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. 

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

• 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.

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

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

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

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).

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.

• 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.

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.