assessment and his/her last assessment values prior to rescue were carried forward.

The physician's clinical global impression (CGI) of efficacy and safety was graded on a four-point scale as poor (0), satisfactory (1), good (2), and excellent (4).

Although data acquisition for the trial was no longer done after 6 months, all patients received palliative care thereafter from Palliative care OPD, Radiotherapy department. They also received palliative radiotherapy/chemotherapy, if indicated.

Statistical analysis: Nonparametric data were compared between the groups by Kruskal—Wallis ANOVA, with P < 0.05 as the cut-off level for significance, which was followed by a post hoc Dunn's test. Comparisons were two-tailed. Data analysis was carried out in Graph Pad instat 3. Analysis was done on the basis of intention-to-treat.

Results

The groups were comparable with respect to age, weight, gender distribution, and clinical features at baseline [Table 1].

Table 1

Gabapentin versus amitriptyline for neuropathic pain in malignancy – demographic and baseline characteristics of the patients

Of the total 88 patients recruited for the study, 48 received gabapentin [group A] and 40 received amitriptyline [group B] according to the randomization pattern. A total of 40 patients in group A and 36 in group B completed the study. Of the 48 recruited patients in group A, two patients were lost to follow-up, four did not complete the medication schedule, and for two patients, compliance was not deemed satisfactory. In group B of 40 patients, two patients were lost to follow-up, one patient died during the study period, and one patient violated the study protocol by taking some nonpermitted medications.

The serial changes in VAS pain score in the gabapentin group show that there is a highly significant difference between V2 and V3 (P < 0.001). No significant difference is detected at any other study point. In the VRS score, a highly significant difference is detected between V1 and V2 (P < 0.001). In PPR analysis, there is a highly significant difference between V0 and V1 (P < 0.001) and also a significant difference is present between V2 and V3 (P < 0.01). In the GPS score, there is a highly significant difference between V2 and V3 and V3 and V4 (P < 0.001).

The serial changes in VAS pain score in the amitriptyline group show that there is a highly significant difference between V2 and V3 (P < 0.001). No significant difference is detected at any other study point. In the VRS score, a significant difference is detected between V2 and V3 (P < 0.01). In PPR analysis, there is a highly significant difference between V2 and V3 (P < 0.001) and also a significant difference is present between V3 and V4 (P < 0.05). In the GPS score, there is a highly significant difference between V2 and V3 (P < 0.001).

The serial changes in VAS pain score in the two study groups are shown in Table 2. Between-group comparisons of the VAS score by Kruskal—Wallis ANOVA showed no significant difference at any time point (P > 0.05). Figure 1 shows the changes in VRS score in the two groups. Between-group comparisons of the VRS score showed no significant difference either at baseline or at study end (P > 0.05). Figure 2 shows the changes in PPR score in the two groups. Between-group comparison of the PPR score did not reach significant level at any study point (P > 0.05). Figure 3 shows the changes in GPS score, as assessed from baseline to end of the study. The results indicate good analgesic efficacy in both groups but between-group comparisons of the GPS score showed no significant difference (P > 0.05). Thus, both the drugs were effective in providing relief to cancer patients with neuropathic pain and there was no statistically detectable difference in efficacy between them.

Table 2

Gabapentin versus amitriptyline for neuropathic pain in malignancy – visual analog scale pain score in the two groups (Mean ± SEM)

Figure 1

Changes in VRS score between the two groups. [P> 0.05]

Figure 2

Changes in PPR score between the two groups. [P > 0.05]

Figure 3

Changes in GPS score between the two groups. [P> 0.05]

Six patients in group A and eight patients in group B required rescue medication. Commonly occurring adverse events are shown in Table 3. A total of 12 subjects in the gabapentin group and 15 subjects in the amitriptyline group experienced adverse events. All the adverse reactions were of mild-to-moderate grades and did not require discontinuation of therapy.

Table 3

Gabapentin versus amitriptyline for neuropathic pain in malignancy — adverse event counts in the study groups

Vital signs and laboratory parameters at the study end did not show any significant deviations from baseline values in either group. Between-group comparison of Clinician's Global Impression (CGI) of efficacy and safety as assessed by the physician at the end of the study did not show any significant difference (P > 0.05) [Table 4].

Table 4

Gabapentin versus amitriptyline for neuropathic pain in malignancy CGI in two groups

Discussion

Neuropathic pain develops as a result of damage to, or dysfunction of, the system that normally signals pain. The International Association for the Study of Pain (IASP 2007) defines neuropathic pain as “Pain initiated or caused by a primary lesion or dysfunction in the nervous system. It may be due to disordered central or peripheral nerves.” In a patient with cancer, it may be due to chemotherapy-induced neuropathy or secondary to tumor infiltration. Neuropathic pain can be intermittent or constant, and spontaneous or provoked. Typical descriptions of the pain include terms such as shooting, stabbing, like an electric shock, burning, tingling, tightness, numb, prickling, itching, and a sensation of pins and needles. There may be symptoms of allodynia and hyperalgesia.[8]

Opioids, the mainstay of palliative cancer pain therapy, have some limitations, as they are accompanied by a significant risk of dose limiting toxicity such as constipation, and respiratory depression. Long-term potential complications are tolerance and dependence. Neuropathic pain in cancer patients is suboptimally effective and poorly tolerated if treated by opioids alone at higher doses. Opioids also carry a significant risk of abuse potential which may at times hinder the effective management of cancer pain. For management of cancer pain problems, WHO recommends use of non-opioids (e.g., nonsteroidal anti-inflammatory drugs) and adjuvant analgesics, in addition to opioids. Gabapentin is used as adjuvant analgesic along with opioids for management of moderate to severe degree of pain in cancer patients.[9] Anticonvulsants and antidepressants are used in neuropathy due to other causes too.[10]

Gabapentin has a role in treatment of painful diabetic neuropathy, postherpetic neuralgia, and other types of neuropathic pain.[11121314] It is also used in neuropathic pain associated with cancer.[5] Amitrypline has been found to be effective in relieving neuropathic pain, but with some associated adverse effects like sedation, dizziness, dry mouth, blurring of vision, constipation, weight gain, ataxia, orthostatic hypotension, and cardiac arrhythmias.[1516]

Gabapentin is a centrally acting GABA agonist and promotes nonvesicular release of GABA. It binds to a protein identical to that of the α2δ subunit of the L type of voltage sensitive calcium channels.[17] It also interacts with N-methyl-D-aspartate receptor system. In most forms of chronic pain, postsynaptic NMDA receptors are opened, which cause calcium influx, neuronal excitability, and gene expression leading to neuronal sensitization, allodynia, and hyperalgesia.

Amitriptyline, a tricyclic antidepressant, acts by facilitating the descending inhibitory pain pathways. It inhibits presynaptic reuptake of norepiniphrine and serotonin. In our study there was significant reduction of neuropathic pain with fewer drop outs in the amitriptyline group. This may be due to a mild degree of adverse effects experienced with lower dose (25–50 mg/day) of amitriptyline. Global improvement and improvement of quality of life were also observed in the amitriptyline group as seen in other studies.[15] Comprehensive assessment of cancer pain is essential in order to plan the best treatment option for the individual patient. Since pain is a subjective sensation, the patient's self assessment of pain intensity is a tool to evaluate efficacy of drugs and hence the VAS pain score, VRS score, PRR, and GPS are used.

In our study both the drugs were effective in providing relief to cancer patients with neuropathic pain though there was no statistically detectable difference in efficacy between them. There was a nonsustained trend of decrement of pain perception within the groups as were judged by different pain scales used in the study. The reason for the variability might be attributed to the ongoing disease activity at the backdrop of analgesic treatment.

The adverse effects experienced by patients were of mild-to-moderate degree and did not require discontinuation of therapy. One patient in the amitriptyline group required catheterization due to retention of urine. This patient had benign hypertrophy of prostrate and had to be withdrawn. The drawbacks of open-label design could not be overcome in the present study which remains its predominant limitation. Due to unavailability of financial support, the patients had to buy their own medications and blinding was thus not possible.

In conclusion, although gabapentin is widely used for neuropathic pain, our study suggests amitriptyline as a suitable alternative in cancer patients. In view of the low cost of amitriptyline, better compliance may be expected with lesser number of drop-outs. Although the number of patients having adverse effects were more in the amitriptyline group but they were not severe enough to warrant discontinuation of treatment. Therefore it can be speculated with due evidence that amitriptyline can emerge as a more cost-effective treatment option for neuropathic pain especially at a government or public set up in a resource-constrained country like India.