Venlafaxine

Venlafaxine

PEP Topic 
Peripheral Neuropathy
Description 

Venlafaxine is used to treat depression and has also been used to treat hot flashes in women who have experienced menopause or who are taking medication to treat breast cancer. Venlafaxine is in a class of medications called selective serotonin and norepinephrine reuptake inhibitors (SNRIs) which increase the amounts of serotonin and norepinephrine in the brain. Venlafaxine comes as a tablet or extended-release capsule to take by mouth. In addition, venlafaxine has been studied as an intervention for sleep-wake disturbances, peripheral neuropathy, and fatigue in patients with cancer.

Effectiveness Not Established

Research Evidence Summaries

Durand, J.P., Deplanque, G., Montheil, V., Gornet, J.M., Scotte, F., Mir, O., . . . Goldwasser, F. (2012). Efficacy of venlafaxine for the prevention and relief of oxaliplatin-induced acute neurotoxicity: Results of EFFOX, a randomized, double-blind, placebo-controlled phase III trial. Annals of Oncology, 23, 200–205.

doi: 10.1093/annonc/mdr045
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Study Purpose:

The aim of the study was to evaluate the efficacy of venlafaxine for the prevention and treatment of oxaliplatin-induced peripheral neuropathy.

Intervention Characteristics/Basic Study Process:

Patients who reported distressing acute neurotoxicity after oxaliplatin-based chemotherapy were randomly assigned to receive either placebo or venlafaxine hydrochloride 50 mg one hour prior to chemotherapy infusion and venlafaxine extended release 37.5 mg twice daily from day 2 to day 11. Placebo was given with the same timing. From day 12 on, no venlafaxine extended release was given. Study treatment continued as long as the oxaliplatin treatment lasted. Study evaluation and data collection was conducted pretreatment, daily on day 1 through 5 of chemotherapy treatment, and at three months after study completion.

Sample Characteristics:

  • A total of 42 patients were studied (21 women, 21 men)
  • The median age was 67.4 years with a range of 32–84.4 years.
  • Patients had multiple tumor types,
  • Most patients were receiving FOLFOX. The median number of cycles at study inclusion was 4.5.

Setting:

The study was conducted at a single outpatient setting in France.

Phase of Care and Clinical Applications:

Phase of care

  • Active antitumor treatment

Study Design:

The study had a double blind, placebo-controlled, randomized trial design.

Measurement Instruments/Methods:

  • Neuropathic pain symptom inventory
  • Numeric rating scale for functional impairment
     

Results:

The proportion of patients reporting full relief of acute neurotoxic symptoms was 31.3% compared to 5.3% in the placebo group (p = 0.03).  In the venlafaxine group, 68.8% reported more than 50% symptom relief compared to 26.3% on placebo (p = 0.02). There were no grade 3 or 4 adverse events related to venlafaxine. Among those receiving venlafaxine, the most common adverse events were nausea and vomiting, asthenia, orthostatic hypotension, and somnolence. These side effects occurred more frequently in the venlafaxine group (p < 0.03).

Conclusions:

The findings suggest that venlafaxine as studied here is effective in reducing acute neurotoxic symptoms associated with oxiplatin chemotherapy.

Limitations:

A small sample size (less than 100 participants)

Nursing Implications:

The findings provide support for the efficacy of venlafaxine to prevent acute oxiplatin-related neurotoxicity. The study is limited by sample size, so the results are inconclusive. Additional research in this area is warranted.

Kus, T., Aktas, G., Alpak, G., Kalender, M.E., Sevinc, A., Kul, S., . . . Camci, C. (2016). Efficacy of venlafaxine for the relief of taxane and oxaliplatin-induced acute neurotoxicity: A single-center retrospective case-control study. Supportive Care in Cancer, 24, 2085–2091. 

doi: 10.1007/s00520-015-3009-x
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Study Purpose:

To evaluate the effect of venlafaxine 75 mg daily oral administration on peripheral neuropathy (PN) pain severity reduction rates in patients on taxane- or oxaliplatin-based chemotherapy with moderate to severe painful chemotherapy-induced PN (CIPN) compared to participants who refused treatment

Intervention Characteristics/Basic Study Process:

Venlafaxine XR 75 mg orally once daily (duration unspecified). Measurement time points were at baseline (before venlafaxine but after neurotoxic chemotherapy initiation) and every three weeks up to nine weeks. 
 
Retrospective chart analysis investigated patients prescribed venlafaxine for CIPN pain and mild depression compared to a case matched control group that had rejected CIPN treatment. All patients were on taxane-, taxane with carboplatin–, or oxaliplatin-based chemotherapy. The charts were first reviewed for participants with documented CIPN history (signs/symptoms). Then participants who had sensory CIPN severity of 1 or greater on the Common Criteria for Adverse Events (CTCAE), version 4.03, and 4 or more out of 10 based on a mean numeric rating scale (NRS) score calculated from responses on the Neuropathic Pain Symptom Inventory (NPSI) were selected. For patients who met these and the eligibility criteria listed below, CIPN severity (NPSI NRS mean score) and adverse events (CTCAE, version 4.03) were evaluated at three, six, and nine-week follow-ups.

Sample Characteristics:

  • N = 199   
  • MEAN AGE = 52.78 years
  • MALES: 15.1%, FEMALES: 84.9%
  • CURRENT TREATMENT: Chemotherapy
  • KEY DISEASE CHARACTERISTICS: Participants had diagnosed and patient-reported moderate to severe painful CIPN while on a taxane- (45.7% of participants), paclitaxel and carboplatin– (30.2%), or oxaliplatin-based regimens (24.1%). Most patients had breast, gynecologic, or colorectal cancer of any stage. Most individuals (68%) were either older than age 65 years or had diabetes.
  • OTHER KEY SAMPLE CHARACTERISTICS: All 91 patients in the treatment group had mild depression treated with oral venlafaxine 75 mg daily. Participants were eligible if they had no history of prior neurotoxic chemotherapy, motor CIPN, diabetic PN, alcohol dependence, neurological metastases, or unstable psychological condition. Patients were also excluded if they were taking psychotropic or analgesic medications, including opioids, gabapentin, pregabalin, and drugs that could influence serotonin levels. However, selected analgesics were allowed, such as acetaminophen, aspirin, and nonsteroidal anti-inflammatory drugs.

Setting:

  • SITE: Single site   
  • SETTING TYPE: Not specified    
  • LOCATION: University Hospital in Turkey

Phase of Care and Clinical Applications:

  • PHASE OF CARE: Active antitumor treatment
  • APPLICATIONS: Elder care, palliative care

Study Design:

Retrospective, case-control, nonblinded design with a venlafaxine-treated group and a case-matched control group that had rejected CIPN treatment

Measurement Instruments/Methods:

Every three weeks, PN was measured using the 10-item NPSI mean composite score, which ranged from 0 (“no pain”) to 10 (“worst pain imaginable”). Each NPSI item used the same 0–10 NRS to measure patient-reported severity for the past 24 hours of various neuropathic pain symptoms (e.g., burning pain, pain provoked by cold, abnormal pin-and-needle sensations). The severity of venlafaxine-associated adverse effects was also measured using the CTCAE, version 4.03, ranging from 0 (normal) to 4 (life-threatening).

Results:

Painful and nonpainful PN symptoms (NPSI scores) significantly improved from baseline to the three-, six-, and nine-week follow-ups for participants on venlafaxine (p < 0.001), but did not change over the nine-week study period for participants not on venlafaxine. A higher percentage of participants in the venlafaxine arm compared to the control experienced at least a 75% reduction in pin-and-needle sensations at each follow-up (p < 0.001). A similar trend was found for symptoms of pain provoked by cold. In subgroup analysis, a higher percentage of participants with grade 1 CIPN at baseline (CTCAE, version 4.03) displayed at least a 75% reduction in PN severity than participants with grade 2 CIPN (p = 0.031). Grade 1–2 nausea/vomiting, asthenia/somnolence, dizziness, and insomnia were experienced by no more than three participants, and no participants experienced grade 3–4 adverse effects from venlafaxine.

Conclusions:

This study provided weak evidence supporting the superiority of venlafaxine compared to no venlafaxine in decreasing PN symptoms among participants with moderate to severe painful CIPN and mild depression while receiving taxane- and/or platinum-based chemotherapy. Participants who received venlafaxine 75 mg once daily experienced a reduction in painful and nonpainful PN symptoms after three weeks that continued through nine weeks, compared to no change in participants who did not receive venlafaxine. Participants with milder PN before treatment experienced the most benefit. However, these results may not be reliable or valid because of the retrospective design and potentially biased study procedures/methods/analysis.

Limitations:

  • Baseline sample/group differences of import
  • Risk of bias (no blinding)
  • Risk of bias (no random assignment)
  • Risk of bias (no appropriate attentional control condition)
  • Risk of bias (sample characteristics)
  • Unintended interventions or applicable interventions not described that would influence results
  • Key sample group differences that could influence results
  • Measurement/methods not well described
  • Measurement validity/reliability questionable 
  • Findings not generalizable
  • Questionable protocol fidelity
  • No report or control for potential confounding factors, such as chemotherapy factors, cancer stage, smoking, supplementation with neuroprotectants or vitamins, vitamin B deficiency, peripheral arterial disease, and diabetes (without PN)
  • It was unclear at what time participants initiated venlafaxine in relation to their chemotherapy treatment, and whether all participants received chemotherapy throughout the entire study or if some had already completed treatment; therefore, differing cumulative doses of chemotherapy and maturation effects could have biased the results.
  • Although the article reported, “Baseline demographic and clinical characteristics were distributed in the two groups (Table 1),” no chi square p values were reported comparing baseline cancer type and chemotherapy regimen between the two groups.
  • Although prior evidence supports the validity/reliability of non-English versions of the NPSI sum score in patients with other neuropathic pain conditions, no evidence was cited to support its validity/reliability as a mean score and among English-speaking participants with painful CIPN.
  • No discussion of who extracted data from the charts
  • Effect size was not reported, and the authors' analysis methods (two-way repeated measure ANOVA) may not have been appropriate to evaluate between- and within-group differences in two independent groups. Rather, a mixed model may have been more appropriate.
 

 

Nursing Implications:

Additional testing of venlafaxine in large prospective, randomized, controlled trials is needed before it can be used in clinical practice to treat CIPN. However, the positive results of this trial emphasize the importance of continual nursing assessment of PN signs and symptoms throughout chemotherapy because pain treatments may be most beneficial to patients with acute mild CIPN.

Zimmerman, C., Atherton, P.J., Pachman, D., Seisler, D., Wagner-Johnston, N., Dakhil, S., . . . Loprinzi, C.L. (2016). MC11C4: A pilot randomized, placebo-controlled, double-blind study of venlafaxine to prevent oxaliplatin-induced neuropathy. Supportive Care in Cancer, 24, 1071–1078.

doi: 10.1007/s00520-015-2876-5
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Study Purpose:

To obtain data to support conducting a phase III trial of venlafaxine to prevent oxaliplatin-induced neurotoxicity

Intervention Characteristics/Basic Study Process:

Patients were stratified according to planned calcium and magnesium administration, cancer stage, and treatment cycle, then randomized to receive venlafaxine extended release 37.5 mg versus placebo twice daily. The study treatment was begun on the evening of the first or second chemotherapy treatment and continued for one week following completion of the FOLFOX treatment. Assessments were taken at baseline, prior to each FOLFOX treatment, and at 1, 3, 6, and 12 months postcompletion.

Sample Characteristics:

  • N = 43
  • MEAN AGE = 61.3 years
  • MALES: 52%, FEMALES: 48%

Setting:

  • SITE: Multi-site  
  • SETTING TYPE: Not specified  
  • LOCATION: USA

Phase of Care and Clinical Applications:

PHASE OF CARE: Active antitumor treatment

Study Design:

Randomized, double-blind, placebo-controlled trial

Measurement Instruments/Methods:

  • European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QLQ)-CIPN20 symptom questionnaire
  • Common Terminology Criteria for Adverse Events (CTCAE), version 4.0
  • Oxaliplatin Acute Symptom Questionnaire

Results:

No significant differences in any measures of neuropathy outcomes existed between groups.

Conclusions:

Venlafaxine did not reduce neuropathic toxicities associated with oxaliplatin.

Limitations:

Small sample (< 100)

 

Nursing Implications:

Data from this trial do not support the use of venlafaxine for the prevention of neuropathic symptoms associated with oxaliplatin. Ongoing research is needed to identify effective interventions for this treatment complication.

Systematic Review/Meta-Analysis

Hershman, D.L., Lacchetti, C., Dworkin, R.H., Lavoie Smith, E.M., Bleeker, J., Cavaletti, G., . . . American Society of Clinical Oncology. (2014). Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. Journal of Clinical Oncology, 32, 1941–1967.

doi: 10.1200/JCO.2013.54.0914
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Purpose:

STUDY PURPOSE: To provide evidence-based guidance on optimum prevention and treatment approaches in the management of chemotherapy-induced peripheral neuropathy in adult cancer survivors

TYPE OF STUDY: Systematic review

Search Strategy:

DATABASES USED: Ovid Medline (1946–April, week 2, 2013); EMBASE (1980–2013, week 16); AMED Allied and Complementary Medicine (1985–April 2013)

KEYWORDS: chemotherapy-induced peripheral neuropathy; adult cancer survivors; randomized clinical trials

INCLUSION CRITERIA: Adult cancer survivors with chemotherapy-induced peripheral neuropathy; randomized trials

EXCLUSION CRITERIA: Phase 1 trials; published in a language other than English; less than 10 patients; focused on radiation or stem cell transplant neuropathy; animal studies

Literature Evaluated:

TOTAL REFERENCES RETRIEVED = 1,252

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: An expert panel representing neurology, nursing, medical oncology, community oncology, pain research, and genetics met through teleconference and emails to review and develop the American Society of Clinical Oncology guidelines.

Sample Characteristics:

  • FINAL NUMBER STUDIES INCLUDED = 48
  • TOTAL PATIENTS INCLUDED IN REVIEW: Treatment studies: 780; prevention studies: 3,741

Phase of Care and Clinical Applications:

  • PHASE OF CARE: Active antitumor treatment

Results:

Forty-two randomized clinical trials involved 19 various interventions for prevention of chemotherapy-induced peripheral neuropathy. These agents included anticonvulsants, antidepressants, vitamins, minerals, and other chemoprotectant drugs. Only six randomized clinical trials discovered six different drugs, such as antidepressants, anticonvulsants, and a topical gel, for the prevention of chemotherapy-induced peripheral neuropathy. The following are not recommended for use: acetyl-l-carnitine, amifostine, amitriptyline, calcium and magnesium, glutathione, nimodipine, ORG 2766, trans retinoic acid, rhuLIF, and vitamin E. Venlafaxine is not recommended for routine use in clinical practice. Although data support potential utility, evidence is not strong enough to suggest use. For treatment of chemotherapy-induced peripheral neuropathy, clinicians can offer duloxetine. No recommendation is made regarding ALC. Tricyclic antidepressants or gabapentin through trial use may be reasonable.  The panel felt that trying topical gel containing baclofen, amitriptyline, and ketamine would be reasonable. 

Conclusions:

No agents were recommended for the prevention of chemotherapy-induced peripheral neuropathy, but duloxetine is moderately recommended for the treatment of chemotherapy-induce peripheral neuropathy. Even though conclusive evidence is lacking to recommend tricyclic antidepressants such as nortriptyline, gabapentin, and a topical gel containing baclofen,amitriptyline, and ketamine for treatment of chemotherapy-induced peripheral neuropathy, the expert panel agreed that offering these agents based on treatment for neuropathic pain is reasonable. The panel also recommended that patients be counseled regarding the lack of evidence in treating chemotherapy-induced peripheral neuropathy with these agents.

Limitations:

  • Small, insufficient sample
  • Inability to compare studies because of different outcomes
  • Measurements and instruments used at different points in treatment

Nursing Implications:

Nurses are at the frontline in assessing patients who are receiving agents with the potential for chemotherapy-induced peripheral neuropathy. Nurses should be aware of the standard of care in treating this population. Many drugs prescribed have no evidence in preventing or treating these patients. However, with these American Society of Clinical Oncology guidelines, a role for duloxetine is clear and a role for tricyclic antidepressants is possible. Nurses need to be knowledgeable about this information to better inform patients.

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