Pain on injection of propofol is a common problem, the cause of which is obscure and there are several proposed mechanisms. The incidence of pain varies between 28% and 90% in adults during induction of anaesthesia . Pain after injection of propofol is thought to be caused by direct stimulation of venous nociceptive receptors or free nerve endings, the nerve impulse being transmitted by thinly myelinated A delta fibres . The chemical mechanism for the pain may be due to direct irritation via the release of kininogens when propofol comes into contact with the vascular endothelium .
Peripheral gustatory information is transmitted from the taste buds to the central nervous system primarily by cranial nerve VII (facial) and cranial nerve IX (glossopharyngeal). Although its exact location is debated, the human primary gustatory area is located within the insula/frontal and/or parietal operculum in the heteromodal paralimbic cortex [4,5]. The precise location of the secondary gustatory area also remains uncertain, but it is likely to be in the orbitofrontal heteromodal paralimbic cortex [5,6]. The location of the cortical gustatory areas within the paralimbic cortex suggests that sensory and affective processing of taste are highly integrated. Taste-responsive neurons have also been described in the amygdala . Many of these same regions are activated in response to pain [8,9]. Pain and taste may interact in these brain regions.
It is possible that there is a general tendency to react strongly to bitter taste and propofol-induced pain (two chemical stimuli) in the body. Therefore, there may be a correlation between bitter sensitivity and propofol-induced pain. In this study, we tested the hypothesis that increasing bitter sensitivity would increase intensity or incidence of pain associated with propofol and we also investigated whether there is a relationship between bitter sensitivity and venepuncture pain.
The study was approved by the Ethics Committee of our institution, and written informed consent from each patient was obtained before surgery. We included 100 patients (50 males and 50 females), ASA Grade I, unpremedicated, aged 18–35 yr, undergoing elective surgical procedures. Patients having difficulty in communication, smoking, abnormalities or illnesses affecting the oral cavity, subjective symptoms of taste or smell disorder or difficulty in venous access were excluded from the study.
For testing bitter taste threshold, the subjects were prohibited from eating or drinking 2 h prior to the start of testing. The taste-threshold measurements were performed by one person. Determination of the taste thresholds employed a series of 11 propylthiouracil (PTU) (Dr F Frik ilac san, Istanbul, Turkey) solutions, in concentration range from (solution 11) 0.0025% to 0.08% (solution 1) PTU in deionized water. The filter paper disk (FPD) method was used to measure the taste threshold in the study . We tested bitter sensitivity over the left side of the base of tongue. Patients were blinded to the type of taste tested. For bitter taste test, the examiner picked up a 8 mm FPD with forceps, dipped it into the lowest concentration of the taste solution and applied the moistened FPD to the locus to be tested. To measure taste over the locus, the disk was placed carefully to avoid a gag reflex. This was achieved by asking the patient to open his/her mouth wide, and then to hold the tongue to the right. If the patient did not identify bitter taste correctly the same process was repeated for the appropriate solution of the next highest concentration. The first concentration at which the patient was able to correctly identify the taste was considered the recognition threshold for bitter taste.
On arrival at the operating theatre, a 20-G intravenous (i.v.) cannula was inserted in the dorsum of the non-dominant hand after placing the routine monitors. The patients were asked to report the pain intensity at the moment of venepuncture. This was assessed by using a numerical rating scale (NRS; 0 (no pain) to 10 (extreme pain)).
The induction of propofol (propofol 1% Fresenius Kabi, Hamburg, Germany) was 2.5 mg kg− 1. About 10 mL propofol (at room temperature) was injected over 30 s. Other investigators, who were unaware of the patients' bitter taste threshold, assessed the level of pain. Intravenous propofol induction of anaesthesia was completed with the remaining dose of propofol and tracheal intubation was facilitated with vecuronium. Anaesthesia was maintained with 40% O2 in N2O, sevoflurane and fentanyl.
The severity of propofol injection pain was evaluated using a 4-point scale . Expression of pain by strong vocal response or response accompanied by facial grimacing, withdrawal of arm or tears was scored as 3 (severe pain). If these signs and symptoms were absent, then patients were questioned every 10 s during induction regarding the presence of pain or discomfort. Negative response to questioning was scored as 0 (none). Pain reported in response to questioning only, without any behavioural signs was scored as 1 (mild pain). Pain reported in response to questioning and accompanied by a behavioural sign, or pain reported spontaneously without questioning was scored as 2 (moderate pain).
Data were expressed as mean ± standard deviation or number (%). Statistical analysis was performed using the GraphPad InStat software (GraphPad Software Inc, San Diego, CA, USA). The NRS was analysed by the U-test. χ 2 analysis was used to compare propofol pain score and PTU threshold between females and males. Pearson correlation analyses were used to compare associations between PTU threshold and propofol pain score or NRS. All tests were considered significant at P < 0.05.
Patient characteristics, incidence and severity of pain on injection of propofol are shown in Table 1. Figure 1 shows the bitter taste threshold and the intensity of propofol pain. There was a statistically significant association between bitter sensitivity and propofol injection pain (Fig. 1) (r = −0.52, P < 0.0001). Propofol pain injection scores were similar between males and females (Table 1, P = 0.4). The bitter taste threshold was also similar between genders (Fig. 2, P = 0.13).
The NRS score of venepuncture pain was 2.8 ± 1.5 for all patients and 3.1 ± 1.6 for females and 2.4 ± 1.3 for males. The differences between genders were statistically significant (P = 0.029). Figure 3 shows the relationship between the bitter taste threshold and venepuncture pain. There was statistically significant, mild association between the bitter taste threshold and venepuncture pain (r = −0.338, P = 0.0007).
In this study, we demonstrated that increased bitter taste sensitivity correlated with increased, propofol injection pain scores and NRS of venepuncture pain.
Taste is the sensory modality mediated by the chemoreceptors of the tongue, mouth and pharynx. Taste should be distinguished from flavours, which includes the olfactory, tactile and thermal attributes of food in addition to taste. The taste chemoreceptors are sensitive to dissolved chemicals, both organic and inorganic. The lowest concentration of a substance that can be discriminated is the threshold concentration of that substance. Increasing the area of the tongue exposed to solution reduces the threshold concentration. The FPD method was used to measure the bitter taste threshold in our study because this method provides a constant intensity and range of stimulation.
Many studies have evaluated thresholds for taste at various loci of the oral cavity [10,12,13]. The differences of the results obtained in these studies are partly due to differences in the loci and methods of measurement. Specifically, it has become widely accepted that the base of the tongue is highly sensitive to bitter taste. However, placing anything on the centre of the base of the tongue tends to elicit the gag reflex. We therefore tested sensitivity on the left side of the base of tongue.
Several studies have examined the impact of smoking on taste threshold, but the results obtained were not consistent. No impact of smoking on taste sensitivity was detected in some studies [14,15]. In contrast, some studies found that smoking tends to increase the recognition threshold for taste [10,13,16]. Smokers were excluded from our study because the impact of smoking on taste thresholds was not manifest. The patients were not premedicated due to the data that using an opiate as premedication reduces the severity of propofol injection pain and using an opiate and a sedative reduces the incidence of pain [17,18].
Although there is no gender difference in the incidence of propofol injection pain, some studies found a difference in taste threshold by gender, whereas others did not [14,19,20]. We found no significant differences either in threshold at the tongue base for the bitter taste or in the incidence of propofol injection pain by gender. But the venepuncture pain sensation was higher in females. It is possible that females might have more sensitive emotional aspects of pain.
Most mammals consistently reject bitter tasting substances as unpalatable . Some theorists have suggested that the perceived unpalatability of bitter substance evolved to facilitate the rejection of naturally occurring poisons . Thus, there may exist quantitative or qualitative differences in brain responses to bitter substances related to other tastes. Given its role in recognizing and responding to potentially threatening stimuli, pain is one sensory experience essential for survival. Individuals born without the ability to perceive pain frequently die from injuries and infections they had never felt . Pain is highly distributed across a diverse area of functionally distinct brain regions . This organization provides a neurophysiological basis for the high degree of covariance between discrete aspects of the pain experience (i.e. feature extraction, affective, attentional, motor components) and perceived pain intensity. The distributed processing of pain intensity within the human brain ensures this critical ability to detect tissue injury. Chronic back pain is associated with brain volume and regional density decreases in the thalamus and prefrontal cortex . The heightened sensitivity to taste is observed in chronic back pain patients. It is possible that thalamic atrophy associated with chronic back pain also leads to disinhibition in the gustatory areas .
Burning mouth syndrome is an oral pain disorder occurring primarily in post-menopausal females and is frequently accompanied by taste complaints. A study suggests that pain pathway activation may affect neural and behavioural taste function in burning mouth syndrome .
These findings suggest a relation between pain and bitter taste at specific brain sites. In conclusion, our results show that increased bitter taste sensitivity is associated with increased intensity or incidence of propofol injection pain and increased intensity of venepuncture pain.
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