Introduction

Opioids are essential in the treatment of moderate to severe pain [1], but also induce debilitating nausea and vomiting. Opioid-induced nausea and vomiting (OINV) occurs in a third of all patients treated with morphine-equivalents [2] and is one of the main reasons for post-operative nausea and vomiting (PONV) [3]. PONV is a significant factor in complications such as pulmonary aspiration, dehydration, and electrolyte imbalance, delaying discharge and leading to hospital admission after ambulatory surgery, which greatly increases health care cost [4]. PONV negatively impacts patient satisfaction [5] and patients even rank it amongst the most distressing non-life-threatening side effects [1].

The exact mechanism of OINV is still not clear. Opioids affect vestibular function, as demonstrated by a decrease in caloric response with morphine [6], a diminished active vestibulo-ocular reflex (VOR) with pethidine and fentanyl administration [7], vestibular dysfunction with heroin abuse [8], and decreased semicircular canal function, measured by the VOR gain, during administration of the short-acting μ-agonist remifentanil [9,10]. Opioid receptors are present within the VOR-three-neuron arc [11,12] and in the cerebellum [13], and could mediate the changes in vestibular-ocular motor function (VOR gain). Additional oculomotor findings during opioid administration, such as gaze-evoked nystagmus, saccadic smooth pursuit and, in particular, downbeat-nystagmus, point to cerebellar involvement [7,9].

Importantly, we demonstrated that head movement greatly exacerbates nausea during administration of the opioid remifentanil, while resting protects from it [9,14]. We suggested that the change in semicircular canal input during remifentanil administration leads to a mismatch between this information and that of other sensors when the head is moved, triggering nausea and vomiting [9].

To understand the role of visual input for this mismatch and, practically, to assess whether, in addition to avoiding head movement, it makes sense to close the eyes to decrease OINV, we examined motion-dependent nausea during opioid administration with and without vision.

Materials and methods

Experimental conditions

Subjects were divided into two subgroups of equal age (26.4±3.5 and 27.3±3.6 years, mean±SD), motion-sickness-susceptibility score (assessed by the Motion Sickness Susceptibility Questionnaire, MSSQ-Short [15], 5.9±9.2 and 5.9±5.8 points) and postoperative-nausea-and-vomiting risk [3] (20±9.7% and 22±8.5%). In a crossover design, each subject was tested twice with at least one-day washout. Seven subjects were first tested “blindfolded,” then “eyes-open”, and vice-versa. In the condition “blindfolded”, subjects wore eye patches for the entire duration of the experiment. They were resting in a semi-recumbent position during 60 minutes of remifentanil administration (Fig 1A). After remifentanil had been administered for 30 minutes, subjects were bent forward and backward ten times at a frequency of 1 Hz. The condition “eyes-open” was the same as the “blindfolded” condition, but the subjects were not blinded and were encouraged to keep their eyes open.

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Fig 1.

A. Experimental design (crossover study). Subjects rested in a semi-recumbent position while remifentanil was continuously administered intravenously. After 30 minutes, subjects were bent forward and backward ten times at a frequency of 1 Hz (“Move”) after which they rested again for 30 minutes. Nausea was assessed on a numerical scale from 0 (no nausea) to 10 (vomiting) before the remifentanil infusion (T₀), during the 30 minutes of rest with remifentanil administration (T₃₀), and during the 30 minutes (T₆₀) after the movement intervention. The study contained two conditions: in the “blindfolded” condition subjects wore an eye patch during the entire duration of the experiment, while in the “eyes-open” condition subjects were encouraged to leave their eyes open. In a crossover design with at least one-day of washout, seven subjects were first tested with the condition “blindfolded” and then “eyes-open”, and vice versa. B. Effects of movement on nausea during remifentanil administration with and without visual input. Median (horizontal line), interquartile range (box) of nausea values quantified on a numerical scale from 0 (no nausea) to 10 (vomiting) in conditions “eyes-open” (white) and “blindfolded” (grey). Crosses designate outliers (outside 75-percentile + 1.5x interquartile range). Whiskers extend to the closest data value not considered an outlier. Data from the two subgroups of the crossover design was pooled, as there was no difference between the subgroups in all conditions (all p>0.20). During rest, nausea ratings did not differ at any time point (T₀, T₃₀ of both conditions; all medians zero, p = 0.26). Movement led to a marked increase in nausea (difference between T₀, T₃₀, and T₆₀, “blindfolded”: p = 0.012, “eyes-open”: p<0.001), independently of visual input (no difference between nausea ratings at T₆₀ in the "blindfolded" and "eyes-open" condition, p = 0.25)

https://doi.org/10.1371/journal.pone.0173925.g001

Subjects rated nausea on a scale from zero (no nausea) to ten (vomiting) before receiving remifentanil (T₀), after the period of 30 minutes rest (before being moved, T₃₀) and after the 30 minutes following the movement intervention (T₆₀). Maximal ratings for each period were analysed.

Results

Nausea ratings did not differ between the subgroups for each time point (T₀, T₃₀, T₆₀). Therefore they were independent of the order of the conditions (all p>0.20), and consequently, data for both subgroups of the crossover design were pooled. Fig 1B shows nausea ratings for the “eyes-open” and the “blindfolded” conditions at rest (T₀, T₃₀) and during the 30 minutes after the movement intervention (T₆₀). At rest, nausea ratings did not differ for all times T₀ and T₃₀ of both conditions (all medians zero; χ²(3) = 4.0, p = 0.26). Comparison of T₀, T₃₀, and T₆₀ within the conditions revealed that movement triggered nausea in both conditions (“blindfolded”: χ²(2) = 8.9, p = 0.012, “eyes-open”: χ²(2) = 16.7,p<0.001). Nausea ratings during T₆₀ did not differ between the conditions (χ²(1) = 1.3, p = 0.25, “eyes-open” 2.5/6.0 (median/interquartile range), “blindfolded” 1.5/3.0).

Discussion

Nausea during remifentanil administration was triggered by movement and avoided by rest in all subjects independently of visual input. This suggests that vision is not the major cause for an inter-sensory mismatch with semicircular canal input during head motion.

Remifentanil reversibly affects vestibulo-ocular reflex function, as measured by the VOR gain of the horizontal semicircular canals [9,10]. This altered information could clash with neck proprioception or other vestibular sensory information. An intra-vestibular mismatch between reduced horizontal semicircular canals [9] and not accordingly altered otolith signals seems likely. Such an intra-vestibular mismatch is acknowledged as a causative factor for seasickness (for review, see Bertolini&Straumann, 2016 [16]) and also seems to provoke space sickness where altered otolith signals in weightlessness clash with regular semicircular canal input [17].

Our study confirms the head-motion dependence of OINV with a striking median of zero on the nausea scale during rest in all conditions. As in our prior work, the incidence of OINV in our study (57/64% or 8/9 out of the 14 subjects in the “blindfolded”/“eyes-open” conditions) is higher than that predicted by the standard risk score[3] for post-operative nausea and vomiting (21±9%, mean±SD or 3/14). This is possibly because the risk score does not control for head movement, i.e., not all patients included in the calculation of the score might have experienced perioperative movement interventions similar to the ones in our study. It should be noted that there is a limitation to the interpretation of this exploratory approach due to the relatively small sample size and the fact that only men were tested.

In conclusion, our study suggests that an intra-vestibular, and not a visual-vestibular, mismatch that becomes apparent during movement exacerbates OINV. Resting thus protects from OINV, while closing the eyes appears less important. Understanding this mechanism will improve pain management with opioids. In clinical practice, especially during transient opioid application, OINV could be reduced by avoiding head movement, e.g. with a head immobilizer peri-operatively.

Acknowledgments

We thank Judy Benson for copy-editing the manuscript.