PEP Topic 
Chronic Pain

Antidepressants are a class of medications to treat depression. They include subgroups of tricyclic antidepressants (i.e., older drugs, those with a high incidence of anticholinergic effects, and drugs that are highly cardiotoxic in overdose) such as desipramine, nortriptyline, amitriptyline, imipramine, doxepin, and clomipramine; selective serotonin reuptake inhibitors (SSRIs), newer drugs with fewer severe side effects, including fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, and escitalopram; serotonin-norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine (duloxetine is most common); psychostimulants (methylphenidate is most common); and others (e.g., bupropion, trazodone, mertrazpine, mianserin*). Antidepressant use in patients with cancer has been evaluated in depression and anxiety and as adjunctive treatment in pain. Specific antidepressants have also been evaluated in peripheral neuropathy.

* Not available in the United States

Effectiveness Not Established

Research Evidence Summaries

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

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.


  • 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)


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.


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


  • 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.

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


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


Literature Evaluated:


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:


Phase of Care and Clinical Applications:

  • APPLICATIONS: Palliative care


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.


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.


  • 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.