Cognitive Effects of Perioperative Pregabalin: Reply

Drs. Allen and McEvoy have some very important comments and questions about our article¹  that we are happy to answer. We find that their input is valuable and relevant, and we thank them for their effort.

In their letter, they note that they routinely use nonopioid multimodal analgesia in their practice of perioperative pain management. We understand this, as pregabalin is part of that routine. One of our key messages is that pregabalin many places is used routinely perioperatively even if this is off-label use without proper documentation of efficacy and safety.²  A quite recent editorial in Anesthesiology discussed this topic related to pregabalin in particular.³ 

Drs. Allen and McEvoy ask if any reduction in dosage of pregabalin was considered if the patient experienced side effects of pregabalin. They also comment that they believe the dose was high (300 mg/day).

The dose used is the recommended dose in several publications.^4,5  Our study differs from clinical practice, as it was a randomized and double-blinded trial, and individual titration of dose was not feasible. Of course, we had “stop rules,” and possibility for unblinding in case of emergencies, but this was not needed except for one patient described in the flow chart who received only 450/600 mg pregabalin due to diplopia.¹  Besides, we think that dose reduction due to side effects is quite difficult when patients are receiving multimodal treatment; which drug caused the side effect?

The battery of cognitive tests was carefully chosen to assess several different aspects of cognitive function. The Cambridge Neuropsychological Test Automated Battery tests are widely used by the pharmaceutical industry and clinicians to test effects of drugs on cognitive function. So-called “parallel tests” make sure retests are not identical (to avoid learning effects), yet comparable and reliable. We did not find it appropriate to readdress this carefully documented test system. The correlation between the tests was not a topic of interest since they test different aspects of cognitive function, and this was an exploratory analysis. The test battery used was quite extensive; most patients used 40 to 50 min each time, and thus repeated testing was not an option.

Drs. Allen and McEvoy find it questionable that 20% of the patients in the control group not were tested at 24 h due to pain or postoperative nausea and vomiting. We agree that this is a real weakness of our trial, and we have discussed this thoroughly in our article.

Drs. Allen and McEvoy also ask what a fraction of an error on day 3 to 5 really means clinically. Our attention has been on the effects on day 1 when patients took the drug. The tests 3 to 5 days after were done only to document whether day 1 changes had disappeared.

Yes, we speculate that the documented changes induced by pregabalin may affect motor control and may increase the risk of falls. There is extensive literature to document that the influences of motor and sensory impairments on falls are moderated by executive functioning. A number of studies suggest this.^6,7  We must admit we were not prepared on this issue, and did not register falls systematically. However, three patients, all three receiving pregabalin, had registered falls in their electronic patient journals. We did not mention this in our article since it was not a part of our preplanned systematic documentation of side effects.

The value and beauty of our study, and the need for exploratory analyses such as ours, are to aid future researchers to better document the effects of the intervention; first do no harm.⁸ 

The authors declare no competing interests.