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Effect of muscle relaxants on experimental jaw-muscle pain and jaw-stretch reflexes: a double-blind and placebo-controlled trial
European Journal of Pain 7 (2003) 449–456 www.EuropeanJournalPain.com
Effect of muscle relaxants on experimental jaw-muscle pain and jaw-stretch reflexes: a double-blind and placebo-controlled trial Peter Svensson b
a,b,c,*
, Kelun Wang b, Lars Arendt-Nielsen
b
a Department of Clinical Oral Physiology, Dental School, Aarhus University, DK-8000 Aarhus C, Denmark Center for Sensory-Motor Interaction, Orofacial Pain Laboratory, Aalborg University, DK-9220 Aalborg E, Denmark c Department of Oral and Maxillofacial Surgery, Aarhus University Hospital, DK-8000 Aarhus C, Denmark
Received 26 April 2002; accepted 3 February 2003
Abstract A randomised, double-blind, placebo-controlled three-way cross-over study was performed to investigate the effect of two muscle relaxants (tolperisone hydrochloride and pridinol mesilate) on experimental jaw-muscle pain and jaw-stretch reflexes. Fifteen healthy men participated in three randomised sessions separated by at least 1 week. In each session 300 mg tolperisone, 8 mg pridinol mesilate or placebo was administered orally as a single dose. One hour after drug administration 0.3 ml hypertonic saline (5.8%) was injected into the right masseter to produce muscle pain. Subjects continuously rated their perceived pain intensity on an electronic 10-cm visual analogue scale (VAS). The pressure pain threshold (PPT) was measured and short-latency reflex responses were evoked in the pre-contracted (15% maximal voluntary contraction) masseter and temporalis muscles by a standardised stretch device (1 mm displacement, 10 ms ramp time) before (baseline), 1 h after medication (post-drug), during ongoing experimental muscle pain (painpost-drug), and 15 min after pain had vanished (post-pain). Analysis of variance demonstrated significantly lower VAS peak pain scores (5:9 0:4 cm) after administration of tolperisone hydrochloride compared with pridinol mesilate (6:8 0:4 cm) and placebo (6:6 0:4 cm) ðP ¼ 0:020Þ. Administration of pridinol mesilate was associated with a significant decrease in PPTs compared with tolperisone hydrochloride and placebo ðP ¼ 0:002Þ after medication, but not after experimental jaw-muscle pain. The normalised peak-to-peak amplitude of the stretch reflexes were not significantly influenced by the test medication ðP ¼ 0:762Þ, but were in all sessions significantly facilitated during ongoing experimental jaw-muscle pain ðP ¼ 0:034Þ. In conclusion, tolperisone hydrochloride provides a small, albeit significant reduction in the perceived intensity of experimental jaw-muscle pain whereas the present dose had no effect on the short-latency jaw-stretch reflex. Ó 2003 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Science Ltd. All rights reserved. Keywords: Tolperisone; Pridinol mesilate; Randomised clinical trial; Temporomandibular disorders; Experimental muscle pain; Stretch reflex; Pressure pain threshold
1. Introduction Current pharmacological management of chronic musculoskeletal pain disorders is to a large extent based on clinical experience rather than on scientific evidence and randomised clinical trials (RCTs) (Curatolo and Bogduk, 2001). Moreover, the pathophysiological mechanisms of chronic pain remain unknown and it can therefore be difficult to select the most rational strategy
*
Corresponding author. Fax: +45-8619-5665. E-mail address: [email protected] (P. Svensson).
to alleviate pain. A common and popular, yet unproved, hypothesis of many musculoskeletal pain disorders including the temporomandibular disorders (TMDs) is the so-called vicious cycle where activation of nociceptive pathways is thought to lead to muscle hyperactivity and spasms which again will cause more pain and subsequently setting up a positive feedback loop (Laskin, 1969; Travell et al., 1942; Travell, 1960). The vicious cycle concept has been challenged since experimental and clinical data generally do not support such a simple reciprocal link between pain and muscle hyperactivity (for a review see Lund et al., 1991 and Svensson and Graven-Nielsen, 2001). Nevertheless, therapies aimed to
1090-3801/$30 Ó 2003 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Science Ltd. All rights reserved. doi:10.1016/S1090-3801(03)00013-2
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reduce muscle hyperactivity and relax tense muscles continue to be advocated, e.g., the use of systemic muscle relaxants. A recent review of pharmacological management of musculoskeletal pain concluded that systemic muscle relaxants only showed limited effectiveness for chronic neck pain and chronic low back pain for up to 4 weeks (Moulin, 2001). Furthermore, another review on pharmacological management stated that there is little supporting evidence in favour of muscle relaxants in chronic TMD pain conditions (Dionne, 1997). For example, a double-blind study, could not demonstrate a better effect of carisoprodol compared with placebo in 60 patients with chronic myofascial pain in the orofacial region (Gallardo et al., 1975). However, it was pointed out that there could be possible exceptions since some muscle relaxants appeared to be more effective than placebo in management of chronic musculoskeletal pain disorders (for a review see Dionne, 1997). Tolperisone hydrochloride (Mydocalm , Strathmann AG, Germany) is a centrally acting muscle relaxant with a chemical structure that partially resembles that of lidocaine (Fels, 1996; Zsila et al., 2000). Thus, in addition to the well-documented inhibitory effect of tolperisone hydrochloride on spinal motoneurones and mono- and polysynaptic reflex pathways in animal preparations (Farkas et al., 1989; Kaneko et al., 1987; Ono et al., 1984; Sakitama, 1993), clinical experience and some studies have indicated beneficial effects on various painful musculoskeletal pain disorders (Amir et al., 1978; Csanyi, 1989; Inovay and Katona, 1991; Pratzel et al., 1996). However, alleviation of pain could possibly also be related to the membrane stabilising potency of tolperisone hydrochloride (Ono et al., 1984). Preliminary electrophysiological studies on cultured hippocampus neurons have, indeed, indicated that tolperisone hydrochloride can block voltage-gated neuronal sodium-channels in a dose dependent manner and reduce the sodium influx (Farkas et al., 2000). Another centrally acting muscle relaxant – pridinol mesilate (Myoson, IPG Pharma, Germany) – appears to have an inhibitory effect on reflex activity of spinal motoneurones via an interaction with the M1 and M4 subtype of the muscarinic receptor (Keim, Mutschler and Lambrecht – unpublished observations). Furthermore, there is preliminary evidence from a clinical trial that administration of pridinol mesilate is associated with improvement in joint function and pain scores in patients with chronic low back pain (Pipino et al., 1991). Nevertheless, it is not clear how closely the pain relieving effect is coupled to the effect of systemic muscle relaxants on the excitability of reflex pathways. We have recently shown a facilitation of the short-latency stretch reflex in the masseter muscle when exposed to experimental jaw-muscle pain (Svensson et al., 2001; Wang et al., 2000, 2001). However, the mechanisms for this facilitation are not clear but changes
in the fusimotor control linked to the nociceptive barrage have been suggested (Pedersen et al., 1997). We therefore speculated that the jaw-stretch reflex and the facilitation by pain would be decreased by administration of centrally acting muscle relaxants. Thus, the aim of the present study was to investigate the effect of two centrally acting muscle relaxants on both experimentally evoked jaw-muscle pain and measures of trigeminal reflex excitability in a double-blind and placebo-controlled trial.
2. Materials and methods 2.1. Subjects The volunteers for this study were all healthy and unmedicated subjects without signs or symptoms of TMD (Dworkin and LeResche, 1992). Fifteen men aged between 22 and 29 years (mean age SEM: 25:6 0:6 years) participated in this study. The study was conducted in accordance with the Helsinki Declaration and written informed consent was obtained from all subjects. The local Ethics Committee and the Danish National Board of Health approved the study. 2.2. Experimental protocol All subjects participated in three sessions separated by at least 1 week (Fig. 1). In each session, the pressure pain thresholds (PPT) and jaw-stretch reflexes were recorded at baseline. Then the test medication (tolperisone hydrochloride, pridinol mesilate or placebo) was administered orally as a single dose and after 60 min the PPT and jaw-stretch reflexes were recorded again (postdrug). Subsequently experimental jaw-muscle pain was evoked by injection of hypertonic saline and the subjects rated the perceived pain intensity on visual analogue scales (VAS). Jaw-stretch reflexes were recorded during the ongoing pain (pain-post-drug). The subjects also used a McGilll Pain Questionnaire (MPQ) to describe the quality of the saline-evoked pain. Finally, the PPT and jaw-stretch reflexes were recorded when the subjects had reported no pain for about 15 min (post-pain).
Fig. 1. Schematic outline of the experimental protocol. PPT ¼ pressure pain thresholds, VAS ¼ visual analogue scale, MPQ ¼ McGill Pain Questionnaire.
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2.3. Test medication The study was performed as a randomised, doubleblind and placebo-controlled trial. The placebo tablets were identical to the active medication in terms of their size, colour, shape and smell. There were two different kinds of placebo tablets, one for pridinol mesilate and one for tolperisone hydrochloride. Thus, to guarantee the blinding conditions each volunteers received a total of 4 tablets at each session (double dummy design): two active (4 mg pridinol mesilate or 150 mg tolperisone hydrochloride) and two corresponding placebo tablets or four placebo tablets. The randomisation code table was prepared and kept by the drug company (Strathmann AG, Germany) with a copy in a sealed envelope at the study centre in case of an emergency situation. After completion of the experimental part of the study the randomisation code for the sequence of the different test medications for each subject was opened. The statistical analysis was then performed in three different groups marked A, B and C and first then the final randomisation code was broken. 2.4. Experimental jaw-muscle pain Injection of 0.3 ml hypertonic (5.8%) sterile saline into the mid portion of the masseter muscle followed the previously described procedures (Svensson et al., 1998, 2001). The subjects continuously scored the perceived pain intensity on an electronic 0-10 cm visual analogue scale (VAS) with the lower extreme labelled ‘‘no pain’’ and the upper extreme labelled ‘‘most pain imaginable’’. A computer sampled the VAS pain scores every 5 s. After stop of the infusion the subjects were furthermore asked to describe the quality of pain on a Danish version of the McGill Pain Questionnaire (MPQ). The pain rating indices (PRIs) of the sensory, affective, evaluative and miscellaneous dimension of pain were calculated in accordance with Melzack (1975). The VAS peak pain score was for each subject defined as the highest value on the time – VAS curve and the pain duration as the difference between the VAS onset and VAS offset. 2.5. Pressure pain threshold A pressure algometer (Somedic, Sweden) was used to measure the PPTs. The PPT was defined as the amount of pressure (kPa), which the subjects first perceived to be painful (Svensson et al., 1995). The probe with 1 cm diameter was applied perpendicular to the central part of the left and right masseter and temporalis muscles (MAL, MAR, TAL and TAR). During the pressure stimulation, the subjects kept their teeth in the intercuspal position with minimum voluntary contraction and
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focused their attention on the experimental task. The subject pushed a button to stop the pressure stimulation when the threshold was reached. The PPTs were determined in triplicate with a constant application rate of 30 kPa/s. There was a time lag of about 2 min between repeated measurements. The mean value was used for further statistical analysis. 2.6. Jaw-stretch reflexes Stretch reflexes were evoked in the jaw-closing muscles with a standardised muscle stretcher (1 mm displacement, 10 ms ramp time), which previously has been described in details (Miles et al., 1993; Svensson et al., 2000, 2001; Wang and Svensson, 2001; Wang et al., 2000, 2001). In brief, bipolar disposable surface electrodes (Neuroline 720-01-K, Medicotest, Ølstykke, Denmark) were placed bilaterally on the central part of the masseter and anterior temporalis muscles (MAL, MAR, TAL and TAR). The skin over the recording positions was cleaned with alcohol and the impedance of the electrodes was kept < 20 kX. A ground electrode soaked with saline was attached to the left wrist. The EMG signals were amplified 2000–5000 times (Counterpoint MK-2, Dantec, Denmark), filtered with bandpass 20 Hz to 1 kHz, sampled at 4 kHz and stored for later analysis. The subjects performed three maximal clenches each lasting up to 3 s on the bar with their incisor teeth to obtain the mean EMG value of the maximal voluntary contraction (MVC) in the four muscles. The MVC calculated from the EMG activity of right masseter (painful side) was used to construct a window of 10% below and above the 15% MVC (i.e., 13.5–16.5% MVC). On-line calculation of the root-mean-square (RMS) value in 200 ms intervals of the EMG was performed with the use of LabView. The subjects received visual feedback from markers on a computer screen, which changed from green to red upon crossing the upper and lower limits of the window (Svensson et al., 1998). If the ongoing EMG activity remained within the pre-set window for more than 400 ms, the program automatically triggered the muscle stretcher. A total of 300 ms EMG activity was recorded with 100 ms prestimulus and 200 ms post-stimulus. Twenty trials with an inter-stimulus interval about 10 s were recorded in each condition (baseline, post-drug, pain-post-drug, post-pain). In the pain-post-drug condition, the reflex recordings were started 20–30 s after the injection of hypertonic saline (Fig. 1). A special-purpose computer program processed the reflex responses evoked in the EMG by the fast stretches. First, the mean EMG in the pre-stimulus interval ()100 to 0 ms) of the averaged and rectified signal was calculated (lV). Then, the peak-to-peak amplitude of the early reflex component, which appeared as a biphasic potential in the average of the non-rectified
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recordings, was measured (lV). Finally, the peak-topeak amplitude was normalised with respect to the mean pre-stimulus EMG activity, i.e., the ratio between the amplitude and pre-stimulus EMG activity (Wang et al., 2000). 2.7. Statistics VAS peak pain scores, pain duration and MPQ scores produced by injection of hypertonic saline were compared with analyses of variance (ANOVA) with repeated measures and one factor: test medication (three levels: tolperisone hydrochloride, pridinol mesilate and placebo). PPTs were analysed with a three-way ANOVA with repeated measures and followed by pairwise multiple comparison procedures (Tukey tests). The factors in the ANOVA were: test medication (three levels), muscle (four levels: MAL, MAR, TAL and TAR) and
time of measurement (three levels: baseline, post-drug and post-pain). The pre-stimulus EMG activity and normalised jaw-stretch reflexes were analysed in a similar way: test medication (three levels), muscle (four levels) and time of measurement (four levels: baseline, post-drug, pain-post-drug and post-pain). Furthermore, as a measure of the intrasubject variability across the three experimental sessions, the coefficient of variation (CV ¼ standard deviation/mean in percentage) was calculated for the different outcome parameters. The significance level was set at P < 0:05. Mean values SEM are presented in the text and figures.
3. Results In total, the test medication was administered to 16 subjects. One subject withdrew from the experiment during first session (pridinol mesilate) due to moderate dizziness. The symptom spontaneously disappeared after 6 h. Fifteen subjects finished all three sessions of the study. Two out of the 15 subjects experienced slight dizziness during the sessions with pridinol mesilate and placebo, respectively. However, the relation to administration of the test medication was unlikely according to the two subjects and the experiments could be continued. 3.1. Experimental jaw-muscle pain
Fig. 2. Perceived pain rated by the subjects ðN ¼ 15Þ on visual analogue scales (VAS) following injection of hypertonic saline into the masseter muscle in the three sessions with administration of tolperisone hydrochloride, pridinol mesilate or placebo. Mean values and SEM.
Injection of 0.3 ml hypertonic saline produced in all subjects a moderate to strong jaw-muscle pain, which was centred on the masseter muscle and spreading towards the temporomandibular joint, temple and teeth. The pain reached its peak intensity after 20–30 s and then gradually decreased lasting up to 600 s (Fig. 2). The pain was consistently (> 30% of the subjects) described on the MPQ as ‘‘hurting’’ (42%), ‘‘pressing’’ (40%), ‘‘boring’’ (38%), ‘‘penetrating’’ (36%), ‘‘tingling’’ (31%) and ‘‘intense’’ (31%). Less frequent words used to describe pain were ‘‘sickening’’ (29%), ‘‘shooting’’ (29%), ‘‘piercing’’ (27%), ‘‘taut’’ (27%), ‘‘tender’’ (24%), ‘‘nagging’’ (24%) and ‘‘tiring’’ (22%). The pain rating indices (PRIs) derived from the MPQ are shown in Table 1. The PRIs were not significantly influenced by the test medication (ANOVA: F < 2:551; P > 0:096). The intraindividual coefficient of variation (CV) for the
Table 1 PRI(S)
PRI(A)
PRI(E)
PRI(M)
Tolperisone hydrochloride Pridinol mesilate Placebo
10:6 1:6 12:0 1:9 11:6 1:7
1:0 0:4 2:1 0:7 1:3 0:5
1:7 0:4 1:7 0:4 2:5 0:5
4:3 0:7 4:8 0:7 4:4 0:9
ANOVA tests
P ¼ 0:623
P ¼ 0:096
P ¼ 0:099
P ¼ 0:842
Pain rating indices (PRI) of sensory (S), affective (A), evaluative (E) and miscellaneous (M) dimension of pain from the McGill Pain Questionnaire. ANOVA tests did not find significant differences between the test medications.
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PRIs were S ¼ 29 4%, A ¼ 65 18%, E ¼ 64 19% and M ¼ 51 11%. There was a significant difference in VAS peak pain scores following the test medications (ANOVA: F ¼ 4:490; P ¼ 0:020). Administration of tolperisone hydrochloride was associated with significantly lower VAS peak pain scores (5:9 0:4 cm) compared with pridinol mesilate (6:8 0:4 cm) and placebo (6:6 0:4 cm) (Tukey: P < 0:05). The duration of the salineevoked jaw-muscle pain in the tolperisone hydrochloride session (417 27 s), pridinol mesilate session (370 28 s) and placebo session (429 26 s) was not significantly different (F ¼ 2:06; P ¼ 0:146). The intraindividual CV for the VAS peak pain score was 12 2% and for the pain duration 20 3%. 3.2. Pressure pain thresholds Analyses of variance of the PPTs showed that there was no main effect of any test medication (F ¼ 0:326; P ¼ 0:725) or time of measurement (F ¼ 0:534; P ¼ 0:592), but a significant difference between muscles (F ¼ 6:894; P < 0:001). However, there was a significant interaction between test medication and time of measurement (F ¼ 4:968; P ¼ 0:002) and post hoc tests demonstrated significantly lower PPTs following administration of pridinol mesilate compared to tolperisone hydrochloride and placebo only in the post-drug condition (Tukey: P < 0:05) (Fig. 3). The intraindividual CVs for the four jaw-muscles were MAL ¼ 10 2%, MAR ¼ 12 2%, TAL ¼ 13 3% and TAR ¼ 10 2%. 3.3. Jaw-stretch reflexes The fast stretch of the contracting jaw-muscles evoked an early (8–9 ms) biphasic response in the EMG in all subjects in accordance with previous reports (Svensson et al., 2001; Wang et al., 2000, 2001).
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Fig. 4. Ratios between peak-to-peak amplitudes of the jaw-stretch reflexes and the pre-stimulus EMG activity at baseline, 60 min after administration of the three test medications (post-drug), during ongoing jaw-muscle pain (pain-post-drug), and after experimental pain (post-pain). Mean values (SEM) from 15 subjects. The values from four muscles (left and right masseter and temporalis) are pooled since there were no significant interactions between muscles and test medication ðF ¼ 0:693; P ¼ 0:656Þ. *Indicates significantly higher values for the pain-post-drug condition compared with baseline and the postdrug condition (Tukey: P < 0:05).
Analyses of variance of the pre-stimulus EMG activity showed that there was no main effect of any test medication (F ¼ 1:932; P ¼ 0:146 or time of measurement (F ¼ 0:184; P ¼ 0:907), but a significant difference between muscles (F ¼ 127:6; P < 0:001). Analyses of the peak-to-peak amplitude normalised with respect to prestimulus EMG activity (i.e., ratio) indicated no significant main effect of test medication (F ¼ 0:275; P ¼ 0:762) or muscle (F ¼ 1:200; P ¼ 0:321) but a significant effect of time of measurement (F ¼ 3:174; P ¼ 0:034). Post hoc tests demonstrated significantly higher amplitudes during ongoing jaw-muscle pain (pain-post-drug) compared with baseline and the postdrug conditions (Tukey: P < 0:05) (Fig. 4). No significant interactions between other factors in the ANOVA were identified (F < 1:831; P > 0:069). The intraindividual CVs for the pre-stimulus EMG activity were MAL ¼ 23 4%, MAR ¼ 13 3%, TAL ¼ 28 4% and TAR ¼ 22 4% and for the normalised peak-topeak-amplitudes MAL ¼ 22 3%, MAR ¼ 24 6%, TAL ¼ 34 4% and TAR ¼ 45 7%.
4. Discussion
Fig. 3. Pressure pain thresholds at baseline, 1 h after administration of the three test medications (post-drug) and after experimental pain (post-pain). Mean values (SEM) from 15 subjects. The PPTs from four muscles (left and right masseter and temporalis) are pooled since there were no significant interactions between muscles and test medication (F ¼ 1:121; P ¼ 0:357). Indicates significantly lower PPTs compared to tolperisone hydrochloride and placebo in the post-drug condition (Tukey: P < 0:05).
The main finding in this experimental study was a marginal hypoalgesic effect of tolperisone hydrochloride on the perceived pain intensity of acute, experimental jaw-muscle pain whereas there were no significant effects of any test medication on measures of trigeminal reflex excitability. 4.1. Muscle relaxants and muscle pain Tolperisone hydrochloride has previously been assessed for its efficacy on pain in the craniofacial region
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(Amir et al., 1978). In the open study, which was performed on a small group of TMD patients (n ¼ 15), 150 mg tolperisone hydrochloride for 4 weeks was found to relieve pain in the majority of patients (88%) (Amir et al., 1978). Similar results were also observed following carisoprodol and occlusal splints and it was subsequently advocated that muscle relaxants could be effective for relieving TMD-related pain (Amir et al., 1978). A double-blind and placebo-controlled study could, however, not demonstrate any significant differences between carisoprodol and placebo in patients with TMD-related pain (Gallardo et al., 1975). Dionne (1997) noted that there appeared to be a discrepancy between the common clinical use of systemic muscle relaxants for relieve of musculoskeletal pain and the results of randomised placebo-controlled clinical trials. Furthermore, nonspecific central nervous system depression could, in part, account for a hypoalgesic effect of muscle relaxants (Dionne, 1997). Tolperisone hydrochloride, however, appears to be a rather unique muscle relaxants because few central nervous system side effects are noted even at high doses (Dulin et al., 1998). Daily administration of 150 or 450 mg tolperisone hydrochloride for 8 days did not impair a battery of psychomotor tests including reaction time measurements in healthy subjects, which suggests that sedation is not a major problem at clinical relevant doses. Furthermore, few side effects like headache and fatigue (four and two out of 24 subjects, respectively) were noted with 450 mg tolperisone hydrochloride (Dulin et al., 1998). This is in accordance with the present study with 300 mg tolperisone hydrochloride as a single dose without significant side effects. It is therefore unlikely that nonspecific central nervous system effects can account for the observed hypoalgesic effect of tolperisone hydrochloride in the present study. A recent RCT in patients with a clinical diagnosis of painful reflex muscle spasms appear to support the notion of a weak hypoalgesic effect of 300 mg tolperisone hydrochloride (Pratzel et al., 1996). In that study, muscle spasms were defined as involuntary muscle contractions and local tenderness on manual palpation. Although no operationalised criteria or direct electrophysiological measurements of the muscle spasms were presented it is interesting to note that treatment with tolperisone hydrochloride compared with placebo after 10 and 21 days was associated with a significantly higher increase in PPTs whereas no significant difference could be found in the manually palpated muscle tone. In the present study no significant effects on PPTs in the jawmuscles could be observed following administration of tolperisone hydrochloride. The reasons for these findings are not known, but it could be, that multiple dosing of tolperisone hydrochloride is needed in order to increase PPTs as it was shown in the clinical trial of Pratzel et al. (1996). Concerning pridinol mesilate a
significant reduction of the PPT compared with placebo and tolperisone was found. This effect of pridinol mesilate was not expected and so far there is no explanation for it. Nevertheless, the differential actions of tolperisone hydrochloride and pridinol mesilate on VAS peak pain scores and PPTs (Figs. 2 and 3) in the present study support the notion of different receptor mechanisms for the two types of muscle relaxants (see Section 1). In the present study there were no significant effects of injection of hypertonic saline on the PPTs (Fig. 3). This finding is in accordance with our previous studies using hypertonic saline injections (Graven-Nielsen et al., 1998a,b; Svensson et al., 1995) and suggests a lack of sensitisation to mechanical stimuli when assessed with PPTs on the local pain area. In contrast to hypertonic saline, injection of the excitatory amino acid glutamate into muscle tissue is associated with a significant decrease in mechanical threshold both in animal preparations (Cairns et al., 2002) and in human studies (Svensson et al., 2003). Thus, further studies may be needed to examine the hypoalgesic effect versus the antiallodynic and anti-hyperalgesic properties of for example muscle relaxants. In summary, there is limited experimental and clinical evidence in favour of a pronounced hypoalgesic effect of systemic muscle relaxants, but a small effect could be detected for tolperisone hydrochloride in a highly standardised acute muscle pain model. 4.2. Muscle relaxants and jaw-reflexes Both tolperisone hydrochloride and pridinol mesilate have a strong and well-documented effect on spinal reflex circuits and motoneurones when assessed in animal preparations (Farkas et al., 1989; Ito et al., 1985; Kaneko et al., 1987; Ono et al., 1984; Sakitama, 1993). The depression of spinal synaptic transmission by tolperisone hydrochloride may be related to both pre-synaptic and post-synaptic mechanisms in addition to a direct membrane stabilising effect on primary afferent fibres (Ono et al., 1984). However, less is known about the trigeminal reflex excitability in human subjects. Takata et al. (1996) demonstrated in an open study on five healthy subjects that 100 mg tolperisone hydrochloride was associated with a marked depression of the tonic vibration reflex measured in the masseter muscles. Vibration (e.g., for 20 s) is a potent stimulus of primary muscle spindles leading to a tonic excitation of motoneurones and activity in the EMG related to the duration of the stimulus (Desmedt and Godaux, 1975). A single rapid stretch (10 ms) is also adequate to activate primary muscle spindles and generate a short-latency reflex (8–9 ms) response in the pre-contracted masseter muscle (Miles et al., 1993; Poliakov and Miles, 1994; Wang et al., 2000; Wang and Svensson, 2001). We have previously shown a facilitation of the short-latency
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stretch reflex in the masseter muscle when exposed to experimental jaw-muscle pain (Svensson et al., 2001; Wang et al., 2000, 2001) in accordance with a significant facilitation of the stretch reflex in the soleus muscle during experimental pain (Matre et al., 1998). The mechanisms for this facilitation are not entirely clear but changes in the fusimotor control linked to the nociceptive barrage have been suggested (Pedersen et al., 1997). We had anticipated that the centrally acting muscle relaxants would suppress the amplitude of the jaw-stretch reflex response by similar mechanisms described above for the spinal reflex circuits but this was not observed in the present study. Furthermore, it was speculated that the facilitation of the jaw-stretch reflex response by experimental muscle pain would be antagonised with the concurrent medication of tolperisone hydrochloride or pridinol mesilate. In accordance with our previous studies on tonic jaw-muscle pain (Svensson et al., 2001; Wang et al., 2000, 2001), the present more phasic type of jaw-muscle pain was in all the sessions associated with a significant increase in the normalised peak-to-peak amplitude of the jaw-stretch reflex, however, there were no significant differences between the sessions with muscle relaxants or placebo. One possible explanation for the lack of effect of tolperisone hydrochloride could be that the jaw-stretch reflex is recorded during a slight (15% MVC) voluntary, pre-contraction of the masseter muscle, which could mask an effect on the trigeminal reflex circuits in agreement with the suggestion of Romaniello et al. (2000). However, this and our previous studies on jaw-stretch reflexes (Wang et al., 2000, 2001; Svensson et al., 2001) have all been able to demonstrate a significant pain-related increase in the reflex amplitude under these experimental conditions. Moreover, in the present study we found no significant differences in the prestimulus EMG activity at any time point during the experiments. Thus, we do not believe that methodological concerns are the main reason for the lack of effect of tolperisone hydrochloride on the jaw-stretch reflex. Another possibility is that the doses and timing of the medication in relation to the recording of the jaw-stretch reflexes were not optimal. Even if the average peak plasma concentration of tolperisone has been identified after 1.5 h (Miskolczi et al., 1987) and the elimination half time is reported to be around 2.5 h (Dulin et al., 1998) it is also known, that tolperisone hydrochloride has a high interindividual variability of pharmacokinetic parameters like peak plasma concentration and elimination half time. Finally, the variability of the outcome measures in experimental pain studies needs to be considered (Yarnitsky et al., 1996). In the present study we employed techniques, which previously have been sufficiently sensitive to detect effects of experimental manipulations in paired designs (Svensson et al., 1995, 2001). The intraindividual coefficient of variations (CV) for the PPTs
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and saline-evoked pain were generally low (< 20%) and within the range of CVs for other psychophysical techniques (Svensson et al., 1991; Yarnitsky et al., 1996). However, the CVs for MPQ measures were higher (29–65%) and could, in part, explain the lack of any significant differences between the three sessions. The CVs for the jaw-reflex measures were moderately low for the masseter muscles (13–24%) but higher for the temporalis muscles (22–45%) suggesting difficulties to find significant differences in the temporalis muscles. Nevertheless, a significant effect of jaw-muscle pain was found on the normalised peak-to-peak amplitude, which indicates that the present technique is adequate to detect consistent effects in a paired design. In conclusion, a single dose of 300 mg tolperisone hydrochloride provides a small, albeit significant reduction in the perceived intensity of experimental jawmuscle pain but did not show a significant effect on the short-latency jaw-stretch reflex in the present set-up.
Acknowledgements The Danish National Research Foundation supported the study and Strathmann AG, Germany provided the test medication.
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Poliakov AV, Miles TS. Stretch reflexes in human masseter. J Physiol (Lond) 1994;476:323–31. Pratzel HG, Alken RG, Ramm S. Efficacy and tolerance of repeated oral doses of tolperisone hydrochloridee in the treatment of painful reflex muscle spasm: results of a prospective placebo-controlled double-blind trial. Pain 1996;67:417–25. Romaniello A, Cruccu G, McMillan AS, Arendt-Nielsen L, Svensson P. Effect of experimental pain from trigeminal muscle and skin on motor cortex excitability in humans. Brain Res 2000;882:120–7. Sakitama K. The effects of centrally acting muscle relaxants on the intrathecal noradrenaline-induced facilitation of the flexor reflex mediated by group II afferent fibers in rats. Jpn J Pharmacol 1993;63:369–76. Svensson P, Arendt-Nielsen L, Nielsen H, Larsen JK. Effect of chronic and experimental jaw muscle pain on pain–pressure thresholds and stimulus–response curves. J Orofac Pain 1995;9:347–56. Svensson P, Bjerring P, Arendt-Nielsen L, Kaaber S. Variability of argon laser-induced sensory and pain thresholds on human oral mucosa and skin. Anesth Prog 1991;38:79–83. Svensson P, Cairns BE, Wang K, Hu JW, Graven-Nielsen T, Arendt-Nielsen L, Sessle BJ. Glutamate-induced sensitization of pressure pain thresholds in human masseter muscle. Pain 2003;101:221–7. Svensson P, De Laat A, Graven-Nielsen T, Arendt-Nielsen L. Experimental jaw-muscle pain does not change heteronymous Hreflexes in the human temporalis muscle. Exp Brain Res 1998;121:311–8. Svensson P, Graven-Nielsen T. Craniofacial muscle pain: review of mechanisms and clinical manifestations. J Orofac Pain 2001;15: 117–45. Svensson P, Macaluso GM, De Laat A, Wang K. Effects of local and remote muscle pain on human jaw reflexes evoked by fast stretches at different clenching levels. Exp Brain Res 2001;139:495–502. Svensson P, Miles TS, Graven-Nielsen T, Arendt-Nielsen L. Modulation of stretch-evoked reflexes in single motor units in human masseter muscle by experimental pain. Exp Brain Res 2000;132: 65–71. Takata Y, Nakajima T, Yamada Y. Quantitative evaluation of the tonic vibration reflex (TVR) in the masseter muscle. J Oral Maxillofac Surg 1996;54:1307–13. Travell J. Temporomandibular joint dysfunction. J Prosthet Dent 1960;10:745–63. Travell J, Rinzler S, Herman M. Pain and disability of the shoulder and arm. Treatment by intramuscular infiltration with procaine hydrochloridee. J Am Med Assoc 1942;120:417–22. Wang K, Svensson P. Influence of methodological parameters on human jaw-stretch reflexes. Eur J Oral Sci 2001;109:86–94. Wang K, Arendt-Nielsen L, Svensson P. Excitatory actions of experimental muscle pain on early and late components of jawstretch reflexes. Arch Oral Biol 2001;46:433–42. Wang K, Svensson P, Arendt-Nielsen. Effect of tonic muscle pain on short-latency jaw-stretch reflexes in humans. Pain 2000;88: 189–97. Yarnitsky D, Sprecher E, Zaslansky R, Hemli JA. Multiple session experimental pain measurement. Pain 1996;67:327–33. Zsila F, Holl osi M, Gergely A. Stereochemical study of tolperisone, a muscle relaxant agent, by circular dichroism and ultraviolet spectroscopy. Chirality 2000;12:720–6.
Effect of muscle relaxants on experimental jaw-muscle pain and jaw-stretch reflexes: a double-blind and placebo-controlled trial Peter Svensson b
a,b,c,*
, Kelun Wang b, Lars Arendt-Nielsen
b
a Department of Clinical Oral Physiology, Dental School, Aarhus University, DK-8000 Aarhus C, Denmark Center for Sensory-Motor Interaction, Orofacial Pain Laboratory, Aalborg University, DK-9220 Aalborg E, Denmark c Department of Oral and Maxillofacial Surgery, Aarhus University Hospital, DK-8000 Aarhus C, Denmark
Received 26 April 2002; accepted 3 February 2003
Abstract A randomised, double-blind, placebo-controlled three-way cross-over study was performed to investigate the effect of two muscle relaxants (tolperisone hydrochloride and pridinol mesilate) on experimental jaw-muscle pain and jaw-stretch reflexes. Fifteen healthy men participated in three randomised sessions separated by at least 1 week. In each session 300 mg tolperisone, 8 mg pridinol mesilate or placebo was administered orally as a single dose. One hour after drug administration 0.3 ml hypertonic saline (5.8%) was injected into the right masseter to produce muscle pain. Subjects continuously rated their perceived pain intensity on an electronic 10-cm visual analogue scale (VAS). The pressure pain threshold (PPT) was measured and short-latency reflex responses were evoked in the pre-contracted (15% maximal voluntary contraction) masseter and temporalis muscles by a standardised stretch device (1 mm displacement, 10 ms ramp time) before (baseline), 1 h after medication (post-drug), during ongoing experimental muscle pain (painpost-drug), and 15 min after pain had vanished (post-pain). Analysis of variance demonstrated significantly lower VAS peak pain scores (5:9 0:4 cm) after administration of tolperisone hydrochloride compared with pridinol mesilate (6:8 0:4 cm) and placebo (6:6 0:4 cm) ðP ¼ 0:020Þ. Administration of pridinol mesilate was associated with a significant decrease in PPTs compared with tolperisone hydrochloride and placebo ðP ¼ 0:002Þ after medication, but not after experimental jaw-muscle pain. The normalised peak-to-peak amplitude of the stretch reflexes were not significantly influenced by the test medication ðP ¼ 0:762Þ, but were in all sessions significantly facilitated during ongoing experimental jaw-muscle pain ðP ¼ 0:034Þ. In conclusion, tolperisone hydrochloride provides a small, albeit significant reduction in the perceived intensity of experimental jaw-muscle pain whereas the present dose had no effect on the short-latency jaw-stretch reflex. Ó 2003 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Science Ltd. All rights reserved. Keywords: Tolperisone; Pridinol mesilate; Randomised clinical trial; Temporomandibular disorders; Experimental muscle pain; Stretch reflex; Pressure pain threshold
1. Introduction Current pharmacological management of chronic musculoskeletal pain disorders is to a large extent based on clinical experience rather than on scientific evidence and randomised clinical trials (RCTs) (Curatolo and Bogduk, 2001). Moreover, the pathophysiological mechanisms of chronic pain remain unknown and it can therefore be difficult to select the most rational strategy
*
Corresponding author. Fax: +45-8619-5665. E-mail address: [email protected] (P. Svensson).
to alleviate pain. A common and popular, yet unproved, hypothesis of many musculoskeletal pain disorders including the temporomandibular disorders (TMDs) is the so-called vicious cycle where activation of nociceptive pathways is thought to lead to muscle hyperactivity and spasms which again will cause more pain and subsequently setting up a positive feedback loop (Laskin, 1969; Travell et al., 1942; Travell, 1960). The vicious cycle concept has been challenged since experimental and clinical data generally do not support such a simple reciprocal link between pain and muscle hyperactivity (for a review see Lund et al., 1991 and Svensson and Graven-Nielsen, 2001). Nevertheless, therapies aimed to
1090-3801/$30 Ó 2003 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Science Ltd. All rights reserved. doi:10.1016/S1090-3801(03)00013-2
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reduce muscle hyperactivity and relax tense muscles continue to be advocated, e.g., the use of systemic muscle relaxants. A recent review of pharmacological management of musculoskeletal pain concluded that systemic muscle relaxants only showed limited effectiveness for chronic neck pain and chronic low back pain for up to 4 weeks (Moulin, 2001). Furthermore, another review on pharmacological management stated that there is little supporting evidence in favour of muscle relaxants in chronic TMD pain conditions (Dionne, 1997). For example, a double-blind study, could not demonstrate a better effect of carisoprodol compared with placebo in 60 patients with chronic myofascial pain in the orofacial region (Gallardo et al., 1975). However, it was pointed out that there could be possible exceptions since some muscle relaxants appeared to be more effective than placebo in management of chronic musculoskeletal pain disorders (for a review see Dionne, 1997). Tolperisone hydrochloride (Mydocalm , Strathmann AG, Germany) is a centrally acting muscle relaxant with a chemical structure that partially resembles that of lidocaine (Fels, 1996; Zsila et al., 2000). Thus, in addition to the well-documented inhibitory effect of tolperisone hydrochloride on spinal motoneurones and mono- and polysynaptic reflex pathways in animal preparations (Farkas et al., 1989; Kaneko et al., 1987; Ono et al., 1984; Sakitama, 1993), clinical experience and some studies have indicated beneficial effects on various painful musculoskeletal pain disorders (Amir et al., 1978; Csanyi, 1989; Inovay and Katona, 1991; Pratzel et al., 1996). However, alleviation of pain could possibly also be related to the membrane stabilising potency of tolperisone hydrochloride (Ono et al., 1984). Preliminary electrophysiological studies on cultured hippocampus neurons have, indeed, indicated that tolperisone hydrochloride can block voltage-gated neuronal sodium-channels in a dose dependent manner and reduce the sodium influx (Farkas et al., 2000). Another centrally acting muscle relaxant – pridinol mesilate (Myoson, IPG Pharma, Germany) – appears to have an inhibitory effect on reflex activity of spinal motoneurones via an interaction with the M1 and M4 subtype of the muscarinic receptor (Keim, Mutschler and Lambrecht – unpublished observations). Furthermore, there is preliminary evidence from a clinical trial that administration of pridinol mesilate is associated with improvement in joint function and pain scores in patients with chronic low back pain (Pipino et al., 1991). Nevertheless, it is not clear how closely the pain relieving effect is coupled to the effect of systemic muscle relaxants on the excitability of reflex pathways. We have recently shown a facilitation of the short-latency stretch reflex in the masseter muscle when exposed to experimental jaw-muscle pain (Svensson et al., 2001; Wang et al., 2000, 2001). However, the mechanisms for this facilitation are not clear but changes
in the fusimotor control linked to the nociceptive barrage have been suggested (Pedersen et al., 1997). We therefore speculated that the jaw-stretch reflex and the facilitation by pain would be decreased by administration of centrally acting muscle relaxants. Thus, the aim of the present study was to investigate the effect of two centrally acting muscle relaxants on both experimentally evoked jaw-muscle pain and measures of trigeminal reflex excitability in a double-blind and placebo-controlled trial.
2. Materials and methods 2.1. Subjects The volunteers for this study were all healthy and unmedicated subjects without signs or symptoms of TMD (Dworkin and LeResche, 1992). Fifteen men aged between 22 and 29 years (mean age SEM: 25:6 0:6 years) participated in this study. The study was conducted in accordance with the Helsinki Declaration and written informed consent was obtained from all subjects. The local Ethics Committee and the Danish National Board of Health approved the study. 2.2. Experimental protocol All subjects participated in three sessions separated by at least 1 week (Fig. 1). In each session, the pressure pain thresholds (PPT) and jaw-stretch reflexes were recorded at baseline. Then the test medication (tolperisone hydrochloride, pridinol mesilate or placebo) was administered orally as a single dose and after 60 min the PPT and jaw-stretch reflexes were recorded again (postdrug). Subsequently experimental jaw-muscle pain was evoked by injection of hypertonic saline and the subjects rated the perceived pain intensity on visual analogue scales (VAS). Jaw-stretch reflexes were recorded during the ongoing pain (pain-post-drug). The subjects also used a McGilll Pain Questionnaire (MPQ) to describe the quality of the saline-evoked pain. Finally, the PPT and jaw-stretch reflexes were recorded when the subjects had reported no pain for about 15 min (post-pain).
Fig. 1. Schematic outline of the experimental protocol. PPT ¼ pressure pain thresholds, VAS ¼ visual analogue scale, MPQ ¼ McGill Pain Questionnaire.
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2.3. Test medication The study was performed as a randomised, doubleblind and placebo-controlled trial. The placebo tablets were identical to the active medication in terms of their size, colour, shape and smell. There were two different kinds of placebo tablets, one for pridinol mesilate and one for tolperisone hydrochloride. Thus, to guarantee the blinding conditions each volunteers received a total of 4 tablets at each session (double dummy design): two active (4 mg pridinol mesilate or 150 mg tolperisone hydrochloride) and two corresponding placebo tablets or four placebo tablets. The randomisation code table was prepared and kept by the drug company (Strathmann AG, Germany) with a copy in a sealed envelope at the study centre in case of an emergency situation. After completion of the experimental part of the study the randomisation code for the sequence of the different test medications for each subject was opened. The statistical analysis was then performed in three different groups marked A, B and C and first then the final randomisation code was broken. 2.4. Experimental jaw-muscle pain Injection of 0.3 ml hypertonic (5.8%) sterile saline into the mid portion of the masseter muscle followed the previously described procedures (Svensson et al., 1998, 2001). The subjects continuously scored the perceived pain intensity on an electronic 0-10 cm visual analogue scale (VAS) with the lower extreme labelled ‘‘no pain’’ and the upper extreme labelled ‘‘most pain imaginable’’. A computer sampled the VAS pain scores every 5 s. After stop of the infusion the subjects were furthermore asked to describe the quality of pain on a Danish version of the McGill Pain Questionnaire (MPQ). The pain rating indices (PRIs) of the sensory, affective, evaluative and miscellaneous dimension of pain were calculated in accordance with Melzack (1975). The VAS peak pain score was for each subject defined as the highest value on the time – VAS curve and the pain duration as the difference between the VAS onset and VAS offset. 2.5. Pressure pain threshold A pressure algometer (Somedic, Sweden) was used to measure the PPTs. The PPT was defined as the amount of pressure (kPa), which the subjects first perceived to be painful (Svensson et al., 1995). The probe with 1 cm diameter was applied perpendicular to the central part of the left and right masseter and temporalis muscles (MAL, MAR, TAL and TAR). During the pressure stimulation, the subjects kept their teeth in the intercuspal position with minimum voluntary contraction and
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focused their attention on the experimental task. The subject pushed a button to stop the pressure stimulation when the threshold was reached. The PPTs were determined in triplicate with a constant application rate of 30 kPa/s. There was a time lag of about 2 min between repeated measurements. The mean value was used for further statistical analysis. 2.6. Jaw-stretch reflexes Stretch reflexes were evoked in the jaw-closing muscles with a standardised muscle stretcher (1 mm displacement, 10 ms ramp time), which previously has been described in details (Miles et al., 1993; Svensson et al., 2000, 2001; Wang and Svensson, 2001; Wang et al., 2000, 2001). In brief, bipolar disposable surface electrodes (Neuroline 720-01-K, Medicotest, Ølstykke, Denmark) were placed bilaterally on the central part of the masseter and anterior temporalis muscles (MAL, MAR, TAL and TAR). The skin over the recording positions was cleaned with alcohol and the impedance of the electrodes was kept < 20 kX. A ground electrode soaked with saline was attached to the left wrist. The EMG signals were amplified 2000–5000 times (Counterpoint MK-2, Dantec, Denmark), filtered with bandpass 20 Hz to 1 kHz, sampled at 4 kHz and stored for later analysis. The subjects performed three maximal clenches each lasting up to 3 s on the bar with their incisor teeth to obtain the mean EMG value of the maximal voluntary contraction (MVC) in the four muscles. The MVC calculated from the EMG activity of right masseter (painful side) was used to construct a window of 10% below and above the 15% MVC (i.e., 13.5–16.5% MVC). On-line calculation of the root-mean-square (RMS) value in 200 ms intervals of the EMG was performed with the use of LabView. The subjects received visual feedback from markers on a computer screen, which changed from green to red upon crossing the upper and lower limits of the window (Svensson et al., 1998). If the ongoing EMG activity remained within the pre-set window for more than 400 ms, the program automatically triggered the muscle stretcher. A total of 300 ms EMG activity was recorded with 100 ms prestimulus and 200 ms post-stimulus. Twenty trials with an inter-stimulus interval about 10 s were recorded in each condition (baseline, post-drug, pain-post-drug, post-pain). In the pain-post-drug condition, the reflex recordings were started 20–30 s after the injection of hypertonic saline (Fig. 1). A special-purpose computer program processed the reflex responses evoked in the EMG by the fast stretches. First, the mean EMG in the pre-stimulus interval ()100 to 0 ms) of the averaged and rectified signal was calculated (lV). Then, the peak-to-peak amplitude of the early reflex component, which appeared as a biphasic potential in the average of the non-rectified
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recordings, was measured (lV). Finally, the peak-topeak amplitude was normalised with respect to the mean pre-stimulus EMG activity, i.e., the ratio between the amplitude and pre-stimulus EMG activity (Wang et al., 2000). 2.7. Statistics VAS peak pain scores, pain duration and MPQ scores produced by injection of hypertonic saline were compared with analyses of variance (ANOVA) with repeated measures and one factor: test medication (three levels: tolperisone hydrochloride, pridinol mesilate and placebo). PPTs were analysed with a three-way ANOVA with repeated measures and followed by pairwise multiple comparison procedures (Tukey tests). The factors in the ANOVA were: test medication (three levels), muscle (four levels: MAL, MAR, TAL and TAR) and
time of measurement (three levels: baseline, post-drug and post-pain). The pre-stimulus EMG activity and normalised jaw-stretch reflexes were analysed in a similar way: test medication (three levels), muscle (four levels) and time of measurement (four levels: baseline, post-drug, pain-post-drug and post-pain). Furthermore, as a measure of the intrasubject variability across the three experimental sessions, the coefficient of variation (CV ¼ standard deviation/mean in percentage) was calculated for the different outcome parameters. The significance level was set at P < 0:05. Mean values SEM are presented in the text and figures.
3. Results In total, the test medication was administered to 16 subjects. One subject withdrew from the experiment during first session (pridinol mesilate) due to moderate dizziness. The symptom spontaneously disappeared after 6 h. Fifteen subjects finished all three sessions of the study. Two out of the 15 subjects experienced slight dizziness during the sessions with pridinol mesilate and placebo, respectively. However, the relation to administration of the test medication was unlikely according to the two subjects and the experiments could be continued. 3.1. Experimental jaw-muscle pain
Fig. 2. Perceived pain rated by the subjects ðN ¼ 15Þ on visual analogue scales (VAS) following injection of hypertonic saline into the masseter muscle in the three sessions with administration of tolperisone hydrochloride, pridinol mesilate or placebo. Mean values and SEM.
Injection of 0.3 ml hypertonic saline produced in all subjects a moderate to strong jaw-muscle pain, which was centred on the masseter muscle and spreading towards the temporomandibular joint, temple and teeth. The pain reached its peak intensity after 20–30 s and then gradually decreased lasting up to 600 s (Fig. 2). The pain was consistently (> 30% of the subjects) described on the MPQ as ‘‘hurting’’ (42%), ‘‘pressing’’ (40%), ‘‘boring’’ (38%), ‘‘penetrating’’ (36%), ‘‘tingling’’ (31%) and ‘‘intense’’ (31%). Less frequent words used to describe pain were ‘‘sickening’’ (29%), ‘‘shooting’’ (29%), ‘‘piercing’’ (27%), ‘‘taut’’ (27%), ‘‘tender’’ (24%), ‘‘nagging’’ (24%) and ‘‘tiring’’ (22%). The pain rating indices (PRIs) derived from the MPQ are shown in Table 1. The PRIs were not significantly influenced by the test medication (ANOVA: F < 2:551; P > 0:096). The intraindividual coefficient of variation (CV) for the
Table 1 PRI(S)
PRI(A)
PRI(E)
PRI(M)
Tolperisone hydrochloride Pridinol mesilate Placebo
10:6 1:6 12:0 1:9 11:6 1:7
1:0 0:4 2:1 0:7 1:3 0:5
1:7 0:4 1:7 0:4 2:5 0:5
4:3 0:7 4:8 0:7 4:4 0:9
ANOVA tests
P ¼ 0:623
P ¼ 0:096
P ¼ 0:099
P ¼ 0:842
Pain rating indices (PRI) of sensory (S), affective (A), evaluative (E) and miscellaneous (M) dimension of pain from the McGill Pain Questionnaire. ANOVA tests did not find significant differences between the test medications.
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PRIs were S ¼ 29 4%, A ¼ 65 18%, E ¼ 64 19% and M ¼ 51 11%. There was a significant difference in VAS peak pain scores following the test medications (ANOVA: F ¼ 4:490; P ¼ 0:020). Administration of tolperisone hydrochloride was associated with significantly lower VAS peak pain scores (5:9 0:4 cm) compared with pridinol mesilate (6:8 0:4 cm) and placebo (6:6 0:4 cm) (Tukey: P < 0:05). The duration of the salineevoked jaw-muscle pain in the tolperisone hydrochloride session (417 27 s), pridinol mesilate session (370 28 s) and placebo session (429 26 s) was not significantly different (F ¼ 2:06; P ¼ 0:146). The intraindividual CV for the VAS peak pain score was 12 2% and for the pain duration 20 3%. 3.2. Pressure pain thresholds Analyses of variance of the PPTs showed that there was no main effect of any test medication (F ¼ 0:326; P ¼ 0:725) or time of measurement (F ¼ 0:534; P ¼ 0:592), but a significant difference between muscles (F ¼ 6:894; P < 0:001). However, there was a significant interaction between test medication and time of measurement (F ¼ 4:968; P ¼ 0:002) and post hoc tests demonstrated significantly lower PPTs following administration of pridinol mesilate compared to tolperisone hydrochloride and placebo only in the post-drug condition (Tukey: P < 0:05) (Fig. 3). The intraindividual CVs for the four jaw-muscles were MAL ¼ 10 2%, MAR ¼ 12 2%, TAL ¼ 13 3% and TAR ¼ 10 2%. 3.3. Jaw-stretch reflexes The fast stretch of the contracting jaw-muscles evoked an early (8–9 ms) biphasic response in the EMG in all subjects in accordance with previous reports (Svensson et al., 2001; Wang et al., 2000, 2001).
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Fig. 4. Ratios between peak-to-peak amplitudes of the jaw-stretch reflexes and the pre-stimulus EMG activity at baseline, 60 min after administration of the three test medications (post-drug), during ongoing jaw-muscle pain (pain-post-drug), and after experimental pain (post-pain). Mean values (SEM) from 15 subjects. The values from four muscles (left and right masseter and temporalis) are pooled since there were no significant interactions between muscles and test medication ðF ¼ 0:693; P ¼ 0:656Þ. *Indicates significantly higher values for the pain-post-drug condition compared with baseline and the postdrug condition (Tukey: P < 0:05).
Analyses of variance of the pre-stimulus EMG activity showed that there was no main effect of any test medication (F ¼ 1:932; P ¼ 0:146 or time of measurement (F ¼ 0:184; P ¼ 0:907), but a significant difference between muscles (F ¼ 127:6; P < 0:001). Analyses of the peak-to-peak amplitude normalised with respect to prestimulus EMG activity (i.e., ratio) indicated no significant main effect of test medication (F ¼ 0:275; P ¼ 0:762) or muscle (F ¼ 1:200; P ¼ 0:321) but a significant effect of time of measurement (F ¼ 3:174; P ¼ 0:034). Post hoc tests demonstrated significantly higher amplitudes during ongoing jaw-muscle pain (pain-post-drug) compared with baseline and the postdrug conditions (Tukey: P < 0:05) (Fig. 4). No significant interactions between other factors in the ANOVA were identified (F < 1:831; P > 0:069). The intraindividual CVs for the pre-stimulus EMG activity were MAL ¼ 23 4%, MAR ¼ 13 3%, TAL ¼ 28 4% and TAR ¼ 22 4% and for the normalised peak-topeak-amplitudes MAL ¼ 22 3%, MAR ¼ 24 6%, TAL ¼ 34 4% and TAR ¼ 45 7%.
4. Discussion
Fig. 3. Pressure pain thresholds at baseline, 1 h after administration of the three test medications (post-drug) and after experimental pain (post-pain). Mean values (SEM) from 15 subjects. The PPTs from four muscles (left and right masseter and temporalis) are pooled since there were no significant interactions between muscles and test medication (F ¼ 1:121; P ¼ 0:357). Indicates significantly lower PPTs compared to tolperisone hydrochloride and placebo in the post-drug condition (Tukey: P < 0:05).
The main finding in this experimental study was a marginal hypoalgesic effect of tolperisone hydrochloride on the perceived pain intensity of acute, experimental jaw-muscle pain whereas there were no significant effects of any test medication on measures of trigeminal reflex excitability. 4.1. Muscle relaxants and muscle pain Tolperisone hydrochloride has previously been assessed for its efficacy on pain in the craniofacial region
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(Amir et al., 1978). In the open study, which was performed on a small group of TMD patients (n ¼ 15), 150 mg tolperisone hydrochloride for 4 weeks was found to relieve pain in the majority of patients (88%) (Amir et al., 1978). Similar results were also observed following carisoprodol and occlusal splints and it was subsequently advocated that muscle relaxants could be effective for relieving TMD-related pain (Amir et al., 1978). A double-blind and placebo-controlled study could, however, not demonstrate any significant differences between carisoprodol and placebo in patients with TMD-related pain (Gallardo et al., 1975). Dionne (1997) noted that there appeared to be a discrepancy between the common clinical use of systemic muscle relaxants for relieve of musculoskeletal pain and the results of randomised placebo-controlled clinical trials. Furthermore, nonspecific central nervous system depression could, in part, account for a hypoalgesic effect of muscle relaxants (Dionne, 1997). Tolperisone hydrochloride, however, appears to be a rather unique muscle relaxants because few central nervous system side effects are noted even at high doses (Dulin et al., 1998). Daily administration of 150 or 450 mg tolperisone hydrochloride for 8 days did not impair a battery of psychomotor tests including reaction time measurements in healthy subjects, which suggests that sedation is not a major problem at clinical relevant doses. Furthermore, few side effects like headache and fatigue (four and two out of 24 subjects, respectively) were noted with 450 mg tolperisone hydrochloride (Dulin et al., 1998). This is in accordance with the present study with 300 mg tolperisone hydrochloride as a single dose without significant side effects. It is therefore unlikely that nonspecific central nervous system effects can account for the observed hypoalgesic effect of tolperisone hydrochloride in the present study. A recent RCT in patients with a clinical diagnosis of painful reflex muscle spasms appear to support the notion of a weak hypoalgesic effect of 300 mg tolperisone hydrochloride (Pratzel et al., 1996). In that study, muscle spasms were defined as involuntary muscle contractions and local tenderness on manual palpation. Although no operationalised criteria or direct electrophysiological measurements of the muscle spasms were presented it is interesting to note that treatment with tolperisone hydrochloride compared with placebo after 10 and 21 days was associated with a significantly higher increase in PPTs whereas no significant difference could be found in the manually palpated muscle tone. In the present study no significant effects on PPTs in the jawmuscles could be observed following administration of tolperisone hydrochloride. The reasons for these findings are not known, but it could be, that multiple dosing of tolperisone hydrochloride is needed in order to increase PPTs as it was shown in the clinical trial of Pratzel et al. (1996). Concerning pridinol mesilate a
significant reduction of the PPT compared with placebo and tolperisone was found. This effect of pridinol mesilate was not expected and so far there is no explanation for it. Nevertheless, the differential actions of tolperisone hydrochloride and pridinol mesilate on VAS peak pain scores and PPTs (Figs. 2 and 3) in the present study support the notion of different receptor mechanisms for the two types of muscle relaxants (see Section 1). In the present study there were no significant effects of injection of hypertonic saline on the PPTs (Fig. 3). This finding is in accordance with our previous studies using hypertonic saline injections (Graven-Nielsen et al., 1998a,b; Svensson et al., 1995) and suggests a lack of sensitisation to mechanical stimuli when assessed with PPTs on the local pain area. In contrast to hypertonic saline, injection of the excitatory amino acid glutamate into muscle tissue is associated with a significant decrease in mechanical threshold both in animal preparations (Cairns et al., 2002) and in human studies (Svensson et al., 2003). Thus, further studies may be needed to examine the hypoalgesic effect versus the antiallodynic and anti-hyperalgesic properties of for example muscle relaxants. In summary, there is limited experimental and clinical evidence in favour of a pronounced hypoalgesic effect of systemic muscle relaxants, but a small effect could be detected for tolperisone hydrochloride in a highly standardised acute muscle pain model. 4.2. Muscle relaxants and jaw-reflexes Both tolperisone hydrochloride and pridinol mesilate have a strong and well-documented effect on spinal reflex circuits and motoneurones when assessed in animal preparations (Farkas et al., 1989; Ito et al., 1985; Kaneko et al., 1987; Ono et al., 1984; Sakitama, 1993). The depression of spinal synaptic transmission by tolperisone hydrochloride may be related to both pre-synaptic and post-synaptic mechanisms in addition to a direct membrane stabilising effect on primary afferent fibres (Ono et al., 1984). However, less is known about the trigeminal reflex excitability in human subjects. Takata et al. (1996) demonstrated in an open study on five healthy subjects that 100 mg tolperisone hydrochloride was associated with a marked depression of the tonic vibration reflex measured in the masseter muscles. Vibration (e.g., for 20 s) is a potent stimulus of primary muscle spindles leading to a tonic excitation of motoneurones and activity in the EMG related to the duration of the stimulus (Desmedt and Godaux, 1975). A single rapid stretch (10 ms) is also adequate to activate primary muscle spindles and generate a short-latency reflex (8–9 ms) response in the pre-contracted masseter muscle (Miles et al., 1993; Poliakov and Miles, 1994; Wang et al., 2000; Wang and Svensson, 2001). We have previously shown a facilitation of the short-latency
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stretch reflex in the masseter muscle when exposed to experimental jaw-muscle pain (Svensson et al., 2001; Wang et al., 2000, 2001) in accordance with a significant facilitation of the stretch reflex in the soleus muscle during experimental pain (Matre et al., 1998). The mechanisms for this facilitation are not entirely clear but changes in the fusimotor control linked to the nociceptive barrage have been suggested (Pedersen et al., 1997). We had anticipated that the centrally acting muscle relaxants would suppress the amplitude of the jaw-stretch reflex response by similar mechanisms described above for the spinal reflex circuits but this was not observed in the present study. Furthermore, it was speculated that the facilitation of the jaw-stretch reflex response by experimental muscle pain would be antagonised with the concurrent medication of tolperisone hydrochloride or pridinol mesilate. In accordance with our previous studies on tonic jaw-muscle pain (Svensson et al., 2001; Wang et al., 2000, 2001), the present more phasic type of jaw-muscle pain was in all the sessions associated with a significant increase in the normalised peak-to-peak amplitude of the jaw-stretch reflex, however, there were no significant differences between the sessions with muscle relaxants or placebo. One possible explanation for the lack of effect of tolperisone hydrochloride could be that the jaw-stretch reflex is recorded during a slight (15% MVC) voluntary, pre-contraction of the masseter muscle, which could mask an effect on the trigeminal reflex circuits in agreement with the suggestion of Romaniello et al. (2000). However, this and our previous studies on jaw-stretch reflexes (Wang et al., 2000, 2001; Svensson et al., 2001) have all been able to demonstrate a significant pain-related increase in the reflex amplitude under these experimental conditions. Moreover, in the present study we found no significant differences in the prestimulus EMG activity at any time point during the experiments. Thus, we do not believe that methodological concerns are the main reason for the lack of effect of tolperisone hydrochloride on the jaw-stretch reflex. Another possibility is that the doses and timing of the medication in relation to the recording of the jaw-stretch reflexes were not optimal. Even if the average peak plasma concentration of tolperisone has been identified after 1.5 h (Miskolczi et al., 1987) and the elimination half time is reported to be around 2.5 h (Dulin et al., 1998) it is also known, that tolperisone hydrochloride has a high interindividual variability of pharmacokinetic parameters like peak plasma concentration and elimination half time. Finally, the variability of the outcome measures in experimental pain studies needs to be considered (Yarnitsky et al., 1996). In the present study we employed techniques, which previously have been sufficiently sensitive to detect effects of experimental manipulations in paired designs (Svensson et al., 1995, 2001). The intraindividual coefficient of variations (CV) for the PPTs
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and saline-evoked pain were generally low (< 20%) and within the range of CVs for other psychophysical techniques (Svensson et al., 1991; Yarnitsky et al., 1996). However, the CVs for MPQ measures were higher (29–65%) and could, in part, explain the lack of any significant differences between the three sessions. The CVs for the jaw-reflex measures were moderately low for the masseter muscles (13–24%) but higher for the temporalis muscles (22–45%) suggesting difficulties to find significant differences in the temporalis muscles. Nevertheless, a significant effect of jaw-muscle pain was found on the normalised peak-to-peak amplitude, which indicates that the present technique is adequate to detect consistent effects in a paired design. In conclusion, a single dose of 300 mg tolperisone hydrochloride provides a small, albeit significant reduction in the perceived intensity of experimental jawmuscle pain but did not show a significant effect on the short-latency jaw-stretch reflex in the present set-up.
Acknowledgements The Danish National Research Foundation supported the study and Strathmann AG, Germany provided the test medication.
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