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The effects of gabapentin in human experimental pain models
Scandinavian Journal of Pain 1 (2010) 143–148
Contents lists available at ScienceDirect
Scandinavian Journal of Pain journal homepage: www.ScandinavianJournalPain.com
Original experimental
The effects of gabapentin in human experimental pain models夽 Thomas P. Enggaard a,b,∗ , Søren S. Mikkelsen a , Stine T. Zwisler a,b , Niels A. Klitgaard c , Søren H. Sindrup b,d a
Department of Anaesthesiology and Intensive Care Medicine, Odense University Hospital, Denmark Clinical Pharmacology, University of Southern Denmark, Denmark Section of Clinical Pharmacology, Clinical Biochemistry and Clinical Genetics, Odense University Hospital, Denmark d Department of Neurology, Odense University Hospital, Denmark b c
a r t i c l e
i n f o
Article history: Received 18 December 2009 Received in revised form 18 April 2010 Accepted 19 April 2010 Keywords: Human experimental pain model Neuropathic pain Electrical nerve stimulation Temporal summation Cold pressor test Gabapentin
a b s t r a c t Background: The antidepressant drugs imipramine and venlafaxine relieve clinical neuropathic pain and have been shown to increase pain thresholds in healthy volunteers during repetitive electrical sural nerve stimulation causing temporal pain summation, whereas pain during the cold pressor test is unaltered by these drugs. If this pattern of effect in experimental pain models reflects potential efficacy in clinical neuropathic pain, the pain summation model may potentially be used to identify new drugs for such pain conditions. Gabapentinoids are evidence-based treatments of clinical neuropathic pain and could contribute with additional knowledge of the usefulness of the pain summation model. The aim of this study: To test the analgesic effect of the gabapentinoid gabapentin in a sural nerve stimulation pain model including temporal pain summation and the cold pressor test. Method: 18 healthy volunteers completed a randomized, double-blind, cross-over trial with medication of 600 mg gabapentin orally dosed 3 times over 24 h against placebo. Pain tests were performed before and 24 h after medication including pain detection and tolerance to single sural nerve stimulation and pain summation threshold to repetitive stimulation (3 Hz). Peak pain intensity and discomfort were rated during a cold pressor test. Results: Compared to placebo, gabapentin had a highly significant effect on the threshold of pain summation to repetitive electrical sural nerve stimulation (P = 0.009). Gabapentin significantly increased the pain tolerance threshold to single electrical sural nerve stimulation (P = 0.04), whereas the pain detection threshold to single electrical sural nerve stimulation tended to be increased (P = 0.06). No significant differences were found on pain ratings during the cold pressor test. Conclusion: Gabapentin had a selective hypoalgesic effect in a human experimental pain model of temporal pain summation and the results lend further support to the usefulness of the pain summation model to identify drugs for neuropathic pain. © 2010 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
DOI of refers to article:10.1016/j.sjpain.2010.01.008. 夽 Preliminary results from this study were presented as a poster at the 80th IARS Clinical and Scientific Congress, San Francisco, CA, USA, March 24–26, 2006 and at the 30th Annual Meeting, in Scandinavian Association for the Study of Pain (SASP), Stockholm, Sweden, May 4–7, 2006. ∗ Corresponding author at: Department of Anaesthesiology and Intensive Care Medicine, Odense University Hospital, Sdr. Boulevard 29, DK-5000 Odense C, Denmark. E-mail address: [email protected] (T.P. Enggaard). 1877-8860/$ – see front matter © 2010 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.sjpain.2010.04.001
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T.P. Enggaard et al. / Scandinavian Journal of Pain 1 (2010) 143–148
1. Introduction Experimental pain models, when designed with careful consideration of the pharmacological mechanisms and pharmacokinetics of analgesics, may help to evaluate the mechanisms of analgesics and target the clinical indications for their use [1]. The antidepressant drugs imipramine and venlafaxine relieve clinical neuropathic pain [2] and have been shown to increase pain thresholds in humans using single and repetitive transcutaneous electrical sural nerve stimulation, whereas pain during the cold pressor test (CPT) is unaltered by these drugs [3,4]. Especially, repetitive nerve stimulation is believed to be of major interest, since it reflects temporal pain summation. The experimental temporal pain summation model is based on a methodical study in which the optimal frequency for facilitating the psychophysical threshold for temporal pain summation was found to be 3 Hz [5]. Temporal pain summation is believed to contribute to central sensitization of pain which represents an important pathopsychological mechanism in the characteristics of chronic pain [6]. Abnormal temporal summation is often a part of the clinical picture in neuropathic pain conditions such as postmastectomy pain and pain in multiple sclerosis [7,8]. The cold pressor test (CPT) is considered a model reflecting opioid analgesia and drugs with non-opioid analgesic mechanisms such as the sodium channel blocking anticonvulsants phenytoin and lamotrigine have only minor effect on pain induced by CPT [9,10], and imipramine is without pain-relieving effect [3]. A pattern with effect in the pain summation model and no effect in the cold pressor model might reflect specific efficacy in clinical neuropathic pain and as such, it is possible that the pain model could be used to identify new drugs for such pain conditions. The anticonvulsant gabapentin is effective in several clinical neuropathic pain conditions [11]. In experimental human pain models, gabapentin has been proven to relieve induced cutaneous hyperalgesia, but not noxious pain induced by heat or cold [12–14]. The aim of this study was primarily to test whether the analgesic effect of gabapentin can be detected in a sural nerve stimulation pain model with single and repetitive electrical stimulation. Assessment of temporal pain summation was included in order to determine the potential of this experimental model as a screening tool to identify substances to be tested in clinical trials in neuropathic pain. Gabapentin has not previously been tested in this pain model using transcutaneous electric nerve stimulation. The temporal summation threshold was the main endpoint in this study. The cold pressor test was added as a supplemental pain model. A previous study has shown that a single dose of 600 mg gabapentin by itself did not reduce pain induced by the cold pressor test in healthy volunteers, but increased the analgesic effect of 60 mg morphine [13]. Since the clinical analgesic effect of gabapentin on chronic neuropathic pain is observed at repetitive doses at 1800 mg daily or higher, an analgesic response at this dose of gabapentin could not be excluded. Gabapentin shows a saturable absorption kinetic, which limits the benefit of a high single dose [15]. Thus, we found it relevant to test the impact of gabapentin using a repetitive dosing design.
dure, and the study was approved by Scientific Ethical Committee of the Vejle and Funen counties (J.No. VF 20030233) and the Danish Medicines Agency (J.No. 2612-2429). 2.2. Design The study design was randomised, double-blind, balanced and cross-over, including 2 study periods of 2 days’ duration with a total oral dose of gabapentin 1800 mg, divided into 3 doses of 600 mg, (2 capsules of 300 mg; manufacturer: Pfizer, Denmark) against identical placebo. Each volunteer was instructed to take the medication with intervals of 8 h, so the last dose of the study medication was taken 2 h before the beginning of the test round of day 2. The study periods were separated by at least one week for washout. 2.3. Nociceptive tests At the time of inclusion in the study, the volunteers were familiarised with the test procedures. On each study day, the measurements of the nociceptive tests were performed in the same way. On the first study day in each round, the volunteers initially were subjected to a test round in which all pain stimulation tests were performed during which no measurements were obtained. This was done in order to minimize adaptation phenomena. As described below, the effect variables were determined before and 24 h after the start of medication. 2.4. Electrical sural nerve stimulation Percutaneous electrical stimulation of the sural nerve was performed along its retromalleolar path by applying a constant-current rectangular pulse consisting of 5 pulses (each of 1 ms duration) delivered at 200 Hz (single stimulation) or this stimulation mode repeated 5 times with a frequency of 3 Hz (repetitive stimulation). Psychophysical pain detection and tolerance thresholds were determined to single stimulation. For the repetitive stimulation, pain summation threshold was defined as the stimulation strength at which the pain distinctly increased through the 5 stimulations and reached a painful level at the 4th or 5th stimulation. All thresholds were determined twice and the mean value was used in the data analysis. 2.5. Cold pressor test
2. Methods
The left hand was immersed into iced water (1.0 Celsius (±0.3 Celsius)) that was continuously stirred by a pump. The subject removed his/her hand from the water after 2 min of immersion, or sooner if the pain was considered intolerable. In the event that the subject had to remove his/her hand from the iced water, pain was automatically determined to be 100 mm on the VAS. Pain intensity was continuously rated during the test by use of an electronic visual analogue scale coupled to a computer. From the data obtained, peak pain intensity was determined [9]. Immediately after the test, the subjects rated the discomfort experienced during the procedure on a visual analogue scale (0–100 mm). The subject was asked to rate the worst discomfort during the cold pressor test by marking a point on the 0–100 mm scale using a pen.
2.1. Subjects
2.6. Reaction time and side effects
The study included 20 healthy volunteers (14 men and 6 women) aged 23–31 years (median 24.5 years). The volunteers were not allowed to consume alcohol or any drugs except for the study medication on study days, and were instructed to consume their usual daily quantity of coffee and tea, if any. Written informed consent was obtained from the volunteers before the study proce-
Reaction time to auditory stimuli was determined by use of a computer program to control for a possible sedating effect of the study drug. A sound was generated at random intervals and reaction time was determined as the time elapsed from appearance of the sound and to the subject responded by pressing a button. A total of 3 tests were carried out for each subject at each pain measurement
T.P. Enggaard et al. / Scandinavian Journal of Pain 1 (2010) 143–148 Table 1 Baseline values showed as median (first versus third quartile). Electrical nerve stimulation
Gabapentin
Single stimulation Pain detection threshold (mA) Pain tolerance threshold (mA) Repeated stimulation Temporal pain summation threshold (mA) Cold pressor test Peak pain intensity (cm VAS) Discomfort (mm VAS)
2.7. Serum drug analysis
Placebo
6.5 (6.0; 10.875) 13.5 (10.25; 20.25)
7.0 (5.75; 9.5)
9.435 (8.325; 10) 76.5 (71.5; 88.5)
8.5 (6.0; 10.0) 14.5 (11.0; 21.125)
8.0 (6.5; 10.0)
9.315 (8.51; 10) 78.5 (70.5; 86.75)
Table 2 Differences in pain thresholds and ratings between post- and pre-medication values. Pain tests Electrical nerve stimulation Single stimulation Pain detection threshold (mA) Pain tolerance threshold (mA) Repeated stimulation Temporal pain summation threshold (mA) Cold pressor test Peak pain intensity (cm VAS) Discomfort (mm VAS)
Gabapentina
Placeboa
145
After each measurement session, 20 ml of blood was drawn for determination of serum drug concentration. The concentration of gabapentin was determined by use of an HPLC. 2.8. Data analysis and statistics For each of the variables, the difference between the premedication value and the post-medication value was calculated in order to obtain a measure of effect for each subject. These differences between gabapentin and placebo were compared by use of the Wilcoxon–Pratt test for paired differences. Correlations between effect and serum concentrations of gabapentin were tested by use of the Spearman rank correlation test. All data analyses were performed by use of the statistical program MEDSTAT (ASTRA Group A/S, Denmark). Statistical significance was accepted at the 5% level.
P valueb
3. Results 0.0 (−2.0;2.5)
−0,5 (−3.0;4.0)
(P = 0.06)
0.75 (−2.5;3.0)
0.5 (−5.0;3.0)
(P = 0.04)
0.25(−3.5;4.0)
−0.5 (−5.5;1.0)
(P = 0.009)
Eighteen volunteers completed the study. Two male volunteers were excluded from the study due to lack of compliance. They did not take the study medication and did not show up on the last day in the last study period. 3.1. Pharmacodynamic results
0.0 (−5.8;0.6)
−0.1 (−1.4;0.5)
(P > 0.2)
−1.5 (−77;5)
−0.5 (−17;13)
(P = 0.18)
a Median and ranges of differences between pre- and post-medication values of gabapentin (three doses of 600 mg) and placebo. b Wilcoxon–Pratt test: gabapentin versus placebo.
and the mean value of the 3 tests was used for data analysis. After each study day, the volunteers were asked if they had experienced any side effects of the medication such as dizziness, tiredness, nausea or discomfort, which was rated 0 = none, 1 = light, 2 = moderate and 3 = severe.
Compared with placebo, gabapentin significantly increased the pain tolerance threshold to single electrical sural nerve stimulation (P = 0.04), whereas the effect on pain detection threshold to single electrical sural nerve stimulation did not reach statistical significance (P = 0.06). Gabapentin had a significant effect on the pain summation threshold to repetitive electrical sural nerve stimulation (P = 0.009). No significant differences were found between gabapentin and placebo on pain ratings during the cold pressor test. Data from the pain tests are shown in Tables 1 and 2. The changes in pain thresholds and ratings calculated in as box plots are shown in Figs. 1–5. Eight volunteers reported at least one side effect related to the medication during the gabapentin treatment but not during the treatment with placebo. Two volunteers reported side effects dur-
Fig. 1. The changes in pain detection thresholds during electrical sural nerve stimulation before medication and after end of medication with placebo (white box) and gabapentin (grey box). The results are calculated as first and third quartile (box) and median values as horizontal line in percentage terms.
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Fig. 2. The changes in pain tolerance detection thresholds during electrical sural nerve stimulation before medication and after end of medication with placebo (white box) and gabapentin (grey box). The results are calculated as first and third quartile (box) and median values as horizontal line in percentage terms.
ing both treatments and 8 did not experience any side effects at all. All side effects were reported as mild. 3.2. Reaction time There were no significant differences in changes from premedication reaction time with gabapentin treatment compared with placebo. 3.3. Serum concentration and concentration–effect relationship Gabapentin could be detected in all the post-medication serum samples on the study day with gabapentin dosing from all volunteers who completed the study. The median
value of serum gabapentin concentration was 35.6 nmol/l (range 30.4–60.0 nmol/l). The serum concentration of gabapentin in the placebo period was below the limit of detection in all the volunteers. No significant correlations between effect and serum concentration of gabapentin were found. 4. Discussion The present study confirms results from a previous study in which gabapentin also had a selective effect in human experimental pain models including temporal pain summation [16]. In contrast to the previous study, we have used multiple doses of gabapentin and demonstrated that the threshold for temporal pain summation can be compared from day to day, which makes repet-
Fig. 3. The changes in temporal pain summation thresholds during electrical sural nerve stimulation before medication and after end of medication with placebo (white box) and gabapentin (grey box). The results are calculated as first and third quartile (box) and median values as horizontal line in percentage terms.
T.P. Enggaard et al. / Scandinavian Journal of Pain 1 (2010) 143–148
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Fig. 4. The changes in peak pain intensity during the cold pressor test before medication and after end of medication with placebo (white box) and gabapentin (grey box). The values are calculated as first and third quartiles (box) and median values as horizontal line in percentage terms.
itive medication possible in phase II trials. This study shows that gabapentin is without pain-relieving effect in the cold pressor test. The cold-induced pain has been shown to be relieved by different acting drugs such as opioids and the sodium channel blocking anticonvulsants phenytoin and lamotrigine [9,10], whereas the monoaminergic antidepressants imipramine and venlafaxine like gabapentin with calcium channel blocking effect are without effect in the cold pressor test [3,4]. This could indicate that gabapentin in line with the monoaminergic antidepressants has a rather selective effect on acute experimental pain which could be indicative for efficacy in clinical neuropathic pain conditions. If an opioid had been included in the study, we would have been able to add a positive control in the cold pressor test. However, the analgesic effect of opioids in the cold pressor test is well documented and was not the primary endpoint in this study. We did not make a sample size calculation before the study. A clinically relevant difference can be difficult to estimate in an experimental pain model. The number of volunteers has been decided
based on previously performed studies using the same pain models [4,17]. This study used multiple instead of single doses of gabapentin to achieve a clinically relevant drug level similar to steady stateconcentrations in patients treated with 1800 mg gabapentin per day [18]. The serum concentrations of gabapentin found in the present study appear to be higher than the values measured in published experimental human pain studies where a single dose of 1200 mg gabapentin was used [11,13] and similar to the concentrations measured in the study using multiple doses of gabapentin per day with a daily dose of 1800 mg during 15 days [19]. Inhibition of temporal pain summation has so far been suggested as an indicator for drug efficacy in neuropathic pain. The NMDA-glutamate receptor antagonist, ketamine increases temporal pain summation threshold in this model [20] and i.v. infusion of ketamine relieves clinical neuropathic pain [21–23]. The antiepileptic drug levetiracetam has been investigated in this pain model and was found to increase the pain tolerance threshold for
Fig. 5. The changes in discomfort during the cold pressor test before medication and after end of medication with placebo (white box) and gabapentin (grey box). The values are calculated as first and third quartiles (box) and median values as horizontal line in percentage terms.
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single electrical nerve stimulation, but did not alter in temporal pain summation [17]. A clinical randomized trial has shown that levetiracetam has no effect on postmastectomy neuropathic pain [24]. The potential effect on temporal pain summation may be relevant in this pain condition, since temporal summation has been investigated in a study on patients suffering from this neuropathic pain after treatment of breast cancer. The frequency of temporal summation evoked by repetitive pinprick was found to be higher in patients with pain than in pain-free patients [25]. The role of the temporal pain summation model as a predictor for relief of clinical neuropathic pain is still to be settled, but this study could indicate that inhibition of temporal pain summation is one of several predictors of analgesic effect on neuropathic pain. 5. Conclusion Gabapentin inhibits temporal pain summation in a human experimental nerve stimulation model using repetitive electrical nerve stimulation, but has no impact on pain during the cold pressor test. In the search for new drugs with potential effect in neuropathic pain condition, experimental human pain models using temporal pain summation may be a useful tool, but further studies defining sensitivity and specificity of the model are needed. Acknowledgements This study was financially supported by Odense University Hospital and University of Southern Denmark. Pfizer Denmark delivered the study medication and supported the study financially. References [1] Staahl C, Olesen AE, Andresen T, Arendt-Nielsen L, Drewes AM. Assessing efficacy of non-opioid analgesics in experimental pain models in healthy volunteers: an updated review. Br J Clin Pharmacol 2009;68:322–41. [2] Sindrup SH, Otto M, Finnerup NB, Jensen TS. Antidepressants in the treatment for neuropathic pain. Basic Clin Pharmacol Toxicol 2005;96:399–409. [3] Enggaard TP, Poulsen L, Arendt-Nielsen L, Hansen SH, Björnsddottir I, Gram LF, Sindrup SH. The analgesic effect of codeine as compared to imipramine in different human experimental pain models. Pain 2001;92:277–82. [4] Enggaard TP, Klitgaard NA, Gram LF, Arendt-Nielsen L, Sindrup SH. Specific effect of venlafaxine on single and repetitive experimental painful stimuli in humans. Clin Pharmacol Ther 2001;69:245–51. [5] Arendt-Nielsen L, Brennum J, Sindrup S, Bak P. Electrophysiological and psychophysical quantification of temporal summation in the human nociceptive system. Eur J Appl Physiol Occup Physiol 1994;68:266–73.
[6] Eide PK. Wind-up and the NMDA receptor complex from a clinical perspective. Eur J Pain 2000;4:5–15. [7] Gottrup H, Andersen J, Arendt-Nielsen L, Jensen TS. Psychophysical examination in patients with post-mastectomy pain. Pain 2000;87:275–84. [8] Svendsen KB, Jensen TS, Hansen HJ, Bach FW. Sensory function and quality of life in patients with multiple sclerosis and pain. Pain 2005;114:473–81. [9] Jones SF, McQuay HJ, Moore RA, Hand CW. Morphine and ibuprofen compared using the cold pressor test. Pain 1988;34:117–22. [10] Webb J, Kamali F. Analgesic effects of lamotrigine and phenytoin on coldinduced pain: a cross-over placebo-controlled study in healthy volunteers. Pain 1998;76:357–63. [11] Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Algorithm for neuropathic pain treatment: an evidence based proposal. Pain 2005;118:289–305. [12] Dirks J, Petersen KL, Rowbotham MC, Dahl JB. Gabapentin suppresses cutaneous hyperanalgesia following heat-capsaicin sensitization. Anesthesiology 2002;97:102–7. [13] Eckhardt K, Ammon S, Hofmann U, Riebe A, Gugeler N, Mikus G. Gabapentin enhances the analgesic effect of morphine in healthy volunteers. Anesth Analg 2000;91:185–91. [14] Werner MU, Perkins FM, Holte K, Pedersen JL, Kehlet H. Effects of gabapentin in acute inflammatory pain in humans. Reg Anesth Pain Med 2001;26:322–8. [15] Stewart BH, Kugler AR, Thompson PR, Bockbrader HN. A saturable transport mechanism in the intestinal absorption of gabapentin is the underlying cause of the lack of proportionality between increasing dose and drug levels in plasma. Pharm Res 1993;10:276–81. [16] Arendt-Nielsen L, Frøkjaer JB, Staahl C, Graven-Nielsen T, Huggins JP, Smart TS, Drewes AM. Effects of gabapentin on experimental somatic pain and temporal summation. Reg Anesth Pain Med 2007;32:382–8. [17] Enggaard TP, Klitgaard NA, Sindrup SH. Specific effect of levetiracetam in experimental human pain models. Eur J Pain 2006;10:193–8. [18] Lindberger M, Luhr O, Johannesen SI, Larsson S, Tomson T. Serum concentrations and effect of gabapentin and vigabatrin: observations from a dose titration study. Ther Drug Monit 2003;25:457–62. [19] Gottrup H, Juhl G, Kristensen AD, Lai R, Chizh BA, Brown J, Bach FW, Jensen TS. Chronic oral gabapentin reduces elements of central sensitization in human experimental hyperalgesia. Anesthesiology 2004;101:1400–8. [20] Arendt-Nielsen L, Petersen-Felix S, Fischer M, Bak P, Bjerring P, Zbinden AM. The effect of N-methyl-d-aspartate antagonist (ketamine) on single and repeated nociceptive stimuli: a placebo-controlled experimental human study. Anesth Analg 1995;81:63–8. [21] Max MB, Byas-Smith MG, Gracely RH, Bennett GJ. Intravenous infusion of the NMDA antagonist, ketamine, in chronic posttraumatic pain with allodynia: a double-blind comparison to alfentanil and placebo. Clin Neuropharmacol 1995;18:360–8. [22] Eide PK, Jorum E, Stubhauge A, Bremnes J, Breivik H. Relief of post-herpetic neuralgia with the N-methyl-d-aspartic acid receptor antagonist ketamine: a double-blind, cross-over comparison with morphine and placebo. Pain 1994;58:347–54. [23] Gottrup H, Bach FW, Juhl G, Jensen TS. Differential effect of ketamine and lidocaine on spontaneous and mechanical evoked pain in patients with nerve injury pain. Anaesthesiology 2006;104:527–36. [24] Vilholm OJ, Cold S, Rasmussen L, Sindrup SH. Effect of levetiracetam on the postmastectomy pain syndrome. Eur J Neurol 2008;15:851–7. [25] Vilholm OJ, Cold S, Rasmussen L, Sindrup SH. Sensory function and pain in a population of patients treated for breast cancer. Acta Anaesthesiol Scand 2009;53:800–6.
Contents lists available at ScienceDirect
Scandinavian Journal of Pain journal homepage: www.ScandinavianJournalPain.com
Original experimental
The effects of gabapentin in human experimental pain models夽 Thomas P. Enggaard a,b,∗ , Søren S. Mikkelsen a , Stine T. Zwisler a,b , Niels A. Klitgaard c , Søren H. Sindrup b,d a
Department of Anaesthesiology and Intensive Care Medicine, Odense University Hospital, Denmark Clinical Pharmacology, University of Southern Denmark, Denmark Section of Clinical Pharmacology, Clinical Biochemistry and Clinical Genetics, Odense University Hospital, Denmark d Department of Neurology, Odense University Hospital, Denmark b c
a r t i c l e
i n f o
Article history: Received 18 December 2009 Received in revised form 18 April 2010 Accepted 19 April 2010 Keywords: Human experimental pain model Neuropathic pain Electrical nerve stimulation Temporal summation Cold pressor test Gabapentin
a b s t r a c t Background: The antidepressant drugs imipramine and venlafaxine relieve clinical neuropathic pain and have been shown to increase pain thresholds in healthy volunteers during repetitive electrical sural nerve stimulation causing temporal pain summation, whereas pain during the cold pressor test is unaltered by these drugs. If this pattern of effect in experimental pain models reflects potential efficacy in clinical neuropathic pain, the pain summation model may potentially be used to identify new drugs for such pain conditions. Gabapentinoids are evidence-based treatments of clinical neuropathic pain and could contribute with additional knowledge of the usefulness of the pain summation model. The aim of this study: To test the analgesic effect of the gabapentinoid gabapentin in a sural nerve stimulation pain model including temporal pain summation and the cold pressor test. Method: 18 healthy volunteers completed a randomized, double-blind, cross-over trial with medication of 600 mg gabapentin orally dosed 3 times over 24 h against placebo. Pain tests were performed before and 24 h after medication including pain detection and tolerance to single sural nerve stimulation and pain summation threshold to repetitive stimulation (3 Hz). Peak pain intensity and discomfort were rated during a cold pressor test. Results: Compared to placebo, gabapentin had a highly significant effect on the threshold of pain summation to repetitive electrical sural nerve stimulation (P = 0.009). Gabapentin significantly increased the pain tolerance threshold to single electrical sural nerve stimulation (P = 0.04), whereas the pain detection threshold to single electrical sural nerve stimulation tended to be increased (P = 0.06). No significant differences were found on pain ratings during the cold pressor test. Conclusion: Gabapentin had a selective hypoalgesic effect in a human experimental pain model of temporal pain summation and the results lend further support to the usefulness of the pain summation model to identify drugs for neuropathic pain. © 2010 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
DOI of refers to article:10.1016/j.sjpain.2010.01.008. 夽 Preliminary results from this study were presented as a poster at the 80th IARS Clinical and Scientific Congress, San Francisco, CA, USA, March 24–26, 2006 and at the 30th Annual Meeting, in Scandinavian Association for the Study of Pain (SASP), Stockholm, Sweden, May 4–7, 2006. ∗ Corresponding author at: Department of Anaesthesiology and Intensive Care Medicine, Odense University Hospital, Sdr. Boulevard 29, DK-5000 Odense C, Denmark. E-mail address: [email protected] (T.P. Enggaard). 1877-8860/$ – see front matter © 2010 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.sjpain.2010.04.001
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T.P. Enggaard et al. / Scandinavian Journal of Pain 1 (2010) 143–148
1. Introduction Experimental pain models, when designed with careful consideration of the pharmacological mechanisms and pharmacokinetics of analgesics, may help to evaluate the mechanisms of analgesics and target the clinical indications for their use [1]. The antidepressant drugs imipramine and venlafaxine relieve clinical neuropathic pain [2] and have been shown to increase pain thresholds in humans using single and repetitive transcutaneous electrical sural nerve stimulation, whereas pain during the cold pressor test (CPT) is unaltered by these drugs [3,4]. Especially, repetitive nerve stimulation is believed to be of major interest, since it reflects temporal pain summation. The experimental temporal pain summation model is based on a methodical study in which the optimal frequency for facilitating the psychophysical threshold for temporal pain summation was found to be 3 Hz [5]. Temporal pain summation is believed to contribute to central sensitization of pain which represents an important pathopsychological mechanism in the characteristics of chronic pain [6]. Abnormal temporal summation is often a part of the clinical picture in neuropathic pain conditions such as postmastectomy pain and pain in multiple sclerosis [7,8]. The cold pressor test (CPT) is considered a model reflecting opioid analgesia and drugs with non-opioid analgesic mechanisms such as the sodium channel blocking anticonvulsants phenytoin and lamotrigine have only minor effect on pain induced by CPT [9,10], and imipramine is without pain-relieving effect [3]. A pattern with effect in the pain summation model and no effect in the cold pressor model might reflect specific efficacy in clinical neuropathic pain and as such, it is possible that the pain model could be used to identify new drugs for such pain conditions. The anticonvulsant gabapentin is effective in several clinical neuropathic pain conditions [11]. In experimental human pain models, gabapentin has been proven to relieve induced cutaneous hyperalgesia, but not noxious pain induced by heat or cold [12–14]. The aim of this study was primarily to test whether the analgesic effect of gabapentin can be detected in a sural nerve stimulation pain model with single and repetitive electrical stimulation. Assessment of temporal pain summation was included in order to determine the potential of this experimental model as a screening tool to identify substances to be tested in clinical trials in neuropathic pain. Gabapentin has not previously been tested in this pain model using transcutaneous electric nerve stimulation. The temporal summation threshold was the main endpoint in this study. The cold pressor test was added as a supplemental pain model. A previous study has shown that a single dose of 600 mg gabapentin by itself did not reduce pain induced by the cold pressor test in healthy volunteers, but increased the analgesic effect of 60 mg morphine [13]. Since the clinical analgesic effect of gabapentin on chronic neuropathic pain is observed at repetitive doses at 1800 mg daily or higher, an analgesic response at this dose of gabapentin could not be excluded. Gabapentin shows a saturable absorption kinetic, which limits the benefit of a high single dose [15]. Thus, we found it relevant to test the impact of gabapentin using a repetitive dosing design.
dure, and the study was approved by Scientific Ethical Committee of the Vejle and Funen counties (J.No. VF 20030233) and the Danish Medicines Agency (J.No. 2612-2429). 2.2. Design The study design was randomised, double-blind, balanced and cross-over, including 2 study periods of 2 days’ duration with a total oral dose of gabapentin 1800 mg, divided into 3 doses of 600 mg, (2 capsules of 300 mg; manufacturer: Pfizer, Denmark) against identical placebo. Each volunteer was instructed to take the medication with intervals of 8 h, so the last dose of the study medication was taken 2 h before the beginning of the test round of day 2. The study periods were separated by at least one week for washout. 2.3. Nociceptive tests At the time of inclusion in the study, the volunteers were familiarised with the test procedures. On each study day, the measurements of the nociceptive tests were performed in the same way. On the first study day in each round, the volunteers initially were subjected to a test round in which all pain stimulation tests were performed during which no measurements were obtained. This was done in order to minimize adaptation phenomena. As described below, the effect variables were determined before and 24 h after the start of medication. 2.4. Electrical sural nerve stimulation Percutaneous electrical stimulation of the sural nerve was performed along its retromalleolar path by applying a constant-current rectangular pulse consisting of 5 pulses (each of 1 ms duration) delivered at 200 Hz (single stimulation) or this stimulation mode repeated 5 times with a frequency of 3 Hz (repetitive stimulation). Psychophysical pain detection and tolerance thresholds were determined to single stimulation. For the repetitive stimulation, pain summation threshold was defined as the stimulation strength at which the pain distinctly increased through the 5 stimulations and reached a painful level at the 4th or 5th stimulation. All thresholds were determined twice and the mean value was used in the data analysis. 2.5. Cold pressor test
2. Methods
The left hand was immersed into iced water (1.0 Celsius (±0.3 Celsius)) that was continuously stirred by a pump. The subject removed his/her hand from the water after 2 min of immersion, or sooner if the pain was considered intolerable. In the event that the subject had to remove his/her hand from the iced water, pain was automatically determined to be 100 mm on the VAS. Pain intensity was continuously rated during the test by use of an electronic visual analogue scale coupled to a computer. From the data obtained, peak pain intensity was determined [9]. Immediately after the test, the subjects rated the discomfort experienced during the procedure on a visual analogue scale (0–100 mm). The subject was asked to rate the worst discomfort during the cold pressor test by marking a point on the 0–100 mm scale using a pen.
2.1. Subjects
2.6. Reaction time and side effects
The study included 20 healthy volunteers (14 men and 6 women) aged 23–31 years (median 24.5 years). The volunteers were not allowed to consume alcohol or any drugs except for the study medication on study days, and were instructed to consume their usual daily quantity of coffee and tea, if any. Written informed consent was obtained from the volunteers before the study proce-
Reaction time to auditory stimuli was determined by use of a computer program to control for a possible sedating effect of the study drug. A sound was generated at random intervals and reaction time was determined as the time elapsed from appearance of the sound and to the subject responded by pressing a button. A total of 3 tests were carried out for each subject at each pain measurement
T.P. Enggaard et al. / Scandinavian Journal of Pain 1 (2010) 143–148 Table 1 Baseline values showed as median (first versus third quartile). Electrical nerve stimulation
Gabapentin
Single stimulation Pain detection threshold (mA) Pain tolerance threshold (mA) Repeated stimulation Temporal pain summation threshold (mA) Cold pressor test Peak pain intensity (cm VAS) Discomfort (mm VAS)
2.7. Serum drug analysis
Placebo
6.5 (6.0; 10.875) 13.5 (10.25; 20.25)
7.0 (5.75; 9.5)
9.435 (8.325; 10) 76.5 (71.5; 88.5)
8.5 (6.0; 10.0) 14.5 (11.0; 21.125)
8.0 (6.5; 10.0)
9.315 (8.51; 10) 78.5 (70.5; 86.75)
Table 2 Differences in pain thresholds and ratings between post- and pre-medication values. Pain tests Electrical nerve stimulation Single stimulation Pain detection threshold (mA) Pain tolerance threshold (mA) Repeated stimulation Temporal pain summation threshold (mA) Cold pressor test Peak pain intensity (cm VAS) Discomfort (mm VAS)
Gabapentina
Placeboa
145
After each measurement session, 20 ml of blood was drawn for determination of serum drug concentration. The concentration of gabapentin was determined by use of an HPLC. 2.8. Data analysis and statistics For each of the variables, the difference between the premedication value and the post-medication value was calculated in order to obtain a measure of effect for each subject. These differences between gabapentin and placebo were compared by use of the Wilcoxon–Pratt test for paired differences. Correlations between effect and serum concentrations of gabapentin were tested by use of the Spearman rank correlation test. All data analyses were performed by use of the statistical program MEDSTAT (ASTRA Group A/S, Denmark). Statistical significance was accepted at the 5% level.
P valueb
3. Results 0.0 (−2.0;2.5)
−0,5 (−3.0;4.0)
(P = 0.06)
0.75 (−2.5;3.0)
0.5 (−5.0;3.0)
(P = 0.04)
0.25(−3.5;4.0)
−0.5 (−5.5;1.0)
(P = 0.009)
Eighteen volunteers completed the study. Two male volunteers were excluded from the study due to lack of compliance. They did not take the study medication and did not show up on the last day in the last study period. 3.1. Pharmacodynamic results
0.0 (−5.8;0.6)
−0.1 (−1.4;0.5)
(P > 0.2)
−1.5 (−77;5)
−0.5 (−17;13)
(P = 0.18)
a Median and ranges of differences between pre- and post-medication values of gabapentin (three doses of 600 mg) and placebo. b Wilcoxon–Pratt test: gabapentin versus placebo.
and the mean value of the 3 tests was used for data analysis. After each study day, the volunteers were asked if they had experienced any side effects of the medication such as dizziness, tiredness, nausea or discomfort, which was rated 0 = none, 1 = light, 2 = moderate and 3 = severe.
Compared with placebo, gabapentin significantly increased the pain tolerance threshold to single electrical sural nerve stimulation (P = 0.04), whereas the effect on pain detection threshold to single electrical sural nerve stimulation did not reach statistical significance (P = 0.06). Gabapentin had a significant effect on the pain summation threshold to repetitive electrical sural nerve stimulation (P = 0.009). No significant differences were found between gabapentin and placebo on pain ratings during the cold pressor test. Data from the pain tests are shown in Tables 1 and 2. The changes in pain thresholds and ratings calculated in as box plots are shown in Figs. 1–5. Eight volunteers reported at least one side effect related to the medication during the gabapentin treatment but not during the treatment with placebo. Two volunteers reported side effects dur-
Fig. 1. The changes in pain detection thresholds during electrical sural nerve stimulation before medication and after end of medication with placebo (white box) and gabapentin (grey box). The results are calculated as first and third quartile (box) and median values as horizontal line in percentage terms.
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Fig. 2. The changes in pain tolerance detection thresholds during electrical sural nerve stimulation before medication and after end of medication with placebo (white box) and gabapentin (grey box). The results are calculated as first and third quartile (box) and median values as horizontal line in percentage terms.
ing both treatments and 8 did not experience any side effects at all. All side effects were reported as mild. 3.2. Reaction time There were no significant differences in changes from premedication reaction time with gabapentin treatment compared with placebo. 3.3. Serum concentration and concentration–effect relationship Gabapentin could be detected in all the post-medication serum samples on the study day with gabapentin dosing from all volunteers who completed the study. The median
value of serum gabapentin concentration was 35.6 nmol/l (range 30.4–60.0 nmol/l). The serum concentration of gabapentin in the placebo period was below the limit of detection in all the volunteers. No significant correlations between effect and serum concentration of gabapentin were found. 4. Discussion The present study confirms results from a previous study in which gabapentin also had a selective effect in human experimental pain models including temporal pain summation [16]. In contrast to the previous study, we have used multiple doses of gabapentin and demonstrated that the threshold for temporal pain summation can be compared from day to day, which makes repet-
Fig. 3. The changes in temporal pain summation thresholds during electrical sural nerve stimulation before medication and after end of medication with placebo (white box) and gabapentin (grey box). The results are calculated as first and third quartile (box) and median values as horizontal line in percentage terms.
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Fig. 4. The changes in peak pain intensity during the cold pressor test before medication and after end of medication with placebo (white box) and gabapentin (grey box). The values are calculated as first and third quartiles (box) and median values as horizontal line in percentage terms.
itive medication possible in phase II trials. This study shows that gabapentin is without pain-relieving effect in the cold pressor test. The cold-induced pain has been shown to be relieved by different acting drugs such as opioids and the sodium channel blocking anticonvulsants phenytoin and lamotrigine [9,10], whereas the monoaminergic antidepressants imipramine and venlafaxine like gabapentin with calcium channel blocking effect are without effect in the cold pressor test [3,4]. This could indicate that gabapentin in line with the monoaminergic antidepressants has a rather selective effect on acute experimental pain which could be indicative for efficacy in clinical neuropathic pain conditions. If an opioid had been included in the study, we would have been able to add a positive control in the cold pressor test. However, the analgesic effect of opioids in the cold pressor test is well documented and was not the primary endpoint in this study. We did not make a sample size calculation before the study. A clinically relevant difference can be difficult to estimate in an experimental pain model. The number of volunteers has been decided
based on previously performed studies using the same pain models [4,17]. This study used multiple instead of single doses of gabapentin to achieve a clinically relevant drug level similar to steady stateconcentrations in patients treated with 1800 mg gabapentin per day [18]. The serum concentrations of gabapentin found in the present study appear to be higher than the values measured in published experimental human pain studies where a single dose of 1200 mg gabapentin was used [11,13] and similar to the concentrations measured in the study using multiple doses of gabapentin per day with a daily dose of 1800 mg during 15 days [19]. Inhibition of temporal pain summation has so far been suggested as an indicator for drug efficacy in neuropathic pain. The NMDA-glutamate receptor antagonist, ketamine increases temporal pain summation threshold in this model [20] and i.v. infusion of ketamine relieves clinical neuropathic pain [21–23]. The antiepileptic drug levetiracetam has been investigated in this pain model and was found to increase the pain tolerance threshold for
Fig. 5. The changes in discomfort during the cold pressor test before medication and after end of medication with placebo (white box) and gabapentin (grey box). The values are calculated as first and third quartiles (box) and median values as horizontal line in percentage terms.
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single electrical nerve stimulation, but did not alter in temporal pain summation [17]. A clinical randomized trial has shown that levetiracetam has no effect on postmastectomy neuropathic pain [24]. The potential effect on temporal pain summation may be relevant in this pain condition, since temporal summation has been investigated in a study on patients suffering from this neuropathic pain after treatment of breast cancer. The frequency of temporal summation evoked by repetitive pinprick was found to be higher in patients with pain than in pain-free patients [25]. The role of the temporal pain summation model as a predictor for relief of clinical neuropathic pain is still to be settled, but this study could indicate that inhibition of temporal pain summation is one of several predictors of analgesic effect on neuropathic pain. 5. Conclusion Gabapentin inhibits temporal pain summation in a human experimental nerve stimulation model using repetitive electrical nerve stimulation, but has no impact on pain during the cold pressor test. In the search for new drugs with potential effect in neuropathic pain condition, experimental human pain models using temporal pain summation may be a useful tool, but further studies defining sensitivity and specificity of the model are needed. Acknowledgements This study was financially supported by Odense University Hospital and University of Southern Denmark. Pfizer Denmark delivered the study medication and supported the study financially. References [1] Staahl C, Olesen AE, Andresen T, Arendt-Nielsen L, Drewes AM. Assessing efficacy of non-opioid analgesics in experimental pain models in healthy volunteers: an updated review. Br J Clin Pharmacol 2009;68:322–41. [2] Sindrup SH, Otto M, Finnerup NB, Jensen TS. Antidepressants in the treatment for neuropathic pain. Basic Clin Pharmacol Toxicol 2005;96:399–409. [3] Enggaard TP, Poulsen L, Arendt-Nielsen L, Hansen SH, Björnsddottir I, Gram LF, Sindrup SH. The analgesic effect of codeine as compared to imipramine in different human experimental pain models. Pain 2001;92:277–82. [4] Enggaard TP, Klitgaard NA, Gram LF, Arendt-Nielsen L, Sindrup SH. Specific effect of venlafaxine on single and repetitive experimental painful stimuli in humans. Clin Pharmacol Ther 2001;69:245–51. [5] Arendt-Nielsen L, Brennum J, Sindrup S, Bak P. Electrophysiological and psychophysical quantification of temporal summation in the human nociceptive system. Eur J Appl Physiol Occup Physiol 1994;68:266–73.
[6] Eide PK. Wind-up and the NMDA receptor complex from a clinical perspective. Eur J Pain 2000;4:5–15. [7] Gottrup H, Andersen J, Arendt-Nielsen L, Jensen TS. Psychophysical examination in patients with post-mastectomy pain. Pain 2000;87:275–84. [8] Svendsen KB, Jensen TS, Hansen HJ, Bach FW. Sensory function and quality of life in patients with multiple sclerosis and pain. Pain 2005;114:473–81. [9] Jones SF, McQuay HJ, Moore RA, Hand CW. Morphine and ibuprofen compared using the cold pressor test. Pain 1988;34:117–22. [10] Webb J, Kamali F. Analgesic effects of lamotrigine and phenytoin on coldinduced pain: a cross-over placebo-controlled study in healthy volunteers. Pain 1998;76:357–63. [11] Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Algorithm for neuropathic pain treatment: an evidence based proposal. Pain 2005;118:289–305. [12] Dirks J, Petersen KL, Rowbotham MC, Dahl JB. Gabapentin suppresses cutaneous hyperanalgesia following heat-capsaicin sensitization. Anesthesiology 2002;97:102–7. [13] Eckhardt K, Ammon S, Hofmann U, Riebe A, Gugeler N, Mikus G. Gabapentin enhances the analgesic effect of morphine in healthy volunteers. Anesth Analg 2000;91:185–91. [14] Werner MU, Perkins FM, Holte K, Pedersen JL, Kehlet H. Effects of gabapentin in acute inflammatory pain in humans. Reg Anesth Pain Med 2001;26:322–8. [15] Stewart BH, Kugler AR, Thompson PR, Bockbrader HN. A saturable transport mechanism in the intestinal absorption of gabapentin is the underlying cause of the lack of proportionality between increasing dose and drug levels in plasma. Pharm Res 1993;10:276–81. [16] Arendt-Nielsen L, Frøkjaer JB, Staahl C, Graven-Nielsen T, Huggins JP, Smart TS, Drewes AM. Effects of gabapentin on experimental somatic pain and temporal summation. Reg Anesth Pain Med 2007;32:382–8. [17] Enggaard TP, Klitgaard NA, Sindrup SH. Specific effect of levetiracetam in experimental human pain models. Eur J Pain 2006;10:193–8. [18] Lindberger M, Luhr O, Johannesen SI, Larsson S, Tomson T. Serum concentrations and effect of gabapentin and vigabatrin: observations from a dose titration study. Ther Drug Monit 2003;25:457–62. [19] Gottrup H, Juhl G, Kristensen AD, Lai R, Chizh BA, Brown J, Bach FW, Jensen TS. Chronic oral gabapentin reduces elements of central sensitization in human experimental hyperalgesia. Anesthesiology 2004;101:1400–8. [20] Arendt-Nielsen L, Petersen-Felix S, Fischer M, Bak P, Bjerring P, Zbinden AM. The effect of N-methyl-d-aspartate antagonist (ketamine) on single and repeated nociceptive stimuli: a placebo-controlled experimental human study. Anesth Analg 1995;81:63–8. [21] Max MB, Byas-Smith MG, Gracely RH, Bennett GJ. Intravenous infusion of the NMDA antagonist, ketamine, in chronic posttraumatic pain with allodynia: a double-blind comparison to alfentanil and placebo. Clin Neuropharmacol 1995;18:360–8. [22] Eide PK, Jorum E, Stubhauge A, Bremnes J, Breivik H. Relief of post-herpetic neuralgia with the N-methyl-d-aspartic acid receptor antagonist ketamine: a double-blind, cross-over comparison with morphine and placebo. Pain 1994;58:347–54. [23] Gottrup H, Bach FW, Juhl G, Jensen TS. Differential effect of ketamine and lidocaine on spontaneous and mechanical evoked pain in patients with nerve injury pain. Anaesthesiology 2006;104:527–36. [24] Vilholm OJ, Cold S, Rasmussen L, Sindrup SH. Effect of levetiracetam on the postmastectomy pain syndrome. Eur J Neurol 2008;15:851–7. [25] Vilholm OJ, Cold S, Rasmussen L, Sindrup SH. Sensory function and pain in a population of patients treated for breast cancer. Acta Anaesthesiol Scand 2009;53:800–6.