Pregabalin for the Prevention of Oxaliplatin-Induced Painful Neuropathy: A Randomized, Double-Blind Trial.

LESSONS LEARNED: Pregabalin is a medication that can decrease neuronal hyperexcitability, relieve neuropathic pain, and reach stable plasma levels after a titration period of only a few days.Its use during oxaliplatin infusions was not able to decrease the incidence of chronic, oxalipaltin-related neuropathic pain, compared with placebo.
BACKGROUND: Patients with colorectal cancer (CRC) receiving oxaliplatin (OXA) develop acute and chronic painful oxaliplatin-induced peripheral neuropathy (OXAIPN). Acute and chronic OXA-related neuropathies have different pathophysiological bases, but both lead to a common phenomenon: central sensitization (CS) of nociceptive neuronal networks, leading to increased sensitivity (hyperlgesia, allodynia) in the somatosensory system, the common ground of chronic neuropathic pain. Because CS is related to increased risk of painful OXAIPN, we hypothesized that preemptive use of the anti-hyperalgesic drug pregabaline (known to decrease CS) during OXA infusions would decrease the incidence of chronic OXAIPN.
METHODS: Pain-free, chemotherapy-naïve CRC patients receiving at least one cycle of modified-FLOX [5-FU(500 mg/m2)+leucovorin(20 mg/m2)/week for] 6 weeks+oxaliplatin(85 mg/m2) at weeks 1-3-5 every 8 weeks] were randomized (1:1) into the study. Patients received either pregabalin or placebo for 3 days before and 3 days after each OXA infusion and were followed for up to 6 months. Clinical assessments were performed at baseline, at the end of chemotherapy, and after the follow-up period. The main outcome was average pain at the last visit assessed by the visual analogic scale (0-10) item of the Brief Pain Inventory (BPI). Secondary endpoints were presence of neuropathic pain according to the Douleur Neuropathique-4 (DN-4), pain dimensions (short- form McGill Pain Questionnaire [MPQ]), Neuropathic Pain Symptom Inventory (NPSI), and changes in nerve conduction studies (NCS) and side effect profile.
RESULTS: One hundred ninety-nine patients (57.0 ± 10.7 years old, 98 female, 101 male) were randomized. Data from 56 patients were not included in the analyses (as they did not receive at least one full cycle of modified FLOX). Data from 78 patients in the pregabalin group and 65 patients in the placebo group were retained for analyses. At the last visit, pain intensity in the pregabalin group was 1.03 (95% confidence interval [CI] = 0.79-1.26), and 0.85 (95% CI = 0.64-1.06) in the placebo group, which did not reach significance. Scores from the BPI, MPQ, DN-4, NPSI, and NCS and side-effect profiles and incidence of death did not differ between groups. Quality of life (QoL) score did not differ between groups (placebo = 76.9 ± 23.1, pregabalin group 79.4 ± 20.6). Mood scores were not significantly different between groups (placebo 9.7 [8.1-11.2]; pregabalin 6.8 [5.6-8.0]).
CONCLUSION: The preemptive use of pregabalin during OXA infusions was safe, but did not decrease the incidence of chronic pain related to OXAIPN. ©AlphaMedPress; the data published online to support this summary is the property of the authors.

RCT Entities:   Population Interventions Outcomes

Discussion

The intensity of acute OXA‐induced neuropathic phenomena may significantly increase the odds of developing chronic long‐term neuropathy. The association between intense acute sensory symptoms and greater risk of developing chronic pain has been described in other settings and is probably related to the development of central neuronal plastic changes such as central sensitization after acute injury. Thus, it has been hypothesized that the modulation of neuronal firing related to acute pain by the use of pregabalin would decrease the likelihood of the development of neuropathic pain.

Consolidated Standards of Reporting Trials flowchart of screened and included patients.

Based on this rationale, we tested the hypothesis that the preemptive use of pregabalin a few days before and after OXA would have a preventive effect on chronic OXAIPN and its most troublesome symptom: neuropathic pain. However, we found no effects of pregabalin in this scenario. It failed to impact both the acute and chronic pains seen after OXA. Pain‐related effects, interference, and QoL were not influenced by the active treatment.

Trial Information

CRC

Prevention

None

Phase III

Randomized

Pain intensity

Safety

QoL

Cummulative mFLOX dose

NPSI score

Presence of neuropathic pain

CTC‐neuropathy

Level of activity did not meet planned endpoint

Drug Information for Phase III Pregabalin

Pregabalin

Lyrica

Pfizer

Other

Other

150–600 mg p.o. q.d. milligrams (mg) per flat dose

Oral (p.o.)

Drug Information for Phase III Placebo

Placebo

Placebo

Other

Other

150–600 milligrams (mg) per flat dose

Oral (p.o.)

Placebo

Placebo

Other

Other

150 milligrams (mg) per flat dose

Oral (p.o.)

Similar to pregabalin

Patient Characteristics for Phase III Pregabalin

99

100

Median (range): 57.13 ± 10.51

Median (range): none

CRC: 199

Primary Assessment Method for Phase III Pregabalin

402

199

199

143

Clinical (questionnaire and scales)

12 months

6 months

Adverse Events: Phase III Pregabalin

Assessment, Analysis, and Discussion

Study completed

Not collected

Level of activity did not meet planned endpoint

The intensity of acute OXA‐induced neuropathic phenomena may significantly increase the odds of developing chronic long‐term neuropathy [1], [2]. The association between intense acute sensory symptoms and greater risk of developing chronic pain has been described in other settings [3], [4] and is probably related to the development of central neuronal plastic changes such as central sensitization after acute injury. Central sensitization occurs in central relay centers, such as the spinal cord, and comprises a series of neuronal processes leading to sensory gain in the nervous system [5]. In fact, it has been shown that OXA triggers activation of glutamate‐NMDA receptors in the spinal cord, a major step in central sensitization to painful stimuli [6]. Thus, it has been hypothesized that the modulation of the neuronal firing related to acute pain by the use of pregabalin would decrease the likelihood of the development of neuropathic pain. This strategy has been tested in several models of postoperative pain, in which gabapentinoids were administered perioperatively with the aim of decreasing the incidence of long‐term chronic pain, yielding promising results [7]. Also, it has been shown that a single 300‐mg dose of oral pregabalin was sufficient to reach significant concentrations in the cerebral spinal fluid [8], and the use of gabapentinoids before and a few days after surgery not only significantly decreased perioperative pain [9] but also seemed to reduce chronic post‐surgical pain.

Based on this rationale, we tested the hypothesis that the preemptive use of pregabalin a few days before and after OXA would have a preventive effect on chronic OXAIPN and its most troublesome symptom: neuropathic pain. However, we found no effects of pregabalin in this scenario. It failed to impact both the acute and chronic pains seen after OXA. Pain‐related effects, interference, and quality of life were not influenced by the active treatment.

Previous studies have tried to prevent [10], [11] or treat [12] OXA‐induced neuropathy with limited or no success. While some studies have tested a prophylactic approach to OXA‐induced neuropathy by administering drugs before chemotherapy was started [10], [11], [13], [14], [15], others have focused on patients already with OXAIPN [12], [16], [17] and already presenting with neuropathic symptoms [18], thus performing a formal treatment trial rather than a preemptive or prophylactic approach. The bulk of evidence is negative for both scenarios [12], [14], [19], [20], with rare exceptions [17], [21]. Importantly, the large majority of studies have not used validated pain measurement tools [10], [11], [13], [14], [16], [19], [22], [23], while most have used the common terminology criteria (CTC) adverse events grading system as the primary outcome measurement. While this choice is sound and supported by robust evidence [24], it must be kept in mind that most patients with OXAIPN have small‐fiber‐predominant polyneuropathy [1], which has as its main symptom neuropathic pain. However, pain itself (i.e., visual analog scale (VAS), BPI) or neuropathic pain symptoms (i.e., NPSI) have rarely been used as a primary outcome in studies on OXAIPN, and only a few have used validated pain scales or questionnaires at all [12], [20], [21], [25]. Also, neuropathic symptoms have only rarely been evaluated [17], [26]. In fact, “pain” is not mentioned in the CTC grading system for “neuropathy”, which is centered on the functional impairment due to paresthesia. It is also noteworthy that no larger trial published so far used formal neuropathic pain criteria or grading system [27] among its endpoints, or one of the many published screening tools for neuropathic pain.

Even though the results of our study are in line with the previous literature, the study has limitations. For instance, the incidence of chronic neuropathic pain was only mild in our sample, maybe due to the inclusion of patients with metastatic disease, who may receive fewer cycles of Oxa. The current management of acute OXA‐induced dysesthesias by reduction of OXA dosage in subsequent chemotherapy sessions may have also played a role in the reduction of chronic OXAINP in our sample. Also, the placebo group receive significantly more medication than the pregabalin arm. However, the net difference between groups was equivalent to approximately one pill of medication (75 mg). Because the average participant took 5 to 6 pills daily and all participants were pregabalin‐nû£ve, we believe this may not have played a major role in our results.

In conclusion, the use of pregabalin failed to decrease acute or chronic OXA‐related pain despite being safe and relatively well tolerated.

Effects of study medications on pain intensity. (A): Brief Pain Inventory pain intensity scores (0–10). (B): Neuropathic pain symptoms (Douleur Neuropatique‐4). Statistical significance is considered when confidence intervals from both groups do not intersect.

Abbreviations: BPI, brief pain inventory; DN‐4, Douleur Neuropatique‐4.

Abbreviations: NC/NA, no change from baseline/no adverse event.

Safety was assessed by the presence and severity of AEs, discontinuation, and death. CTCAE term (AE description) and grades were recorded according to the NCI‐CTCAE‐v3.0.(17)

At the last visit, AEs were present in 31% (CTC‐grade 1 = 54%) of patients in the pregabalin arm and in 33% of patients (CTC‐grade 1 = 50%) in the placebo arm. Twenty‐six patients died in the pregabalin arm and 25 patients died in the placebo arm during the study, none related to the trial.

Table 1.

Baseline characteristics in both study groups

For all these scores/questionnaires (VAS, HADS, rTNS), higher values indicate more pain/more intense mood symptoms/more signs of neuropathy.

The values are presented as mean ± SD or n. Statistical significance was set at p < .05.

Abbreviations: HADS, hospital anxiety and depression scale; rTNS, total neuropathy score‐reduced; SD, standard deviation; VAS, visual analog scale.

Table 2.

Study outcomes taking into account all measurements over the entire trial period

The values were presented as predicted means from generalized estimating equations (95% CI). Statistical significance is considered when CI from both groups do not intersect.

For all these scores/questionnaires (BPI, DN4, HADS, rTNS), higher values indicate more pain/more intense mood symptoms/more signs of neuropathy.

Main outcome.

Abbreviations: BPI, brief pain inventory; CI, confidence interval; DN‐4, Douleur Neuropathique‐4; HADS, hospital anxiety and depression scale; NPSI, neuropathic pain symptom inventory; rTNS, total neuropathy score‐reduced.

Table 3.

Pain outcomes comparison between interventions considering the dichotomous variables

For all these scores/questionnaires, higher values indicate more severe symptoms.

Abbreviations: CI, confidence interval; CTC, common toxicity criteria; DN‐4, Douleur Neuropathique‐4; VAS, visual analog scale.