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Anesth Analg 2004;98:408-413
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000096002.53818.BD

PAIN MEDICINE

A Placebo-Controlled Randomized Crossover Trial of the N-Methyl-D-Aspartic Acid Receptor Antagonist, Memantine, in Patients with Chronic Phantom Limb Pain

Katja Wiech, PhD1,*, Ralph-Thomas Kiefer, MD1,{dagger}, Stephanie Töpfner, MD{dagger}, Hubert Preissl, PhD*, Christoph Braun, PhD*, Klaus Unertl, MD{dagger}, Herta Flor, PhD{ddagger}, and Niels Birbaumer, PhD*,§

*Institute of Medical Psychology and Behavioral Neurobiology and the {dagger}Department of Anesthesiology and Intensive Care Medicine, University of Tübingen, Tübingen, Germany, the {ddagger}Department of Neuropsychology, University of Heidelberg, Central Institute of Mental Health, Mannheim, Germany, and the §Center for Cognitive Neuroscience, University of Trento, Trento, Italy

Adress correspondence and reprint requests to R.-T. Kiefer, MD, Center for Medical Research, Department of Anesthesiology and Intensive Care Medicine, University of Tuebingen, Waldhoernlestrasse 22, 72072 Tuebingen, Germany. Address e-mail to thomas.kiefer{at}uni-tuebingen.de


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
In the present study we investigated the effect of the N-methyl-D-aspartic acid (NMDA) receptor antagonist memantine (30 mg/d) on the intensity of chronic phantom limb pain (PLP) and cortical reorganization. In 8 patients with chronic PLP, memantine was tested in a placebo-controlled double-blinded crossover trial of 4 wk duration per trial. The intensity of PLP was rated hourly by the patients on a visual analog scale during baseline and both treatment periods. At the same time points, the functional organization of the primary somatosensory cortex (SI) was determined by neuromagnetic source imaging. In comparison to baseline and placebo, the NMDA receptor antagonist had no effect on the intensity of chronic PLP. In none of the periods were significant changes in the functional organization of SI observed. Although the conclusions regarding the clinical effect are limited because of the small sample size, the data indicate that in the studied dosage the NMDA receptor antagonist memantine is ineffective in the treatment of chronic PLP and is also ineffective for the reduction of associated neural plasticity in the primary SI.

IMPLICATIONS: NMDA receptors play a substantial role in central nervous system changes underlying neuropathic pain. In a placebo-controlled double-blinded study we tested the effect of 30 mg memantine on chronic phantom limb pain and pain-associated cortical reorganization.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
During recent years, new insights into the mechanisms underlying induction and maintenance of chronic pain states have been gained through studies in animals and humans with peripheral nerve lesions. In neuropathic pain conditions, neuroplasticity in the central nervous system (CNS) seems to play a crucial role (1,2). Among different subsets of neuropathic pain, phantom limb pain (PLP) is the most illustrative example for the contribution of the CNS to chronic pain disorders. As PLP is felt in a part of the body that is absent, it is probable that other sites than the periphery might be the generating source of pain.

Using neuroimaging techniques, it has been demonstrated that PLP is associated with persisting changes in the somatotopic representation of the primary somatosensory cortex (SI) and motor cortex (3–7). In these brain areas, patients with chronic PLP subsequent to upper limb amputation showed an "invasion" of adjacent representation zones (e.g., the lower lip) into the deafferented area. In comparison with the unaffected side, the representation of the lower face and lip was shifted towards the former representation of the limb. Interestingly, the amount of cortical reorganization was directly proportional to the magnitude of PLP. These PLP-associated alterations in SI organization can be reversed by peripheral analgesia (4). Patients who reported substantial pain relief during brachial plexus blockade showed an almost symmetrical representation of the left and right lower lip in SI whereas patients without pain reduction showed an increase of cortical reorganization.

The neural mechanisms underlying cortical reorganization in PLP are not yet fully understood. Short-term changes, as induced by local anesthesia, may be based on an unmasking of preexisting input of adjacent areas after denervation by changes in the dynamic balance of excitatory and inhibitory input (8–10). For the establishment of the new cortical maps, synaptic changes have been discussed (11). Among the receptor types involved in synaptic plasticity, the N-methyl-D-aspartic acid (NMDA) receptor seems to be a key structure. In the context of chronic pain, NMDA receptors in the spinal cord have been shown to mediate processes of central sensitization (12). Under physiological conditions, NMDA ion channels are voltage-dependently blocked by magnesium (13). A depolarization that removes or decreases the magnesium block enhances inward currents through the ion channel, triggering several intracellular second messenger activated pathways (14). As a consequence, the excitability of the neuron increases, which thereby leads to long-term enhancement of synaptic efficacy and amplification of nociceptive input.

The significance of NMDA receptors for pain-maintaining processes has initiated the first clinical studies using NMDA receptor antagonists (e.g., ketamine, memantine) to block the receptor and thereby protect the neuron from sensitization (15). However, whether NMDA receptors are essential for the induction of this central sensitization as well as its maintenance is still under debate. In experimental models of chronic pain, ketamine led to a reduction of mechanical and thermal hyperalgesia (16–20) and allodynia (21). In addition, ketamine was beneficial in patients suffering from chronic neuropathic pain. The NMDA receptor antagonist diminished spontaneous pain attacks as well as evoked pain, such as allodynia or hyperalgesia (22–26). As the clinical use of ketamine is limited because of its psychotomimetic side effects, further clinical trials were conducted with less potent, but better tolerated, noncompetitive NMDA receptor antagonists such as memantine. However, in patients with chronic PLP memantine did not sufficiently decrease the pain in a placebo-controlled clinical trial in a dosage of 20 mg/d given over 5 wk (27).

In one study it was shown that 30 mg/d memantine given over a 4-wk period not only prevented PLP but also reversed the pain early after its onset (28). These were, however, patients with acute as compared with chronic pain. The aim of the present study was to evaluate the effect of memantine at the same dosage in patients with chronic PLP. In addition to clinical outcome we investigated whether the NMDA receptor antagonist affects cortical reorganization.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Eight patients (7 males and 1 female) aged 45 ± 12.51 yr (mean ± SD; range, 26–64 yr) were included in the study. All patients had suffered traumatic amputation of the hand, forearm, or upper arm. On average, the patients were included 13.01 ± 17.34 yr after amputation (range, 1.4–54 yr). During the entire study period the patients were requested not to change their additional analgesic medication. Patients with a history of neurological, psychiatric, or renal diseases were excluded. Demographic and clinical characteristics of the subjects are presented in Table 1.


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  		Table 1. Baseline Characteristics
 
Patients were recruited at the Department for Hand, Plastic and Burn Surgery of the University Hospital of Tübingen. All participants gave informed signed consent. The Ethics Committee of the Medical Faculty at the University of Tübingen approved the study.

To investigate the effect of memantine on chronic PLP, the NMDA receptor antagonist was tested in a placebo-controlled double-blinded crossover trial. The order of treatment (memantine first and placebo second or vice versa) was randomized. Randomization was known by one member of the central pharmacy of the University hospital who also provided the blinded tablets. A scientist not involved in the study kept a record of treatment assignment. After a 4-wk baseline evaluation the patients received either memantine or placebo for 4 wk followed by a 14-day washout phase. During the second 4-wk treatment period the patients received the alternate treatment. All outcome measures were assessed before treatment and at the last day of each treatment period.

The NMDA receptor antagonist, memantine (Akatinol Memantine®; Merz Pharmaceuticals GmbH, Frankfurt, Germany), was administered orally in increasing dosage (first week, 10 mg/d; second week, 20 mg/d; third and fourth weeks, 30 mg/d). In the placebo treatment period the patients received placebo tablets of identical appearance following the same scheme of dosage. Common adverse effects of memantine (nausea, fatigue, dizziness, agitation, and headache) were documented by the patients during baseline and in both treatment periods on a visual analog scale (VAS; end-points: "not at all" to "extreme"; transformed into a scale from 0 to 100) 3 times per day.

Pain Assessment
The subjective intensity of PLP and pain in the residual limb was rated hourly by the patients on a VAS (end-points: 0 = "no pain" and 100 = "extreme pain") during baseline and both treatment phases. The mean pain intensity of each phase was used for statistical analysis.

Magnetoencephalographic Recordings
Magnetic source imaging was performed to assess reorganization of primary SI using a whole head magnetoencephalographic (MEG) system (CTF, Port Coquitlam, BC) with 151 first-order gradiometers. MEG recordings were performed before baseline and after the memantine and placebo period. A BTI (Biomagnetic Technologies, San Diego, CA) pneumatic stimulator was use to generate a pressure-controlled deformation of a small membrane (stimulus duration, 100 ms; ISI, 500 ms ± 50 ms; sampling rate, 612.5 Hz). One-thousand pneumatic stimuli were applied to the left and right lower lip. Trials with amplitudes exceeding 1 picoTesla in a frontal channel indicating eye movements were excluded from further analysis. The remaining trials (more than 90% in all recordings) were averaged. The first prominent peak of the evoked field ranging from 60 to 100 ms for lower lip stimulation of both sides was analyzed by fitting a single equivalent dipole (29,30). The localization of the single dipole was determined in spherical coordinates and for further analysis only the declination angle {Delta} was used (Fig. 1). The declination angle {Delta} indicates the distance of the somatosensory representation in relation to Cz along the central sulcus. Changes in the functional organization in the primary SI were defined as a hemispheric difference (representation of the intact—amputated side) of the declination angle ({Delta}). Positive values in the hemispheric difference indicate a shift of the representation of the lower lip into the deafferented area (former hand representation) in comparison with the intact side. Negative values in {Delta}; indicate that the SI representation of the lower lip on the affected side was localized more inferior and lateral compared with the unaffected lower lip.



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  		Figure 1. Changes in the functional organization in the primary somatosensory cortex (SI) were defined as hemispheric difference (representation of the intact—amputated side) of the declination angle ({Delta}) of the dipole representing the lip localization in SI. The {Delta} angle is determined as the angle between the localization vector of the dipole location (blue circle) and the z-axis. For a better visualization of the mirroring procedure only the coronal plane is shown. The blue circle represents the localization of the lower lip of the intact (right) side and the red circle indicates the localization of the lower lip of the amputated (left) side. The dashed line is the assumed "normal" representation of the lower lip.

 
Because of the small sample size the data were analyzed using nonparametric tests. For the intensity of PLP, pain in the residual limb, cortical reorganization, and side effects, Friedman tests were performed with the time points baseline, memantine period and placebo period. P values <0.05 were considered to be statistically significant in all tests. Nonsignificant results are marked by NS (not significant). The data analysis was performed with SPSS 10.0 (SPSS, Chicago, IL).


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
PLP
The Friedman test for the intensity rating of PLP showed no significant differences between baseline and the 2 treatments ({chi}2r(corr) = 3.71; P = 0.16; NS). During administration of memantine 3 of the 8 patients showed no or only slight pain reduction compared with baseline, whereas 5 patients reported a slight increase in pain intensity (baseline, 46.98 ± 20.38 versus memantine, 51.51 ± 20.61) (Fig. 2). In the placebo period (49.46 ± 21.11) the PLP intensity was higher than during baseline in 6 of 8 patients.



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  		Figure 2. Intensity of phantom limb pain and pain in the residual limb during baseline, the memantine, and the placebo period (mean and SEM).

 
Pain in the Residual Limb
Over all patients the differences among baseline, memantine, and placebo treatment did not reach statistical significance ({chi}2r(corr) = 3.82; P = 0.15; NS). In comparison with the baseline rating (18.42 ± 27.53) the intensity of pain in the residual limb increased in the memantine (22.02 ± 31.32) as well as in the placebo period (22.43 ± 32.26) (Fig. 2). The more intense pain in both treatment periods was mainly experienced by one patient (code 206) who reported a pain increase of 20.79 on the VAS while taking the NMDA receptor antagonist and 27.30 under placebo.

Cortical Reorganization
Before treatment a slight asymmetry in the cortical representation of the lower lip on the amputated and healthy side was found ({Delta}, -3.32 ± 6.98) (Fig. 3). In the memantine period, the difference was slightly larger (mean {Delta}, 1.22 ± 10.35) whereas {Delta} decreased during placebo intake (mean {Delta}, -2.51 ± 8.79). The differences among the three observation periods did not reach statistical significance ({chi}2r(corr) = 3.71; P = 0.16; NS).



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  		Figure 3. Amount of cortical reorganization during baseline, the memantine, and the placebo period (mean and SEM).

 
Side Effects
No significant differences were seen among the baseline, memantine, and placebo period regarding the intensity of nausea ({chi}2r(corr) = 0.80; P = 0.96; NS), tiredness ({chi}2r(corr) = 2.00; P = 0.37; NS), vertigo ({chi}2r(corr) = 3.77; P = 0.15; NS), and headache ({chi}2r(corr) = 2.57; P = 0.28; NS; see Table 2). Only for the extent of agitation did the analysis of variance showed a trend towards a phase difference ({chi}2r(corr) = 5.85; P = 0.054).


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  		Table 2. Side Effects
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The present study did not demonstrate a therapeutic effect of the NMDA receptor antagonist memantine in a dosage of 30 mg/d over a 4-week period on chronic PLP or on pain in the residual limb. Furthermore, changes in the functional organization of the primary SI that have been found to occur in relation to the subjective intensity of PLP were not seen to be affected by memantine.

Results from several clinical studies that used different analgesics showed that the treatment of chronic PLP remains a clinical challenge (31). One reason for this seems to be that implicit somatosensory "pain memories" occur (32), i.e., long-term changes in nociceptive pathways of the CNS resulting from persistent painful input that may not be targeted by common analgesics. Once these pain traces are established and PLP has become chronic, effective therapy becomes difficult because the pain has already induced persisting functional and structural alterations in nociceptive structures.

Among a variety of different receptors involved in the central processing of pain, NMDA receptors have been discussed as crucial for central sensitization after nerve trauma (1,33). Activated by the increased peripheral nociceptive input, they mediate complex intracellular processes leading to persisting changes in neural transmission resulting from pain (34). It has been shown that NMDA receptor antagonists can prevent neuropathic pain if they are applied before the nerve lesion (15,20,35–38). As preincisional application can only be realized in elective surgery, the question of whether the same regimes can also be initiated after nerve injury is of more clinical relevance. In upper limb amputees where denervation is caused by an injury in the majority of patients (39) preventive strategies are usually not feasible. Recently, it has been shown that the application of the NMDA receptor antagonist, memantine, in combination with prolonged regional analgesia early after nerve transection might be effective in preventing PLP in traumatic upper limb amputations (28,40). In a randomized trial it was shown that memantine reversed PLP in those patients who had developed pain early after deafferentation (28). Therefore, although memantine seems to be ineffective in long-standing chronic pain, the blockade of NMDA receptors may be an effective component in preventing the generation of chronic PLP.

The time-dependent effect of memantine may be related to several factors. First, the impact of neural transmission via NMDA receptors on pain maintenance may decrease over time. This assumption is supported by animal studies that directly compared the preventive and treatment effect of NMDA receptor antagonists. The results show that these substances are more effective preventing central sensitization when given before nerve injury in comparison with postsectional application (35,41). Another hypothesis derives from observations regarding the divergent effects of the different clinically available NMDA receptor antagonists. The substances vary regarding their affinity and selectivity of receptor binding. Ketamine is effective in chronic pain states and does not selectively affect NMDA receptors, but it also modulates transmission of {sigma}-opioid and adenosine receptors (42). Furthermore, the affinity of ketamine at the phencyclidine-binding site of the NMDA receptor is significantly higher compared with other noncompetitive antagonists, e.g., dextromethorphan or amantadine (43). Therefore, it can be assumed that low-affinity and highly selective NMDA receptor antagonists may not be potent enough to block the increased transmission via NMDA receptors during chronic pain states. Observations that the analgesic effect of this substance class (and even of ketamine) depends on the dosage support this hypothesis (18,22,44).

Although 30 mg memantine did not reduce PLP significantly in the 8 patients included, conclusions drawn from the present study are limited by the small sample size that was restricted by the time-consuming MEG recordings. The presently available data on NMDA receptor antagonists should encourage large-scale clinical trials to investigate dose-, time-, and potency-dependent effects of this substance class with different pharmacological profiles.


   Acknowledgments
 
Supported, in part, by grants of the Deutsche Forschungsgemeinschaft (Bi 195/39–1, Fl 156/25), the Federal Ministry of Education, Science, Research and Technology (Fö. 01KS9602), the Interdisciplinary Center of Clinical Research (IZKF) Tübingen, and the Fortüne Program of the Medical Faculty of the University of Tübingen (459-0-0).

We thank Sylvia Gustin for assistance in magnetoencephalographic recordings and Markus Schley for contribution to clinical data collection and postoperative pain management.


   Footnotes
 
1 Drs. Katja Wiech and Ralph-Thomas Kiefer contributed equally to this work. Back

Akatinol Memantine® was provided free of charge by Merz & Co, Frankfurt.


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Accepted for publication August 21, 2003.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press