Pregabalin Has Analgesic, Ventilatory, and Cognitive Effects in Combination with Remifentanil

Multimodal, balanced analgesia is used for the treatment of postoperative pain. The concept is based on a combination of drugs with different modes of action to achieve optimal pain relief and reduce opioid-related side effects such as nausea and sedation, which may have a substantial impact on patient recovery after surgery.^1,2 

During the past decade, gabapentin and its successor pregabalin have been introduced as potential analgesics for early and long-term pain after surgery.^3,4  Multiple studies have shown significant pain reduction and opioid-sparing effects in early postoperative pain^5–11 ; however, the analgesic efficacy of these compounds for acute postoperative pain conditions remains controversial, as other studies did not confirm these positive findings.^12–15  A Cochrane review¹⁶  concluded that there was no evidence of any beneficial effects of pregabalin in acute postoperative pain, whereas another systematic review¹⁷  reported a reduced cumulative opioid consumption at 24 h postsurgery. Furthermore, two recent meta-analyses^18,19  concluded that pregabalin was associated with significantly reduced postoperative pain score both at rest and with movement, as well as significantly reduced opioid consumption at 24 h postsurgery compared with placebo.

Although gabapentin and pregabalin may have acute analgesic and antihyperalgesic properties in a postsurgical setting,^20,21  they are associated with undesirable side effects, such as sedation,¹⁹  dizziness, visual disturbance,^22,23  and cognitive dysfunction.²⁴  In addition, a respiratory depressive effect of pregabalin has been proposed in one case series,²⁵  but no studies have examined this effect by using validated methods. To prove their utility in the perioperative period, the combination of opioids and gabapentinoids must demonstrate that the combination of the two drugs provides superior analgesia than either drug alone. Furthermore, the combination should be shown to be beneficial compared with higher doses of the opioid alone, and analgesic-related side effects should be reduced.

Drug combinations can most easily be studied in healthy volunteers. Validated methods for examining analgesia,²⁶  ventilation,²⁷  and cognitive function^28,29  exist and can be repeated within the same subject, thus increasing the statistical power.

The aim of this experimental crossover study in healthy volunteers was to examine the analgesic effect of pregabalin, the short-acting opioid remifentanil,³⁰  and their combination compared with placebo. Moreover, the study aimed at exploring the effects of pregabalin and remifentanil on ventilatory and cognitive functions.

The study was performed at Oslo University Hospital, Oslo, Norway, between November 2011 and February 2012. Approval was obtained from the Regional Committee for Medical Research Ethics for Eastern Norway, Oslo, and the Norwegian Medicines Agency, Oslo. The study is registered at ClinicalTrial.gov (NCT01419405, principal investigator: A.S.; June 30, 2011) and was reported in accordance with recommendations in the CONSORT 2010 Statement for randomized trials.³¹ 

The participants were recruited by an open invitation to students at the University of Oslo. Twelve healthy adults (equal numbers of males and females), American Society of Anesthesiologists classification Ι, age 23 yr (range, 20 to 28 yr), and weight 67 kg (range, 54 to 87 kg), participated in the study after written consent had been obtained. None of the participants had any known drug allergies or used any type of medication before or during the study. A history of alcohol or drug abuse was an exclusion criterion. All participants completed the study as planned, without dropouts or interfering medications.

This was a randomized, double-blind, placebo-controlled complete crossover study with four treatments: (1) pregabalin + remifentanil, (2) pregabalin + placebo, (3) placebo + remifentanil, and (4) placebo + placebo. Every participant received all four treatments in a randomized sequence, and each of the four treatments was administered on 4 different days. An investigator with no clinical involvement in the study prepared a computerized randomization list of the four treatment sequences A–D using block randomization. The block size was four or eight after randomization. The block size and randomization code were unknown to the investigators, and the treatment allocation was concealed in opaque, sealed, and sequentially numbered envelopes. The participants were assigned to the next consecutive participant number and provided with corresponding study medication. The randomization was not revealed to the investigators (M.M. and A.S.) before all measurements were conducted and entered into a database. To balance any possible period effects and carryover effects, a variance-balanced reduced Latin square design was used. This Latin square ensured that all subjects received all of the treatments, each treatment appeared an equal number of times in each period, and each treatment was followed by the same treatment an equal number of times.³²  Carryover effects were minimized by maintaining a consistent washout time of 72 h between two treatments, which corresponds to 11 times the elimination half-life (t_½ mean = 6.3 h)³³  of pregabalin, which was considered to be sufficient to ensure appropriate washout.³⁴ 

Pregabalin 75-mg capsules and placebo capsules of identical appearance were produced by Oslo University Pharmacy, Oslo, Norway, and the capsules were prepacked in numbered and identical containers according to the randomization list and labeled with study information. Two nurses, who were not otherwise involved in the study, prepared 60-ml syringes of remifentanil 20 μg/ml (Ultiva^®; GlaxoSmithKline, United Kingdom) or placebo (saline) immediately before administration and consistent with the treatment allocation. The prepared syringes had an identical appearance and were marked with the corresponding patient number and neutral study information.

Thirteen hours before the start of the trial, two capsules, each containing 75 mg of either pregabalin (a total of 150 mg) or placebo, were swallowed whole with a sip of water. The same dose of two capsules, each containing 75 mg of either pregabalin (a total of 150 mg) or placebo, was then repeated 1 h before the trial started. Food intake was restricted for 3 h before the start of the trial. By arrival, two IV cannulas were inserted, and an infusion of Ringer’s acetate solution at a rate of 30 ml/h was started. Remifentanil or placebo was applied as a target-controlled infusion (TCI) (effect-site TCI, Minto model and Alaris^® PK Syringe Pump; CareFusion, United Kingdom)³⁵  with increasing concentrations of 0.6, 1.2, and 2.4 ng/ml (TCI levels 1 to 3), with each level being maintained for approximately 40 min. This model takes into consideration the effect of age, sex, and lean body mass on pharmacokinetic parameters of remifentanil. To minimize the possible abrupt side effects such as hemodynamic instability, dizziness, or nausea and to reduce unblinding, the infusion rate was increased in a standardized stepwise manner over 2 min to reach the next level. During each study day, cognitive tests, ventilatory measurements, and experimental pain tests were performed four times. The first test was conducted approximately 1.5 h after the last oral medication but before the remifentanil/placebo infusion was started (level 0 = baseline), and then the tests were repeated at each TCI level 0.6 to 2.4 ng/ml (levels 1 to 3).

First, cognition was examined with tests designed to measure executive functions and the ability to sustained attention. The Delis-Kaplan Executive Function System Color-Word Interference Test (CWIT)²⁸  is a test for inhibition and attention and consists of four parts: basic naming of color patches, basic reading of color words printed in black ink, inhibition of reading the words through naming dissonant ink colors in which those words are printed (Color-Word Interference), and switching between naming dissonant ink colors and reading the words (Color-Word Interference and switching). A total completion time and number of errors were calculated for all tests. The Rapid Visual Processing (RVP) test is a subtest from the Cambridge Neuropsycological Test Automated Battery (Cambridge Cognition, United Kingdom).³⁶  The test is measuring the ability to sustained attention and information processing. Two outcome variables were recorded: the RVP A’ as a measure of sensitivity to the target based on the probability of correct hits and false alarms (0.00 to 1.00; bad to good) and the RVP mean latency defined as the mean time taken to respond within the response window of 1,800 ms.

Second, ventilatory function was measured by spirometry (Vmax Spectra 229^®; SensorMedics Corp., USA). The device consisted of a facial mask, a mass flow sensor, and a nonrebreathing circuit with a low-resistance breathing valve. The mass flow sensor was calibrated daily and before every new participant with a 3-l syringe and against a standardized test gas (16% O₂ and 4% CO₂) according to the manufacturer’s instructions. While sitting in a semiupright position with the facial mask carefully adjusted, the participants were requested to relax and breathe normally. Respiratory frequency, minute volume, and end-tidal carbon dioxide (ETco₂) tensions were automatically recorded. ETco₂ was used as main ventilatory parameter as this parameter is highly correlated to ventilation and all other ventilatory parameters. Furthermore, ETco₂ is mostly used in clinical practice. The participants were connected to the nonrebreathing circuit for approximately 10 min, and ventilatory data, considered representative from a 2-min period, were used for further analyses. For participant safety, peripheral capillary oxygen saturation was maintained above 90% by adding oxygen to the inhaled air. In cases of apnea periods greater than 15 s and significant oxygen desaturations to less than 92%, the participants were asked to take a deep breath, and additional oxygen was provided.

Finally, acute experimental pain was induced using a standardized cold pressor test (CPT). A refrigerated circulator (Julabo FP40-HE; Julabo Labortechnik GmbH, Germany) connected to a 13-l external custom-made Plexiglas (Evonik Industries AG, Germany) container was used providing a water temperature of 3.0° ± 0.01°C. The water temperature in the external container was calibrated with a precision thermometer, and the pump flow rate was 22 to 26 l/min. The subjects were asked to submerge their nondominant arm to the wrist into the water bath, holding the hand motionless and with fingers spread, for a maximum of 120 s. Pain was rated on a computerized visual analog scale (VAS) consisting of a vertical bar on a computer screen becoming red when the participants were scrolling the cursor with their dominant hand. The numeric value of the pain score, ranging from 0 mm (= no pain, lower anchor) to 100 mm (= unbearable pain, upper anchor), was hidden from the participants and was directly captured by the custom-made software. The pain score was reported every 10 s for a total of 12 times during each test, and the average of the last three values was used for further analysis. If a participant had to interrupt the CPT because of unbearable pain before the test was completed, the rest of the values were set to VAS = 100 mm. This was only the case in one of the subjects when treated with placebo + remifentanil (at TCI level 1) and placebo + placebo (at TCI levels 0, 1, 2, and 3).

At the end of each treatment, the participants were asked to specify side effects such as sedation, nausea, dizziness, pruritus, and headache. All test procedures were performed in the same manner at each level of remifentanil or placebo infusion. The cognitive tests started 10 min after change of TCI level, followed by spirometry, whereas CPTs started approximately 35 min after change in target level. Throughout the study, the participants were monitored with 3-lead electrocardiography, noninvasive blood pressure, and peripheral pulse oximetry. A written procedure describing how to handle adverse events, including a detailed list of rescue medications as well as predefined interruption criteria, was familiarized by all investigators.

The primary outcome was the mean of the three last VAS scores (0 to 100 mm) during the CPT. Secondary outcomes were the ETco₂ (mmHg), scores from cognitive tests, and side effects.

The sample size was calculated using the software nQuery Advisor^® Version 7.0 (Statistical Solutions, Ireland). We expected an average difference of 10 in pain intensity (VAS, 0 to 100 mm) between treatment groups. To compensate for six pairwise comparisons, the α level for the sample size calculation was set at 0.008 (Bonferroni correction). At least 12 subjects in total were required to demonstrate the difference with a power of 0.80 assuming an SD of 8.0 for the difference and no dropouts.

The mean and SD or median and ranges were given for normally and nonnormally distributed variables, respectively. Estimations of effect and differences between treatment group effects over infusion levels were examined using linear mixed random intercept models with pain intensity, ventilatory, and cognitive data as dependent variables. Treatment groups, infusion levels, and treatment-by-level interactions were defined as fixed effects, whereas subjects were treated as a random effect, and a compound symmetric correlation structure was assumed. A test for period effects was performed. The means and SDs from descriptive analysis were used to create figures 1–3. Two-sided P values corrected for multiple comparisons (Bonferroni adjusted) are presented. The significance level was set to 0.05.

Additivity of drug effects on analgesia was tested. For each individual subject, the differences between placebo and each active treatment group (pregabalin, remifentanil, and the combination of pregabalin and remifentanil) were calculated. The sum of the calculated differences for pregabalin and remifentanil was then compared with the observed effect of the combination of pregabalin and remifentanil in a linear mixed random intercept model. Data analyses were performed with IBM SPSS Statistics 22 (SPSS Inc., USA).

Pain intensity during the CPT (mean VAS ± SD) for all treatment groups and dose levels is displayed in figure 1. Mean pain intensity (mean VAS) was 72 mm (95% CI, 62 to 83) after placebo capsules and placebo infusion. In a linear mixed model analysis with pairwise comparisons with subjects as random intercept, pregabalin reduced pain score by mean −10 mm (−14 to −7, P < 0.001) compared with placebo. Remifentanil alone had a dose-dependent analgesic effect compared with placebo, reducing VAS score by −11 mm (−18 to −5, P < 0.001) at level 1, −21 mm (−28 to −14, P < 0.001) at level 2, and −47 mm (−54 to −39, P < 0.001) at level 3. Pregabalin in combination with remifentanil reduced VAS score by −22 mm (−29 to −16, P < 0.001) at level 1, −42 mm (−49 to −35, P < 0.001) at level 2, and −57 mm (−64 to −50, P < 0.001) at level 3 compared with placebo. By pairwise comparisons, the combination of pregabalin and remifentanil significantly increased the analgesic effect compared with remifentanil alone, showing additive analgesic effect of pregabalin (fig. 1). The analgesic effect of the combination at TCI levels 1 to 3 did not differ from the theoretical sum of the individual drug effects of pregabalin and remifentanil (combination − calculated sum; mean, −1 mm; 95% CI, −10 to 8, P = 1.0).

Ventilatory effects were evaluated by ETco₂, respiratory frequency, and minute volume (fig. 2, A–C). Mean ETco₂ for placebo was 39.3 mmHg (95% CI, 37.2 to 41.3). Pregabalin alone did not change ETco₂ compared with placebo: 1.8 mmHg (−0.9 to 4.6, P = 0.4) at level 0, with minor changes on the other levels (fig. 2A). Remifentanil impaired all ventilatory parameters increasing ETco₂ by 4.1 mmHg (0.7 to 7.6, P = 0.013) at level 1, 8.6 mmHg (5.6 to 11.7, P < 0.001) at level 2, and 10.1 mmHg (4.9 to 15.4, P < 0.001) at level 3 compared with placebo. Pregabalin in combination with remifentanil increased ETco₂ by 6.6 mmHg (3.1 to 10.0, P < 0.001) at level 1, 11.7 mmHg (8.6 to 14.7, P < 0.001) at level 2, and 16.4 (11.3 to 21.5, P < 0.001) at level 3 compared with placebo. At level 3, this corresponds with a potentiation of the ventilatory depressant effect of remifentanil by 62% (95% CI, 10 to 113%; P = 0.012) caused by pregabalin.

Cognitive tests were evaluated based on the CWIT (completion time, number of errors) and RVP test (RVP mean latency, RVP A’) (fig. 3, A–D). Pregabalin increased the number of errors in CWIT compared with placebo (P = 0.004), whereas remifentanil increased the completion time (P = 0.029) and the RVP mean latency (P = 0.009) compared with placebo. Pregabalin + remifentanil impaired all tests significantly compared with placebo (fig. 3, A–D). By pairwise comparison between pregabalin + remifentanil and placebo + remifentanil, there was no difference between the groups, except for increased number of errors when pregabalin + remifentanil was administered (P < 0.001).

The numbers of side effects in each treatment group are provided in table 1. In both groups receiving remifentanil, there were increased incidences of sedation, dizziness, and nausea compared with the placebo, and antiemetic drugs (metoclopramide and ondansetron) only had to be used when remifentanil was administered. When pregabalin was added to remifentanil, only minor differences were observed in the reported side effects compared with remifentanil alone. Pregabalin caused an increased number of side effects compared with placebo. Sedation and dizziness were reported in 75% of the cases in the pregabalin group compared with 42 and 25%, respectively, in the placebo group. There was no significant period effect between the treatments or visits (P > 0.05).

In this experimental placebo-controlled crossover study, we investigated the analgesic, ventilatory, and cognitive effects of pregabalin alone, remifentanil alone, and their combination. The main findings were significant additive analgesic effect and potentiated respiratory depressive effect when pregabalin and remifentanil were administered together. Furthermore, cognitive performance was significantly reduced by the combination of pregabalin and remifentanil, whereas inconsistent with either drug alone.

We chose to study the analgesic, ventilatory, and cognitive effects of pregabalin and remifentanil because the combination of opioids and pregabalin is of specific interest in the perioperative setting and has been implemented in several clinical protocols³⁷  although systematic reviews have shown conflicting results.^16,38  In this study, we found a small analgesic effect of pregabalin 150 mg × 2 compared with the placebo on acute cold pressor pain. Furthermore, when pregabalin and remifentanil were combined, the results showed additive analgesic effect with significant reduction in pain intensity on every TCI level compared with remifentanil alone. By adding pregabalin, comparable analgesia was achieved with an approximately 50% reduction in remifentanil dose, which can definitely be considered clinically significant.

In a previous study on cold pressor pain,³⁹  a single dose of 600 mg gabapentin combined with 60 mg oral morphine significantly increased the pain tolerance time with 76% compared with baseline, whereas morphine alone increased the pain tolerance time with 41%. Gabapentin alone did not increase the tolerance time significantly. The smaller analgesic effect of gabapentin alone compared with the significant effect of pregabalin alone in our study may be due to the different methods of pain assessment used. In the previous study, the CPT was evaluated by pain tolerance time. We assessed pain using the VAS,⁴⁰  which provides a continuous picture of pain intensity and is a sensitive method for evaluating pain.

The ventilatory effects were investigated in a non–steady-state model, measuring the effect of the drug on ETco₂ and on ventilation, without external manipulation of the inhaled carbon dioxide concentration (closed-loop system).^27,41  Pregabalin alone did not change ETco₂ significantly at any TCI level, whereas remifentanil had a dose-dependent ventilatory depressant effect. When pregabalin was added to remifentanil, the combination revealed a significant increase in ETco₂ compared with remifentanil alone. At the highest TCI level (2.4 ng/ml), pregabalin + remifentanil increased the ventilatory depressant effect by 62% compared with remifentanil alone. These results show that pregabalin, similar to other sedatives such as propofol and benzodiazepines,^42,43  potentiates the ventilatory depressant effects of opioids.

In one clinical case series,²⁵  pregabalin was associated with respiratory depression in combination with opioids, and higher age, renal failure, and obstructive apnea syndrome were noted as relative contraindications for administering pregabalin in the perioperative setting. Our results show that the enhancement of the ventilatory depressant effect is present even in young, healthy subjects. A recent study⁴⁴  investigating pregabalin abuse in postmortem toxicology found that pregabalin was most commonly abused in combination with opioids. The authors suggested that profound central nervous system depression with possible respiratory failure could cause overdose-related deaths with pregabalin, particularly when coadministration with opioids occurred, thus indicating a potential interaction between opioids and pregabalin.

The cognitive tests were moderately affected by pregabalin, only increasing the number of errors in the CWIT, as a measure of impaired cognitive performance. The moderate effect of pregabalin alone on cognitive function in the current study is in accordance with comparable studies in healthy volunteers.⁴⁵  Remifentanil impaired the completion time (CWIT) and the mean latency (RVP) significantly, thus confirming results from earlier studies^46,47  indicating reduced psychomotor speed. However, the combination of pregabalin and remifentanil impaired all tests significantly compared with placebo and affected all cognitive tests numerically more extensively than each single drug alone. These effects on cognition may be of importance in the perioperative period, where delirium is a common risk factor for poor outcome, especially in elderly patients.⁴⁸ 

Side effects were recorded after every treatment. Sedation and dizziness were more commonly reported when pregabalin was administered compared with placebo, thus confirming findings from other clinical studies.^18,49  Remifentanil alone increased sedation, nausea, and dizziness significantly compared with placebo, whereas the combination of pregabalin and remifentanil only showed minor differences in side effects compared with remifentanil alone.

In this study, we chose to administer pregabalin 150 mg × 2 based on perioperative studies favoring 150 to 300 mg pregabalin daily.^50,51  A recent meta-analysis found consistent opioid-sparing effect with single doses of pregabalin from 75 or greater to 300 mg.¹⁹  In addition, a Cochrane review reported high incidence of side effects (68%) and 4% serious adverse events after a single dose of 300 mg pregabalin.¹⁶  Thus, our choice of 150 mg × 2 may be relevant for the perioperative period. In a study reported by Buvanendran et al.,⁵²  the maximum cerebrospinal fluid concentration of pregabalin was achieved as late as 8 h after an oral dose. We administered pregabalin 13.5 and 1.5 h before conducting the first CPT to optimize the drug concentration in the central nervous system. Such repeated dosing regimens is often used perioperatively.

Remifentanil, a strong and short-acting μ-agonist, was applied as opioid to achieve rapid onset of action and allowing for immediate changes between infusion levels.³⁰  The target concentration of remifentanil was set at TCI of 0.6 to 2.4 ng/ml. These concentrations are comparable to the steady-state infusion of 0.025 to 0.1 μg·kg⁻¹·min⁻¹⁵³  and have been shown to be relevant for early postoperative analgesia and superior to 10 to 20 mg IV morphine in the immediate postoperative setting.⁵⁴ 

There are some limitations to this study. First, the study protocol did not include blood sampling and measurements of plasma drug concentrations. This means that, although unlikely,⁵⁵  a pharmacokinetic interaction between pregabalin and remifentanil cannot be ruled out. Second, we examined only one dose of pregabalin. Thus, no formal analysis of interaction between pregabalin and the opioid could be done, and our results cannot be extrapolated to other doses of pregabalin. Third, the ventilatory tests were conducted separately from the CPT and consequently not influenced by pain. Although this procedure allowed for perfect conditions to study the physiological effects of the drugs alone, it differs from the clinical reality, where patients are simultaneously influenced by both drugs and pain in addition to several other factors. Finally, the level of anxiety was not measured in our study, but anxiety may influence pain. Pregabalin has well-known effects in the treatment of general anxiety disorders⁵⁶  as well as in preoperative anxiety; hence, theoretically pregabalin may lead to lower pain scores due to an effect on anxiety. However, in a study investigating the effects of midazolam, an even stronger anxiolytic agent than pregabalin, doses up to 3 mg administered intravenously, did affect mood and psychomotor speed but not sensory and affective components of the cold pressor pain experience.⁵⁷  The same group found that midazolam did not enhance fentanyl analgesia in the same model.⁵⁸  This suggests that the severe CPT pain experience may be less affected by mood than other pain experiences and that the analgesia we observed after pregabalin is a pure analgesic effect not mediated by anxiolysis.

Taken together, our experimental human data show that the combination of pregabalin and the opioid remifentanil has additive analgesic effect. However, the results also reveal that pregabalin potentiates the ventilatory depressant effects of remifentanil and that the combination also affects cognitive function negatively. These results question the clinical benefit of the combination compared with higher doses of the opioid alone. Improved analgesia or reduced opioid consumption must be weighed against patient harms. Our findings raise serious concerns about the increasing use of pregabalin as an analgesic adjunct without strong evidence for improved recovery and overall patient benefit.

The authors thank Harald Breivik, M.D., D.Med.Sci. (Prof. Emeritus, Department of Pain Management and Research, Division of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway), and Luis Romundstad, M.D., Ph.D. (Department of Anesthesiology, Division of Emergencies and Critical Care, Oslo University Hospital), for generous support and advice, and Linda M. Pedersen, Ph.D. (Department of Pain Management and Research, Division of Emergencies and Critical Care, Oslo University Hospital), for skilled laboratory assistance. The authors also thank the intensive care nurses Bente Heide, Grete Sand, and Øystein Fahre (all affiliated with the Department of Intensive Care Medicine, Division of Emergencies and Critical Care, Oslo University Hospital) for excellent drug handling, and Leiv Arne Rosseland, M.D., Ph.D. (Department of Anesthesiology, Division of Emergencies and Critical Care, Oslo University Hospital), for assistance with randomization.

Dr. Myhre received research scholarship from University of Oslo, Oslo, Norway, and economic support for this study from Inven2 (www.inven2.no), which is a nonprofit research organization owned by Oslo University Hospital.

The authors declare no competing interests.

Full protocol available at: marianne.myhre@medisin.uio.no. Raw data available at: marianne.myhre@medisin.uio.no.