Antidepressants

Antidepressants

PEP Topic 
Chronic Pain
Description 

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
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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.

Setting:

  • 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)

Results:

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.

Conclusions:

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

Limitations:

  • 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.

Xiao, Y., Liu, J., Huang, X. E., Ca, L.H., Ma, Y.M., Wei, W., . . . Wu, Y.J. (2014). Clinical study on fluvoxamine combined with oxycodone prolonged-release tablets in treating patients with moderate to severe cancer pain. Asian Pacific Journal of Cancer Prevention, 15, 10445–10449.

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Study Purpose:

To assess the safety and efficacy of fluvoxamine combined with prolonged-release oxycodone for the management of cancer-related chronic pain

Intervention Characteristics/Basic Study Process:

Patients with moderate to severe cancer-related pain were randomized to either the control group, which was treated with only prolonged-release oxycodone, or the prolonged-release oxycodone combined with fluvoxamine group. A daily maintenance dose of oxycodone was determined per patient after two weeks. Fluvoxamine began at 50 mg per day and increased by 50–100 mg per day to a maximum of 150 mg twice daily. Patients were assessed three times daily for pain response and dosage adjustment.

Sample Characteristics:

  • N = 120
  • AGE = Not provided
  • MALES: Not provided, FEMALES: Not provided
  • KEY DISEASE CHARACTERISTICS: Not provided
  • OTHER KEY SAMPLE CHARACTERISTICS: Patients had a life expectancy of at least two months at study entry.

Setting:

  • SITE: Single site  
  • SETTING TYPE: Not specified  
  • LOCATION: China

Study Design:

Randomized, open-label trial

Measurement Instruments/Methods:

  • Numeric Rating Scale (NRS)
  • Opioid consumption

Results:

Pain severity declined in both groups. There were no reported significant differences between groups for pain severity or opioid consumption.

Conclusions:

The findings of this study did not demonstrate the efficacy of fluvoxamine for chronic pain management.

Limitations:

  • Risk of bias (no blinding)
  • Measurement/methods not well described
  • Measurement validity/reliability questionable
  • Other limitations/explanation: The timing of measurement and duration were not well described. Although pain was measured every three hours, the exact measure used in the analysis was not stated. There was no information about the duration of the study, total opioid dosages in both groups before and after the intervention, or demographic information. The sample numbers differed between the tables and the body of the article, calling into question the overall validity of the results.

Nursing Implications:

This study did not show any benefit from the addition of fluvoxamine to prolonged-release opioids in the management of moderate to severe chronic cancer-related pain.

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
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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.

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