Correspondence to: Dr G. E. Boeckxstaens, Department of Gastroenterology and Hepatology Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands. E-mail: email@example.com
Background : The use of N-methyl-d-aspartate (NMDA) receptor antagonists may hold promise for the treatment of pain of visceral origin, in particular in conditions characterized by visceral hypersensitivity.
Aim : To study the effect of dextromethorphan, a low affinity, non-competitive NMDA receptor antagonist, on visceral perception in healthy volunteers.
Methods : Nine healthy volunteers (5 female, median age 22 years) underwent a gastric barostat study after oral administration of placebo, dextromethorphan 10 mg or dextromethorphan 30 mg, on three separate days in a double-blind, randomised order. Sensations induced by step-wise isobaric gastric distension (2 mmHg/2 min) were studied during fasting and 30 min after a meal. In addition, proximal gastric tone was measured during fasting and postprandially.
Results : Compared to placebo, dextromethorphan 30 mg significantly increased the distension-evoked sensation scores for nausea (P=0.004) and satiation (P=0.004) during fasting; and for bloating (P= 0.001), nausea (P=0.000) and satiation (P=0.01) 30 min postprandially. Dextromethorphan did not alter pain scores, proximal gastric tone or gastric compliance.
Conclusions : Dextromethorphan increases the perception of non-painful sensations during gastric distension, without altering the perception of pain. Therefore, application of dextromethorphan as a visceral analgesic is questionable. Future studies with more specific NMDA receptor antagonist are warranted.
Functional bowel disorders (FBDs) are characterized by chronic abdominal pain or discomfort, often associated with abnormal motility, in the absence of any detectable organic cause.1 The most frequent of these disorders are the irritable bowel syndrome and functional dyspepsia. Although there is no single mechanism responsible for the development of FBDs, it is generally accepted that visceral hypersensitivity may play a central role in the pathogenesis of these disorders.2,3 Visceral hypersensitivity could result from the sensitization of primary afferent fibres, or sensitization of dorsal horn neurones, a mechanism referred to as ‘central sensitization’.4,5 The search for specific drugs interfering at these levels, resulting in visceral analgesia, is therefore important in the development of new treatments for FBDs.
From a growing number of studies, there is evidence that N-methyl-d-aspartate (NMDA) receptors can play a fundamental role in the development of central sensitization.6,7 Chronic irritation, for example by tissue damage, causes the release of glutamate from afferent C-fibres, leading to a prolonged sensitization of spinal NMDA receptors to various afferent stimuli. This ‘wind-up’ causes the phenomenon that both noxious stimuli and physiological stimuli that are not normally perceived, can cause pain. Although these data are derived mainly from models of somatic pain, the concept also seems to be applicable to the development of visceral hypersensitivity. For example, in rats, the hypersensitive response to colorectal distension after the intrarectal administration of zymosan or turpentine was attenuated by NMDA receptor blockade.8,9 Moreover, although NMDA receptors only seem to play a minor role in acute somatic pain, there is evidence suggesting that both spinal and peripheral NMDA receptors are involved in the processing of afferent input from normal viscera. For example, NMDA receptors have been shown to mediate acute noxious stimulation of the ureter10 and the processing of both acute noxious and non-noxious colorectal distension.11,12 The application of drugs with NMDA receptor antagonistic properties may therefore hold promise for the treatment of pain of visceral origin in general, and in particular for states of increased visceral sensitivity, such as FBDs.
Dextromethorphan ((+)-3-methoxy-N-methylmorphinan) is a non-opioid anti-tussive agent that acts as a low affinity, non-competitive NMDA receptor antagonist.13 Clinical studies have shown that dextromethorphan can be used in the treatment of experimental models of acute pain and chronic neuropathic pain, although some studies show conflicting results.14–16 It is, however, a well known drug, with an excellent safety profile and dose-dependent adverse effects.17 Moreover, in contrast to other NMDA antagonistic agents such as ketamine, that are available for human use, it has the advantage that it can be administered orally. In the current study, we hypothesized that dextromethorphan, because of its NMDA-receptor antagonistic properties, can be used as a visceral anti-nociceptive drug. Therefore, we studied the effect of dextromethorphan on gastric perception in healthy volunteers, in a placebo controlled, randomised crossover fashion.
Materials and methods
Nine healthy volunteers were studied (4 male, 5 female, median age 22, range 19–36 years). All subjects were free of gastrointestinal symptoms, without previous gastrointestinal surgery and were not taking any medication. Subjects were studied during fasting and were not allowed to smoke or drink alcohol at least 24 h before the study. All volunteers gave their written and informed consent to participate in the protocol, which had been approved by the Medical Ethics Committee of the Academic Medical Centre (AMC), Amsterdam.
The barostat allows a continuous recording of proximal gastric volume at a fixed pressure level, which is an indirect measure of proximal gastric tone.18 In addition, perception of gastric distension can be assessed by inflating the intragastric barostat bag. Following anaesthesia of the throat (10% xylocaine spray) subjects swallowed a 1200 mL polyethylene bag, tightly wrapped on the distal and of a double lumen polyvinyl tube (Salem Sump tube, outer diameter 4 mm; Sherwood Medical, St Louis, MO). The balloon was unfolded by inflating it with 500 mL of air and positioned in the proximal stomach by gently pulling the catheter back. The catheter was connected to the barostat device that automatically corrected for the compressibility of the air (Medtronic Functional Diagnostics, Stockholm, Sweden). Intrabag pressure and volume were continuously recorded during the protocol and the data were stored on a personal computer, using commercially available software (Polygram for Windows, Medtronic Functional Diagnostics, Stockholm, Sweden). The minimal distending pressure (MDP) was determined as the minimum pressure at which intrabag volume was > 30 mL. This pressure equals the intra-abdominal pressure. Gastric distension was performed according to a step-wise, isobaric protocol, with an increment of 2 mmHg/2 min above MDP and an inflation rate of 38 mL/s. For measuring the fasting volume and meal-induced fundic relaxation, the baseline operating pressure was set at MDP + 2 mmHg.
Sensations evoked by gastric distension during fasting and 30 min following the ingestion of a standard test meal were evaluated. Individual sensations of bloating, nausea, pain and satiety were scored halfway along each distension step, using a 100 mm, continuous visual analogue scale (VAS: 0 mm=no sensation, 100 mm=worst ever).
To study the effect of the dextromethorphan on visceral perception, we assessed sensations evoked by distending the proximal stomach before and after meal intake. As changes in proximal gastric tone and gastric elasticity (or gastric compliance) may influence perception, we also wanted to be informed about the effect of dextromethorphan on fundic volume (i.e. fundic tone), meal-induced relaxation and the pressure-volume relationship during isobaric distension.
All subjects underwent three gastric barostat studies while receiving placebo, 10 mg dextromethorphan (DXM-10) or 30 mg dextromethorphan (DXM-30), on three separate days, at least two days apart, in a double-blind, crossover fashion. Dextromethorphan (SmithKline Beecham, Rijswijk, Netherlands) was administered orally. Because dextromethorphan reaches its peak plasma level after approximately 70–120 min,19 the subjects swallowed the study medication 60 min before the start of the study (t = −60 min), with 100 mL of tap water. Thirty min later, the barostat bag was introduced, unfolded and positioned in the proximal stomach. After an equilibration period of approximately 30 min at t=0, the MDP was determined and the baseline operating pressure was set at MDP + 2 mmHg. Intrabag volume was recorded for 15 min, followed by a step-wise isobaric distension with an increment of 2 mmHg/2 min, starting at the level of MDP. Sensations were assessed halfway along each pressure step. The balloon was deflated if the subject reported discomfort. Again, the operating pressure was set at MDP + 2 mmHg. Fifty min after the start of the first distension, at t=65 min, a liquid test meal with a caloric load of 300 kCal and a volume of 200 mL (Nutridrink, Nutricia, Zoetermeer, Netherlands) was consumed through a straw. Intrabag volume was recorded during the following 30 min. Subsequent to this, a second distension was started. Gastric sensation was assessed and the study was ended if the subject reported discomfort.
During gastric distension, individual sensation scores for bloating, nausea, pain and satiation were assessed halfway along each 2-min distension step. The pressure–sensation curve and the mean sensation scores during distension were analysed. The threshold for discomfort was defined as the distending pressure at which the subject reported discomfort. Gastric compliance was defined as the slope of the pressure–volume curve, as described previously.20 The pressure–volume curve was obtained by calculating the mean volume over the last 30 s of each distension step and plotting it against the corresponding distending pressure. Proximal gastric tone was measured by calculation of the mean intragastric bag volume over 15 min before ingestion of the test meal and over 30 min post meal. Proximal gastric relaxation, or delta V, was determined as the difference between the mean volume before and after meal intake.
Sensations induced by gastric distension were analysed using a repeated measures anova with Bonferroni adjustment for multiple comparisons. All other data were analysed using one-way anova with Bonferroni adjustment for multiple comparisons. Statistic evaluations were performed using a standard software package (SPSS 9.0, SPSS Inc. Chicago, IL). All data are presented as mean ± S.E.M. and P-values < 0.05 were considered statistical significant.
All subjects tolerated the study well, without any side-effects besides mild drowsiness. The number of subjects reporting mild drowsiness during the course of the study was two for placebo, two for DXM-10 and two for DXM-30. Both DXM-10 and DXM-30 did not alter reaction time, as assessed by means of a specially designed reaction measurement device (Reactometer, Department of Medical Physics, AMC Amsterdam, Netherlands; data not shown). Only one volunteer reported severe discomfort after the meal at the operating pressure of MDP + 2 mmHg while receiving DXM-30. The bag was therefore deflated, resulting in an immediate relief of symptoms. Consequently, during distension 30 min post-meal, the threshold for discomfort for this subject was MDP + 2 mmHg.
Sensitivity to gastric distension
At baseline, the subjects reported comparable scores for bloating, nausea, pain and satiation in all three groups (see Figure 1a–d, pressure=0 mmHg). DXM-10 did not alter any of the sensation scores, compared to placebo (Figure 1a–d). In contrast, DXM-30 significantly increased the mean scores for nausea during distension, compared to both DXM-10 and placebo (Figure 1b, P=0.03 and P=0.004, respectively) and significantly increased the slope of the pressure–sensation curve for nausea (Figure 1b,P=0.02). DXM-30 also significantly increased the mean scores for satiation during distension, compared to placebo, but not compared to DXM-10 (Figure 1d, P=0.004 and P=0.2, respectively). Scores for bloating and pain during distension were not significantly altered by dextromethorphan (Figure 1a,c). The threshold for discomfort induced by gastric distension was not significantly altered by dextromethorphan (see Figure 2a. Placebo: 14 ± 2 mmHg; DXM-10: 13 ± 1 mmHg; DXM-30: 13 ± 1 mmHg, P=0.6).
Thirty minutes after ingestion of the test meal, a second distension was performed. Again, at baseline, subjects reported comparable scores for bloating, nausea, pain and satiation in all three groups (see Figure 3a–d, pressure=0 mmHg). DXM-10 did not alter any of the sensation scores, compared to placebo (Figure 3a–d). DXM-30 significantly increased the mean scores for bloating, nausea and satiation during disten sion, compared to both DXM-10 and placebo (Figures 3a,b and 2d: bloating P=0.000 and P= 0.001, respectively; nausea P=0.004 and P=0.000, respectively; satiation P=0.003 and P=0.01, respectively). Pain scores were not significantly altered by dextromethorphan (Figure 3c). Although not statistically significant, there was a trend that DXM-30, but not DXM-10, decreased the threshold for discomfort induced by gastric distension postprandially, compared to placebo (See Figure 2b. Placebo: 15 ± 1 mmHg; DXM-10: 13 ± 1 mmHg; DXM-30: 10 ± 2 mmHg, P=0.07).
Proximal gastric tone, meal-induced gastric relaxation and gastric wall compliance
Dextromethorphan did not significantly alter fundic tone, expressed as mean intragastric bag volume, during fasting (see Figure 4. Placebo: 293 ± 30 mL; DXM-10: 222 ± 27 mL; DXM-30: 275 ± 52 mL, P= 0.4) and postprandially (placebo: 544 ± 60 mL; DXM-10: 518 ± 93 mL; DXM-30: 554 ± 108 mL, P=0.9). Proximal gastric relaxation upon meal intake was also not altered by dextromethorphan (placebo: 251 ± 52 mL; DXM-10: 296 ± 76; DXM-30 279 ± 76 mL, P=0.9).
Gastric wall compliance was not significantly altered by dextromethorphan both during fasting and postprandially (see Figure 5. Fasting: 61 ± 5, 63 ± 4 and 74 ± 8 mL/mmHg for placebo, DXM-10 and DXM-30, respectively, P=0.3; Postprandial: 53 ± 6, 60 ± 8 and 82 ± 25 mL/mmHg for placebo, DXM-10 and DXM-30, respectively, P=0.4).
In this study, we evaluated the effect of two low doses of the low affinity, non-competitive NMDA receptor antagonist dextromethorphan, on gastric perception, fundic tone and gastric wall compliance in healthy human subjects. We showed that dextromethorphan dose-dependently increased the perception of nausea and satiation during isobaric distension of the fasting stomach and the perception of bloating, nausea and satiation during gastric distension postprandially. Dextromethorphan did not alter the perception of pain during gastric distension. Proximal gastric tone and gastric wall compliance were also not altered. These findings question a role for dextromethorphan in the control of pain from visceral origin.
NMDA receptors have been shown to mediate acute noxious stimulation of the ureter10 and the processing of both acute noxious and non-noxious colorectal distension.11 In addition, it has been demonstrated that dorsal root ganglia neurones innervating the rat colon not only express NMDA receptors on their cell bodies, but also on their peripheral terminals innervating the gut wall.12 With a series of experiments, it was shown that single fibre responses of pelvic nerves to noxious colorectal distension were attenuated by the NMDA receptor antagonist memantine, indicating that peripheral NMDA receptors are involved in visceral nociceptive processing.12 In addition, NMDA receptors may participate in the processing of vagal afferent input from the stomach to the brainstem. Upon low threshold gastric distension in rats, NMDA blockade reduced activation of some subnuclei in the nucleus tractus solitarii (NTS) of the vagus nerve, but not in the NTS overall.21 Hence, these data suggest that pharmacological blockade of NMDA receptors may represent an interesting target to influence visceral perception.
Dextromethorpan is a well known low affinity noncompetitive NMDA receptor antagonist previously studied in pain syndromes from various origin, including acute, post-operative, chronic and neuropathic pain, with variable results. For example, pre-medication of a single dose of 30, 40 and 45 mg reduced post-operative pain.22,23 In chronic neuropathic pain, oral dextromethorphan reduced pain scores in patients with diabetic neuropathy (mean dose 381 mg/day), but not in post-herpetic neuralgia (mean dose 439 mg/day).24 Others found no benefit for dextromethorphan over treatment with placebo for neuropathic pain.25 Therefore, it is generally accepted that some but certainly not all patients with neuropathic pain respond to oral dextromethorphan.14
We chose to use two low doses of dextromethorphan, in order to avoid significant side-effects such as sedation, that may interfere with perceptive responses. It has previously been reported that in healthy subjects, 30 mg of oral dextromethorphan causes a significant reduction of citric acid induced cough, lasting up to 4 h, showing that the agent is indeed active at this dose. However, in our study, dextromethorphan increased rather than decreased visceral perception. The perception of non-painful sensations such as bloating, nausea and satiation upon isobaric gastric distension was increased, a finding which was even more pronounced while distending the stomach after a meal. In contrast, the sensation of pain was not altered. This finding strongly contrasts with earlier findings and would argue against NMDA receptors as possible targets for correcting visceral hypersensitivity in functional bowel disorders.
Theoretically, the observed increase in perception induced by dextromethorphan may result from the modulation of proximal gastric motility and gastric wall elasticity. Indeed, NMDA and NMDA antagonists have been shown to modulate phasic and tonic motor activity in in-vitro and animal studies. For example, the microinjection of NMDA into the rat dorsal vagal complex increased intragastric pressure and motility, which was abolished by NMDA blockade.26,27 In addition, NMDA induced tonic contractions in the isolated gastric fundus in the rat.28 However, we did not observe an effect of dextromethorphan on proximal gastric tone or gastric wall compliance, excluding this possibility. Alternatively, the increase in perception may result from a non-specific effect of dextromethorphan on NMDA receptors. Like other NMDA receptor antagonists, dextromethorphan has been shown to modulate the release of specific neurotransmitters, such as noradrenaline, dopamine GABA and serotonin, in selective regions in the central nervous system.29–31 This non-specific effect may modulate the central processing of stimuli induced by gastric distension. An additional possible mechanism that may help to explain our findings could be that NMDA receptors may be involved in activating descending inhibitory pathways, so that blocking these receptors would increase rather than decrease the perception of visceral sensations. This could involve a subset of NMDA receptors on vagal afferents, since vagal afferents are also known to activate CNS structures that have a descending, inhibitory influence on spinal nocicepive transmission.32 In addition, activation of central NMDA receptors has been shown to be involved in the facilitation of descending inhibitory pain modulating pathways, which can be blocked by an NMDA receptor antagonist.33 Furthermore, dextromethorphan has a widespread, high affinity to non-NMDA binding sites throughout the central nervous system including sigma receptors and, possibly, dopamine neurones.30,34,35 The mechanism by which dextromethorphan via non-specific or non-NMDA binding sites would lead to the increased perception of non-painful sensations evoked by gastric distension remains to be studied. However, the frequent and relatively dose-independent gastrointestinal side-effects (nausea, vomiting) of dextromethorphan may be explained by non-NMDA mediated effects on the perceptive responses to gut stimuli.
Based on previous studies evaluating the effect of dextromethorphan in various pain syndromes, we expected decreased pain scores during gastric distention. In the present study however, we failed to demonstrate an effect on pain perception. This lack of analgesic effect may be explained by the possibility that dextromethorphan acts preferentially on NMDA receptors with a specific subunit composition. For example, there is evidence suggesting that dextromethorphan has a high affinity at NR1b/NR2C receptors,36 whereas most dorsal root ganglia neurones innervating the rat colon expressed NR1/NR2A and/or NR1/NR2B receptors. It should be stressed though, that no attempt was made to demonstrate NR1/NR2C co-expression.12 A similar NMDA receptor distribution may be found throughout the gut, including in spinal afferents innervating the stomach, possibly explaining their lack of sensitivity to dextromethorphan.
The fact that we did not observe an analgesic effect of dextromethorphan in healthy volunteers, who generally do not report high pain scores upon gastric distension, does not exclude an effect in patients characterized by visceral hypersensitivity. However, we suggest that the role of dextromethorphan in the treatment of visceral pain is limited, because of the enhanced perception of non-painful visceral stimuli even at doses that do not alter the perception of pain, and because of the profound side-effects at higher doses, as reported in the literature.17,37 Future applications of dextromethorphan for pain control will probably be limited to co-administration with opiates, for which it has a potentiating analgesic effect.16 Nevertheless, the application of drugs with NMDA receptor antagonistic properties may still hold promise for the treatment of pain of visceral origin and specifically states of increased visceral sensitivity such as functional bowel disorders.2,3 However, future studies using more selective NMDA receptor antagonists, such as ketamine and memantine, are needed to verify this hypothesis. In addition, these studies may need to include patients with known visceral hypersensitivity.
In conclusion, we showed that dextromethorphan increases the perception of non-painful sensations during gastric distension, without altering the perception of pain. Therefore, application of dextromethorphan as a visceral analgesic is questionable. Future studies on visceral perception in humans with more specific NMDA receptor antagonists are warranted.
S.D.K. is supported by a grant from the Netherlands Digestive Diseases Foundation (MLDS), grant number WS 99-38.