Prevention of central sensitization and pain by N-methyl-D-aspartate receptor antagonists

Antonio Pozzi Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.

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William W. Muir III Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.

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Francesca Traverso Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.

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The ability to sense pain (nociception) is lifesaving. Without it, tissue trauma would not be detected, potentially resulting in the development of more severe tissue injury and infection. Severe tissue injury and infection can initiate a systemic inflammatory response syndrome that results in multiple organ failure and death. In humans, congenital insensitivity to pain results in extensive tissue damage typified by destruction of the joints, pressure ulcers, and muscle ischemia in addition to self-induced mutilation.1 Most humans afflicted with this condition die within the first or second decade of life because of overwhelming infec-tions.1 Therefore, the pain-detecting system has a vital life-sustaining role, and it is the key warning system for alerting an animal to the presence of potential tissue-damaging stimuli, which results in initiation of protective physiologic, somatic motor, and behavioral responses to maintain the integrity of the body.2

Typically, most noxious stimuli (mechanical, thermal, chemical, and electrical) are transient, non–tissue-damaging events that generate pain (physiologic pain) by activating high-threshold pain receptors (nociceptors) located on the terminal ends of thinly myelinated or unmyelinated peripheral Aδ and C nerve fibers.3 A noxious stimulus is transduced into electrical impulses that are transmitted to the dorsal horn of the spinal cord, thereby initiating the release of glutamate from presynaptic nerve terminals. Glutamate activates postsynaptic AMPA and KA receptors.3 The AMPA and KA receptors are the primary mediators of fast excitatory pain transmission (Figure 1). Sensory processing is subsequently controlled by electrical impulses generated in local spinal cord segmental circuits and by descending tonic and phasic facilitatory and inhibitory influences originating from the brain.3,4 If tissue damage occurs despite the activities of this defensive system, changes in pain sensitivity occur that help to protect the animal from and prevent further injury. Severe tissue injury (trauma, surgery, or inflammation) or sustained nociceptive input (trauma) increases glutamate release from the presynaptic nerve terminals and results in increases in neuronal activity of the superficial dorsal horn and removal of Mg+2 from NMDARs (named on the basis of the synthetic agonist that activates them).4,5

Figure 1
Figure 1

Schematic diagram of the structures and processes involved in sensitization and wind-up of the CNS in mammals. During physiologic pain, most NMDARs are blocked by Mg2+. Consequently, there is no postsynaptic cumulative depolarization or wind-up of the CNS. During somatic and visceral pathologic pain conditions, C fibers become sensitized by inflammatory mediators (peripheral sensitization); the lower threshold and spontaneous impulse generation result in persistent release of glutamate and substance P in the C fibers of the dorsal horns of the spinal cord. These substances cause increases in intracellular Ca2+ and Na+ concentrations in the dorsal horn neurons of the spinal cord and trigger the activation of PKC, phosphorylates, and NMDARs, leading to removal of the Mg2+ block and to the wind-up phenomenon. I, II, III, IV, V, and VI = Various laminae of the dorsal horn of the spinal cord. Aβ, Aδ, and C = Sensory nerve fibers. SP = Substance P. GLU = Glutamate. KAR = Kainate receptors. P = Phosphorylation.

Citation: Journal of the American Veterinary Medical Association 228, 1; 10.2460/javma.228.1.53

The activation and modulation of NMDARs by the excitatory neurotransmitter glutamate are believed to be key components in the development of central sensitization and secondary hyperalgesia and in the consequent amplification of the pain response.5 Increases in sensitivity to noxious or non-noxious stimuli (hypersensitivity) are recognized as allodynia and hyperalge-sia.3,4 Allodynia is pain caused by a stimulus that does not normally provoke pain. Depending on the severity and duration of noxious stimuli, allodynia or hyperalgesia may spread from the site of injury (primary hyperalgesia) to surrounding noninjured tissues (secondary hyperalgesia). Primary hyperalgesia can be caused by a reduction in the threshold (peripheral sensitization) of normally high-threshold peripheral nociceptors. Peripheral sensitization is caused by the generation of inflammatory mediators, including prostaglandins, bradykinin, cytokines, neuropeptides, and nerve growth factors (collectively referred to as a sensitizing soup).3,4 Many of these sensitizing agents also activate quiescent (so-called silent or sleeping) nociceptors, thereby magnifying the pain response to nonpainful stimuli.4 Intense or sustained peripheral stimuli can also effect changes in the excitability of neurons located in the dorsal horn of the spinal cord. Temporal summation and cumulative depolarization (ie, wind-up) of impulses transmitted by pain fibers amplify and facilitate neuronal activity in dorsal horn neurons, leading to central sensitization (Figure 1).4,6–9 Clinically, central sensitization contributes to the development of allodynia and hypersensitivity at the site of injury (primary hyperalgesia) and further expands the extent of the painful area to noninjured tissue (secondary hyperalgesia). Peripheral and central sensitizations are responsible for primary and secondary hyperalgesia and contribute to the development of pain memory and chronic pain syndromes and to the establishment of pain as a disease in affected individuals.10–13

The NMDARs were first identified in the late 1980s, when it was demonstrated that NMDAR antagonists (eg, MK-801 [dizocilpine]) inhibited hyperexcitability in nociceptive neurons of the dorsal horn of the spinal cord.5,14 Since that time, NMDARs have been detected in the brain (where they have been linked to learning, memory, behavior, and motor coordination), on myelinated and unmyelinated nerves in peripheral regions of the body (where they have been implicated in the pathogenesis of chronic pain), and in the viscera (where they have been linked to visceral pain hyper-sensitivity).11,15–18 It is important to realize that NMDARs have minimal baseline activity under normal circumstances and are therefore relatively unimportant in normal or physiologic pain perception (that is associated with no or minimal tissue damage). The role of NMDARs in the development of dorsal horn neuron hyperexcitability or wind-up, induction of central sensitization, changes in dorsal horn phenotype (neuronal plasticity), and spinal cord neuronal degeneration is well established.4,8 Their activation has also been implicated in the development of tolerance to opioid treatment.19 The NMDAR is composed of NR1, NR2 (types A, B, C, and D), and NR3 (types A and B) subunits.20–23 All NMDARs have unique properties that distinguish them from other receptors, including high permeability to cations (Na+ and Ca2+) once their Mg2+ block has been removed, dependence on glutamate and glycine for efficient activation, and a comparatively prolonged duration of activation (compared with AMPA/KA receptors) during which the channel remains open.24 Functional NMDARs are formed by the combination of the ubiquitously expressed NR1 subunit with at least 1 of 4 secondary NR2 subunits (type A, B, C, or D) to form functional ligand (glutamate)-activated channels or pores, which carry currents (primarily movement of Ca2+) that mediate excitatory neurotransmission in the CNS.25,26 The NR2 subunit is essential for the formation of a functional current-conducting channel or pore.26 Regardless of the requirement for the NR1 subunit and the diversity of NMDAR subtypes, the NR2B subunit is believed to play a fundamental role in nociception.26 The presence of the NR2B subunit in the heteromeric NR1/NR2 pore-forming channels of NMDARs is responsible for most of the biophysical and pharmacologic properties of those receptors, such as sensitivity to Mg2+ block, long-term potentiation of transmission, and activity-dependent plasticity.5,11,13 The importance of the NR2B subunit increased after the discoveries that such subunits were present in the dorsal horn of the spinal cord, in the brain, and on myelinated and unmyelinated peripheral nerves and that the activation of this subunit type was largely responsible for the development and maintenance of inflammatory hyperalgesia.20,21 The NR2D subunits are located only on peripheral nociceptive fibers, and NR2A subunits are poorly sensitive to glutamate.21 Furthermore, pain-related behaviors were not altered in genetically modified (ie, knockout) mice that lack NR2A subunits, compared with those of genetically normal control mice.27 The NR3 subunit is not believed to be important in regard to pain because its coassembly with other subunits (eg, NR1 and NR2) forms channels that are unaffected by glutamate and impermeable to Ca2+. Together, these data suggest that NMDAR antagonists should have analgesic effects and that selective NR2B antagonists that are devoid of notable CNS effects could be developed.

NMDAR Antagonists

The critical role of NMDARs of the CNS in learning, memory, cognition, and coordination of motor activity and their importance in animal models of severe acute and chronic pain are well established. Their central role in the development of central and peripheral sensitization has led to the investigational and clinical administration of drugs with diverse pharmacologic properties (including NMDAR-blocking activity), with the goal of improving pain control in various species. However, the development and manufacture of drugs that block only NMDARs have been problematic because of CNS and neurotoxic adverse effects associated with those drugs. Dizocilpine, a nonspecific NMDAR antagonist, was one of the first drugs recognized for its potential analgesic effects, but it has never been approved for clinical use in humans because of nervous system-associated adverse effects in clinical patients.28 The dissociative anesthetics, ketamine and tiletamine, are considered to be the most potent of the currently available NMDAR antago-nists.22,28 Several opioid analgesics (meperidine, fentanyl, morphine, and codeine) produce NMDAR antagonistic effects in vitro, although only methadone and dextromethorphan inhibit NMDARs at concentrations that overlap with the plasma concentrations that are deemed clinically relevant for drug efficacy.23 Interestingly, long-term opioid administration for the treatment of chronic pain in humans is associated with the development of tolerance and delayed hyperalgesia, a phenomenon now known to be the result of opioid-induced increases in PKC and the activation of NMDARs.19,29 Finally, the infusion of magnesium (although rationalized on the basis that NMDARs are typically blocked by Mg2+ ions) is not associated with effective control of pain caused by wind-up and central sensitization.21 Reports of the analgesic effects of magnesium infusion are most likely mistaken assessments of the central muscle relaxant and mild sedative properties of Mg2+ ions.30

Several drugs (eg, memantine and amantadine) that have been approved for other clinical uses are now considered to be reasonably effective NMDAR antagonists21,31,32 At present, attempts are being made to develop and market NR2B subunit-specific NMDAR antagonists (eg, ifenprodil, besonprodil, and eliprodil) with the hope of eliminating or minimizing CNS adverse effects while retaining the analgesic activity of this type of drug (Appendix).20,21 Regardless of these efforts, a great deal of controversy presently exists regarding the efficacy and usefulness of NMDAR antagonists for the clinical treatment of acute pain in humans and other animals. Data supporting claims of pain relief in humans are highly variable, and in many instances, analgesic efficacy has been difficult to substantiate unless the NMDAR antagonist was administered in conjunction with other analgesic drugs, particularly opioids.21 Potential reasons for poor efficacy when NMDAR antagonists are administered alone are not immediately apparent but are likely related to the dependence of these agents on the development of wind-up or central sensitization, administration of an inadequate dose or inappropriate dosing regimens, and the high variability in affinities for the various NR2 receptor subtypes (particularly the NR2B receptor subtype). Current opinion suggests that NMDAR antagonists may be most effective as analgesics when used to treat severe acute or chronic pain that has wind-up or central sensitization as a major component and that more effective pain relief can be achieved by their administration as preemptive and multimodal therapy21,42,43 Others have suggested that non-NMDARs have an exclusive role in the maintenance of dorsal horn neuron activation early after surgical incision.44 This would indicate that cerebral NMDARs have a greater role in development of hyperalgesia after surgery than spinal cord NMDARs, which is in agreement with findings of a previous clinical study45 in humans.

Specific NMDAR Antagonist Drugs

Ketamine hydrochloride (an aryl-cyclohexylamine congener of phencyclidine) is a popular injectable dissociative anesthetic agent that is used to provide short-term anesthesia in humans and other animals; it is a noncompetitive NMDAR antagonist.22 Tiletamine, like ketamine, is also a congener of phencyclidine and an NMDAR antagonist. Tiletamine is commercially available in combination with zolazepam hydrochloride (CI-744), which is a benzodiazepine derivative with potent muscle relaxant and anticonvulsant effects.33 Ketamine is rapidly distributed after IV administration and has been administered IV, IM, SC, epidurally, intraarticularly, and orally to achieve anesthesia or as an adjunct to other anesthetic agents.22,33–50 Studies50,51 in humans and other animals have revealed that ketamine administered IV or epidurally produces anesthetic-sparing effects; furthermore, in humans, ketamine appears to provide analgesia for the treatment of severe acute or chronic pain when administered in subanesthetic doses. Ketamine acts both centrally and peripherally at multiple receptor sites, including NMDA, opioid, AMPA, KA, and GABA-A receptors.22,52 However, the relative affinity of ketamine for NMDARs suggests that its analgesic efficacy is predominantly mediated via these receptors.22 In humans and other animals, a single IV or IM bolus of ketamine is associated with effective short-acting (duration of 1 to 2 hours) pain relief, whereas infusion following a loading dose is associated with analgesia of longer duration and opi-oid-sparing effects.53–55 Subcutaneous administration has the advantage of relatively slow absorption into the bloodstream, low peak blood concentrations, and reduced CNS effects.56 Oral administration of ketamine produces few adverse effects and may be more effective than SC administration of the drug.56,57 In a recent review, it has been suggested that the analgesic efficacy of ketamine was moderate to weak at best and that ketamine should be considered a third-line option after other treatments had proven ineffective.58 Additional clinical studies in animals are needed to define the analgesic effects, doses, routes of administration, and efficacy of ketamine and the tiletamine-zolazepam drug combination when administered in subanesthetic doses to animals.

Methadone and dextromethorphan are opioid derivatives. Methadone is a mu opioid agonist with analgesic potency similar to that of morphine, whereas dextromethorphan is the D-isomer of codeine and acts as an antitussive. Both drugs are weak, noncompetitive NMDAR antagonists. Results of experimental studies29,59–61 have suggested that these drugs decrease NMDA-mediated hyperexcitability and wind-up in dorsal horn neurons, thereby helping to prevent the development of central sensitization. In clinical studies23,61–66 in humans, methadone and dextromethorphan have been associated with quantifiable analgesic effects following oral, IV, or IM administration. Compared with ketamine and high-affinity NMDAR-blocking drugs (eg, dizocilpine), adverse effects associated with methadone and dextromethorphan are rare. Only methadone has clinical potential as a mixed opioid agonist-NMDAR antagonist because parenteral formulations of dextromethorphan are currently unavailable and administration of oral preparations does not result in clinically useful analgesic effects. Methadone is considered an optimal choice for treatment of pain in human patients with cancer because of its high oral bioavailability, rapid onset, and time to peak analgesic effect and the relatively long duration of activity that allows for long intervals between doses.63–65

Tramadol, a weak mu opioid agonist, is a centrally acting analgesic that is effective in the management of moderate to severe acute postoperative pain in humans and is well tolerated by patients.66 Tramadol inhibits norepinephrine and serotonin reuptake and also has opioid activity. These complementary actions enhance analgesic efficacy and improve the drug's tolerability profile. Interestingly, tramadol is efficacious in the treatment of allodynia.67 Also, tramadol has been reported to inhibit NMDARs at clinically relevant concentrations and GABA receptors at high concentration. The inhibitory effect of tramadol on NMDARs may contribute to its efficacy in the treatment of allodynia or hyperalgesia. The potential for convulsant adverse effects (as a result of the inhibition of GABA receptors) occurs when large doses are administered.68

Gabapentin, an anticonvulsant, has antihyperalgesic effects when administered to humans with neuropathic pain.69,70 Gabapentin does not have activity at GABA receptors but does interfere with glutamatergic neurotransmission.69,71 Recent studies70–76 have revealed that gabapentin interacts with and modifies NMDAR activity; its action may be PKC dependent and may rely on the state of phosphorylation of the NMDAR chan-nel.71 Other proposed mechanisms include binding to the α2δ subunit of the voltage-dependent Ca2+ channel and interference with Na+ entry through presynaptic NMDAR channels.73,77 Although consensus regarding the mechanism by which gabapentin induces analgesia has not yet been reached, gabapentin has been used successfully in clinical trials to achieve a significant reduction in pain in the early or late postoperative period in humans.78–82,b

Amantadine, memantine, and acamprosate are low-affinity NMDAR antagonists that are currently commercially available as oral preparations. Amantadine is available as an oral antiviral preparation, and the drug interferes with viral replication; it is well absorbed from the gastrointestinal tract after oral administration and is excreted relatively unchanged in urine. 83,84,c The duration of action of amantadine is highly variable in humans (8 to 18 hours) and is dependent on renal function.83 In humans, memantine is advocated for the treatment of moderate to severe Alzheimer's disease and acamprosate is prescribed as treatment for alcoholism and alcoholic relapse.85,86 The duration of action of each of those drugs is long and highly variable.86,87 Although all 3 drugs have the potential to bind to NMDARs and thereby induce analgesia, only amantadine has been associated with analgesic activity in randomized and masked human clinical studies.32,85,88–94 To our knowledge, no studies have investigated the pharmacokinetics or analgesic efficacy of any of these drugs in animals with naturally occurring pain.

Although results from animal and human studies are encouraging, undesirable drug effects have hampered the widespread use of high-affinity NMDAR antagonists (eg, dizocilpine) as analgesics.95 In humans with chronic pain, low-affinity NMDAR antagonists (eg, ketamine) have been reported to be associated with sedation, hallucinations, muscle rigidity, seizures, respiratory depression, excessive salivation, nausea, and vomiting. Furthermore, SC injection of ketamine induces inflammation at the site of injection.96 Despite potential adverse effects, there is evidence that administration of low doses of ketamine results in clinically relevant analgesic effects without notable adverse effects.96–98 Similarly, the adverse effects associated with methadone and dextromethorphan are dose dependent, and no or minimal adverse effects have been reported following oral administration of those drugs to human patients.99 Parenteral administration of methadone, however, has produced sedation and respiratory depression in humans.63 Minimal adverse effects of gabapentin have been reported, including sedation, nausea, and vomiting.78,81,82 Potential adverse effects after administration of excessive doses of amantidine, memantine, and acamprosate in humans include tachycardia, hypertension, respiratory distress, renal dysfunction, and gastrointestinal tract disturbances.69,84

Therapeutic Approaches

Preemptive analgesia is based on the premise that administration of appropriate analgesic treatment prior to introduction of pain-initiating events (including intraoperative and postoperative noxious inputs) may inhibit or block sensitization and therefore block development of acute pain and decrease exacerbations of chronic pain.100 Efficacious preemptive analgesia is based on knowing or anticipating the principle mechanisms responsible for pain (ie, mechanism-based treatment.5,101,102 Prevention or reduction of central sensitization can be achieved by blocking NMDARs before or soon after pain is established.103,104 Development of hyperalgesia and allodynia can be inhibited by decreasing NMDAR activity, thereby reducing the cascade of events that are characteristic of central sensitization.103 It has been suggested that the concept and clinical application of the term preemptive analgesia are too restrictive because they do not incorporate the administration of analgesic interventions after the surgical incision, which may also act to decrease central sensitization and postoperative pain intensity.26 It is further suggested that the term preventive analgesia has greater clinical relevance because the goal is to prevent central sensitization that develops throughout the periopera-tive period and not just that brought about by a surgical incision.21,105

Single-modality drug therapy is rarely effective for the treatment of severe pain because peripheral and central sensitization originate from activation of multiple molecular signaling mechanisms, including NMDARs, and are exaggerated by the release of other factors, including substance P, prostaglandins, and adenosine.102,103 Balancing the application of different treatments, each aimed at decreasing signs of pain in a different manner, can be successful in most clinical situations.32,42,105 Multimodal or balanced analgesia is the combination of analgesic drugs that act via different or similar mechanisms with the aim of improving analgesic efficacy while decreasing individual drug dosages and treatment-associated adverse effects.42,101,103,106 Other goals include a reduction in total analgesic drug consumption and extension of analgesic activity beyond the duration of action of each of the individual drugs that are combined. The NMDAR antagonists can be combined with opioids or with opioids and NSAIDs.107–114 The main advantage of these drug combinations is that their respective mechanisms of action are different; complementary; and, oftentimes, supra-additive (synergistic), consequently decreasing drug doses and treatment-associated adverse effects.109,112–116 For example, opioid analgesics (eg, morphine and hydromorphone) and NSAIDs (carprofen, meloxicam, and deracoxib) can be combined with the NMDAR antagonist ketamine to provide analgesia intraoperatively and during the perioperative period. Opioids can act at peripheral opioid receptors but are believed to achieve most of their analgesic effects by activating opioid receptors at presynaptic sites in neurons of the dorsal horn of the spinal cord.107 The predominant action of opioids is to block the initial response of nociceptive neurons to noxious stimuli, but they are relatively ineffective for preventing wind-up and central sensitization. In contrast, NMDAR antagonists have little effect presynaptically and do not prevent development of initial pain but do reduce wind-up and central sensitization. Morphine-ketamine synergism is most likely explained by the inhibition of presynaptic afferent transmission secondary to reduced transmitter release and postsynaptic NMDAR blockade.117 From the results of some studies,19,118,119 it has been postulated that the combination of low doses of ketamine with opioids may be beneficial during long-term opioid treatment of chronic pain because it decreases opioid-induced tolerance and the potential for development of opioid-induced hyperalgesia secondary to opioid-induced increases in serum PKC activity. The effects of ketamine should therefore be considered both antihyperalgesic and antiallodynic, rather than analgesic.24,112,114,120

Noted advantages of therapeutic strategies involving opioids and NMDAR antagonists are enhanced analgesic efficacy, prolonged duration, the prevention of opioid tolerance, and decreased occurrence of adverse effects.114 Most NSAIDs achieve their antiinflammatory and analgesic effects via inhibition of cyclooxygenase, thereby decreasing the production of prostaglandins (ie, prostaglandin E2).121 Prostaglandin production at a peripheral site of injury is known to play a key role in the development of peripheral sensitization; its production in the CNS following traumatic injury leads to sensitization of NMDARs.122 Thus, synergy between NSAIDs and NMDAR antagonists may occur because of reductions in the peripheral nervous system and CNS prostaglandin production as a result of inhibition of cyclooxygenase activity and NMDAR antagonism.123 There is also evidence that hyperalgesia depends to some extent on cyclooxygenase and subsequent central prostaglandin production triggered by NMDAR activation. Although it is evident that combining drugs that act via different mechanisms of action can be successful, low drug dosages must be strictly adhered to so that the potential for additive or synergistic drug adverse effects can be minimized.

Without doubt, the activation of NMDARs is a key factor in the development of severe acute pain and chronic pain syndromes because of their pivotal role in the development of hyperexcitability of nociceptive neurons in the dorsal horn of the spinal cord and the development of central sensitization. Central sensitization can be recognized clinically as signs of pain that become progressively more severe, that originate from outside the area of primary tissue injury, and that are difficult to treat with single (unimodal) therapy. Central sensitization results in allodynia and secondary hyperalgesia. The NMDAR antagonists are represented by a variety of drugs with diverse clinical uses and differing affinities for the NMDARs. Their administration should be considered in conjunction with other first-line analgesics (eg, opioids and NSAIDs) as part of a comprehensive multimodal approach to the treatment of pain in animals.

AMPA

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

KA

Kainate

NMDA

N-methyl-D-aspartate

NMDAR

NMDA receptor

PKC

Protein kinase C

GABA

γ-aminobutyric acid

NSAID

Nonsteroidal anti-inflammatory drug

a

Lascelles D. Case examples in the management of cancer pain in dogs and cats, and the future of cancer pain alleviation (abstr), in Proceedings. 21st Annu Meet Am Coll Vet Intern Med Forum 2003;500.

b

Veterinary Anesthesia and Analgesia Support Group Web site. Available at: www.vasg.org. Accessed Sep 9, 2004.

c

Jefferson T, Deeks JJ, Demicheli V, et al. Amantadine and rimantadine for preventing and treating influenza A in adults (abstr). Cochrane Database Syst Rev 2004;CD001169.

References

  • 1

    Meranda C, Di Virgilio M, Selleri S, et al. Novel pathogenic mechanism of congenital insensitivity to pain with anhidrosis genetic disorders unveiled by functional analysis of neurotropic tyrosine receptor kinase type 1/nerve growth factor mutations. J Biol Chem 2002;277:64556462.

    • Search Google Scholar
    • Export Citation
  • 2

    Craig AD. Interoception: the sense of the physiological condition of the body. Curr Opin Neurobiol 2003;13:500505.

  • 3

    Muir WW III, Woolf CJ. Mechanisms of pain and their therapeutic implications. J Am Vet Med Assoc 2001;219:13461356.

  • 4

    Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000;288:17651769.

  • 5

    Petrenko AB, Yamakura T, Baba H, et al. The role of N-methyl-D-aspartate (NMDA) receptors in pain: a review. Anesth Analg 2003;97:11081116.

    • Search Google Scholar
    • Export Citation
  • 6

    Woolf CJ. Pain: moving from symptom control towards mechanism-specific pharmacologic management. Ann Intern Med 2004;140:441451.

  • 7

    Pogatzki EM, Niemeier JS, Sorkin LS, et al. Spinal glutamate receptor antagonists differentiate primary and secondary mechanical hyperalgesia caused by incision. Pain 2003;105:97107.

    • Search Google Scholar
    • Export Citation
  • 8

    Kawamata M, Watanabe H, Nishikawa K, et al. Different mechanisms of development and maintenance of experimental incision-induced hyperalgesia in human skin. Anesthesiology 2002;97:550559.

    • Search Google Scholar
    • Export Citation
  • 9

    Baranauskas G, Nistri A. Sensitization of pain pathways in the spinal cord: cellular mechanism. Prog Neurobiol 1998;54:349365.

  • 10

    Carroll RC, Zukin RS. NMDA-receptor trafficking and targeting: implications for synaptic transmission and plasticity. Trends Pharmacol Sci 2002;25:571577.

    • Search Google Scholar
    • Export Citation
  • 11

    Ji RR, Kohno T, Moore KA, et al. Central sensitization and LPT: do pain and memory share similar mechanism? Trends Neurosci 2003;26:696705.

    • Search Google Scholar
    • Export Citation
  • 12

    Pogatzki EM, Vandermeulen EP, Brennan TJ. Effect of plantar local anesthetic injection on dorsal horn neuron activity and pain behaviors caused by incision. Pain 2002;97:151161.

    • Search Google Scholar
    • Export Citation
  • 13

    Siddall PJ, Cousins MJ. Persistent pain as a disease entity: implications for clinical management. Anesth Analg 2004;99:510520.

  • 14

    Nagy J. Renaissance of NMDA receptor antagonists: do they have a role in the pharmacotherapy for alcoholism? IDrugs 2004;7:339350.

  • 15

    Li J, McRoberts JA, Nie J, et al. Electrophysiological characterization of N-methyl-D-aspartate receptors in rat dorsal root ganglia neurons. Pain 2004;109:443452.

    • Search Google Scholar
    • Export Citation
  • 16

    Kakinohana M, Kakinohana O, Jun JH, et al. The activation of spinal N-methyl-D-aspartate receptors may contribute to degeneration of spinal motor neurons induced by neuraxial morphine after a noninjurious interval of spinal cord ischemia. Anesth Analg 2005;100:327334.

    • Search Google Scholar
    • Export Citation
  • 17

    Olivar T, Laird JMA. Differential effects of N-methyl-D-aspartate receptor blockade on nociceptive somatic and visceral reflexes. Pain 1999;79:6773.

    • Search Google Scholar
    • Export Citation
  • 18

    Willert RP, Woolf CJ, Hobson AR, et al. The development and maintenance of human visceral pain hypersensitivity is dependent on the N-methyl-D-aspartate. Gastroenterology 2004;126:683692.

    • Search Google Scholar
    • Export Citation
  • 19

    Ossipov MH, Lai J, King T, et al. Antinociceptive and nociceptive actions of opioids. J Neurobiol 2004;61:126148.

  • 20

    Chizh BA, Headley PM, Tzschentke TM. NMDA receptor antagonists as analgesics: focus on the NR2B subtype. Trends Pharmacol Sci 2001;22:636641.

    • Search Google Scholar
    • Export Citation
  • 21

    McCartney CJL, Sinha A, Katz J. A qualitative systematic review of the role of N-methyl-D-aspartate receptor antagonists in preventive analgesia. Anesth Analg 2004;98:13851400.

    • Search Google Scholar
    • Export Citation
  • 22

    Ilkjaer S, Petersen Kl, Brennum J, et al. Effect of systemic N-methyl-D-aspartate receptor antagonist (ketamine) on primary and secondary hyperalgesia in humans. Br J Anaesth 1996;76:829834.

    • Search Google Scholar
    • Export Citation
  • 23

    Callahan RJ, Au JD, Paul M, et al. Functional inhibition by methadone of N-methyl-D-aspartate receptors expressed in xenopus oocytes: stereospecific and subunit effects. Anesth Analg 2004;98:653659.

    • Search Google Scholar
    • Export Citation
  • 24

    Chen L, Huang LYM. Protein kinase C reduces Mg2+ block of NMDA-receptor channels as a mechanism of modulation. Nature 1992;356:521523.

    • Search Google Scholar
    • Export Citation
  • 25

    Brenner GJ, Ji RR, Shaffer S, et al. Peripheral noxious stimulation induces phosphorylation of the NMDA receptor NR1 subunit at the PKC-dependent site, serine-896, in spinal cord dorsal horn neurons. Eur J Neurosci 2004;20:375384.

    • Search Google Scholar
    • Export Citation
  • 26

    Guo W, Zou S, Guan Y, et al. Tyrosine phosphorylation of the NR2B subunit of the NMDA receptor in the spinal cord during the development and maintenance of inflammatory hyperalgesia. J Neurosci 2002;22:62086217.

    • Search Google Scholar
    • Export Citation
  • 27

    Petrenko AB, Yamakura T, Baba H, et al. Unaltered pain-related behavior in mice lacking NMDA receptor GluRepsilon 1 subunit. Neurosci Res 2003;46:199204.

    • Search Google Scholar
    • Export Citation
  • 28

    Olney JW, Labruyere J, Price MT. Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science 1989;244:13601362.

    • Search Google Scholar
    • Export Citation
  • 29

    Eisenach JC. Preemptive hyperalgesia, not analgesia? Anesthesiology 2000;92:308309.

  • 30

    Bowen JM, Blackmon DM, Heavner JE. Neuromuscular transmission and hypocalcemic paresis in the cow. Am J Vet Res 1970;31:831839.

  • 31

    Sobow T. The clinical relevance of memantine use [in Polish]. Psychiatr Pol 2004;38:321330.

  • 32

    Wiech K, Kiefer RT, Topfner S, et al. A placebo-controlled randomized crossover trial of the N-methyl-D-aspartic acid receptor antagonist, memantine, in patients with chronic phantom limb pain. Anesth Analg 2004;98:408413.

    • Search Google Scholar
    • Export Citation
  • 33

    Lin HC, Thurmon JC, Benson GJ, et al. Telazol: a review of its pharmacology and use in veterinary medicine. J Vet Pharmacol Ther 1993;16:383418.

    • Search Google Scholar
    • Export Citation
  • 34

    Amarpal GR, Aithal HP, Singh GR, et al. Pre-emptive effects of epidural ketamine for analgesia in dogs. Indian Vet J 1999;76:300302.

  • 35

    Wagner AE, Walton JA, Hellyer PW, et al. Use of low doses of ketamine administered by constant rate infusion as an adjunct for postoperative analgesia in dogs. J Am Vet Med Assoc 2002;221:7275.

    • Search Google Scholar
    • Export Citation
  • 36

    Jones RS. Epidural analgesia in the dog and cat. Vet J 2001;161:123131.

  • 37

    Martin DD, Tranquilli WJ, Olson WA, et al. Hemodynamic effects of epidural ketamine in isoflurane-anesthetized dogs. Vet Surg 1997;26:505509.

    • Search Google Scholar
    • Export Citation
  • 38

    Muir WW III, Wiese AJ, March PA. Effects of morphine, lidocaine, ketamine and morphine-lidocaine-ketamine drug combination on minimum alveolar concentration in dogs anesthetized with isoflurane. Am J Vet Res 2003;64:11551160.

    • Search Google Scholar
    • Export Citation
  • 39

    Schwieger IM, Szlam F, Hug CC Jr. The pharmacokinetics and pharmacodynamics of ketamine in dogs anesthetized with enflurane. J Pharmacokinet Biopharm 1991;19:145156.

    • Search Google Scholar
    • Export Citation
  • 40

    Joubert K. Ketamine hydrochloride—an adjunct for analgesia in dogs with burn wounds. J S Afr Vet Assoc 1998;69:9597.

  • 41

    Slingsby LS, Waterman-Pearson AE. The post-operative analgesic effects of ketamine after canine ovariohysterectomy: a comparison between pre- or post-operative administration. Res Vet Sci 2000;69:147152.

    • Search Google Scholar
    • Export Citation
  • 42

    Woolf CJ, Chong MS. Preemptive analgesia—treating post-operative pain by preventing the establishment of central sensitization. Anesth Analg 1993;77:362379.

    • Search Google Scholar
    • Export Citation
  • 43

    Woolf CJ, Max MB. Mechanism-based pain diagnosis. Anesthesiology 2001;95:241249.

  • 44

    Zahn PK, Pogatzki-Zahn EM, Brennan TJ. Spinal administration of MK-801 and NBQX demonstrates NMDA-independent dorsal horn sensitization in incisional pain. Pain 2005;114:499510.

    • Search Google Scholar
    • Export Citation
  • 45

    De Kock M, Lavand'homme P, Waterloos H. ‘Balanced analgesia’ in the perioperative period: is there a place for ketamine? Pain 2001;92:373380.

    • Search Google Scholar
    • Export Citation
  • 46

    Grant IS, Nimmo WS, Clements JA. Lack of effect of ketamine analgesia on gastric emptying in man. Br J Anaesth 1981;53:13211323.

  • 47

    Amarpal GR, Aithal HP, Kinjavdekar P, et al. Interaction between epidurally administered ketamine and pethidine in dogs. J Vet Med 2003;50:254258.

    • Search Google Scholar
    • Export Citation
  • 48

    Dal D, Tetik O, Altunkaya H, et al. The efficacy of intraarticular ketamine for postoperative analgesia in outpatient arthroscopic surgery. Arthroscopy 2004;20:300305.

    • Search Google Scholar
    • Export Citation
  • 49

    Redua MA, Valadao CAA, Duque JC, et al. The pre-emptive effect of epidural ketamine on wound sensitivity in horses tested by using von-Frey filaments. Vet Anesth Analg 2002;29:200206.

    • Search Google Scholar
    • Export Citation
  • 50

    Schmid RL, Sandler AN, Katz J. Use and efficacy of low-dose ketamine in the management of acute postoperative pain: a review of current techniques and outcomes. Pain 1999;82:111125.

    • Search Google Scholar
    • Export Citation
  • 51

    Hirota K, Lambert DG. Ketamine: its mechanism(s) of action and unusual clinical uses. Br J Anesth 1996;77:441444.

  • 52

    Scheller M, Bufler J, Hertle I, et al. Ketamine blocks currents through mammalian nicotinic acetylcholine receptor channels by interaction with both the open and the closed state. Anesth Analg 1996;83:830836.

    • Search Google Scholar
    • Export Citation
  • 53

    Smith DJ, Pekoe GM, Martin LL, et al. The interaction of ketamine with the opiate receptor. Life Sci 1980;26:789795.

  • 54

    Willetts J, Balster RL, Leander JD. The behavioral pharmacology of NMDA receptor antagonists. Trends Pharmacol Sci 1990;11:423428.

  • 55

    Stubhaug A, Breivik H, Eide PK, et al. Mapping of punctuate hyperalgesia around a surgical incision demonstrates that ketamine is a powerful suppressor of central sensitization to pain following surgery. Acta Anaesthesiol Scand 1997;41:11241132.

    • Search Google Scholar
    • Export Citation
  • 56

    Schwinn DA, Leslie JB, Watkins WD. Basic principles of pharmacology and anesthesia. In: Miller RD, ed. Anesthesia, 1. New York: Churchill Livingstone Inc, 1994;4366.

    • Search Google Scholar
    • Export Citation
  • 57

    Enarson MC, Hays H, Woodroffe MA. Clinical experience with oral ketamine. J Pain Symptom Manage 1999;17:384386.

  • 58

    Hocking G, Cousins MJ. Ketamine in chronic pain management: an evidence based review. Anesth Analg 2003;97:17301739.

  • 59

    Weinbroum AA, Ben-Abraham R. Dextromethorphan and dexmedetomidine: new agents for the control of perioperative pain. Eur J Surg 2001;167:563569.

    • Search Google Scholar
    • Export Citation
  • 60

    Ebert B, Andersen S, Krogsgaard-Larsen P. Ketobemidone, methadone and pethidine are non-competitive N-methyl-D-aspartate (NMDA) antagonists in the rat cortex and spinal cord. Neurosci Lett 1995;187:165168.

    • Search Google Scholar
    • Export Citation
  • 61

    Ebert B, Thorkildsen C, Andersen S, et al. Opioid analgesics as noncompetitive N-methyl-D-aspartate (NMDA) antagonists. Biochem Pharmacol 1998;56:553559.

    • Search Google Scholar
    • Export Citation
  • 62

    Manfredi PL, Foley KM, Payne R, et al. Parenteral methadone: an essential medication for the treatment of pain. J Pain Symptom Manage 2003;26:687688.

    • Search Google Scholar
    • Export Citation
  • 63

    Manfredi PL, Gonzales GR, Cheville AL, et al. Methadone analgesia in cancer pain patients on chronic methadone maintenance therapy. J Pain Symptom Manage 2001;21:169174.

    • Search Google Scholar
    • Export Citation
  • 64

    Mercadante S. Methadone in cancer pain. Eur J Pain 1997;1:7785.

  • 65

    McDonnell FJ, Sloan JW, Hamann SR. Advances in cancer pain management. Curr Oncol Rep 2000;2:351357.

  • 66

    Scott LJ, Perry CM. Tramadol: a review of its use in perioperative pain. Drugs 2000;60:139176.

  • 67

    Sindrup SH, Andersen G, Madsen C, et al. Tramadol relieves pain and allodynia in polyneuropathy: a randomised, double-blind, controlled trial. Pain 1999;83:8590.

    • Search Google Scholar
    • Export Citation
  • 68

    Hara K, Minami K, Sata T. The effects of tramadol and its metabolite on glycine, gamma-aminobutyric acid, and N-methyl-D-aspartate receptors expressed in Xenopus oocytes. Anesth Analg 2005;100:140014015, table of contents.

    • Search Google Scholar
    • Export Citation
  • 69

    Sang CN. NMDA-receptor antagonists in neuropathic pain: experimental methods to clinical trials. J Pain Symptom Manage: 2000;19 (suppl 1):S21S25.

    • Search Google Scholar
    • Export Citation
  • 70

    Taylor CP, Gee NS, Su TZ, et al. A summary of mechanistic hypotheses of gabapentin pharmacology. Epilepsy Res 1998;29:233249.

  • 71

    Serpell MG, Neuropatic Pain Study Group. Gabapentin in neuropathic pain syndromes: a randomized, double-blind, placebo-controlled trial. Pain 2002;99:557566.

    • Search Google Scholar
    • Export Citation
  • 72

    Maneuf YP, Gonzalez MI, Sutton KS, et al. Cellular and molecular action of the putative GABA-mimetic, gabapentin. Cell Mol Life Sci 2003;60:742750.

    • Search Google Scholar
    • Export Citation
  • 73

    Gottrup H, Juhl G, Kristensen AD, et al. Chronic oral gabapentin reduces elements of central sensitization in human experimental hyperalgesia. Anesthesiology 2004;101:14001408.

    • Search Google Scholar
    • Export Citation
  • 74

    Gu Y, Huang LY. Gabapentin actions on N-methyl-D-aspartate receptor channels are protein kinase C-dependent. Pain 2001;93:8592.

  • 75

    Dirks J, Petersen KL, Rowbotham MC, et al. Gabapentin suppresses cutaneous hyperalgesia following heat-capsaicin sensitization. Anesthesiology 2002;97:102107.

    • Search Google Scholar
    • Export Citation
  • 76

    Harding LM, Kristensen JD, Baranowski AP. Differential effects of neuropathic analgesics on wind-up–like pain and somatosensory function in healthy volunteers. Clin J Pain 2005;21:127132.

    • Search Google Scholar
    • Export Citation
  • 77

    Gilron I, Orr E, Tu D, et al. A placebo-controlled randomized clinical trial of perioperative administration of gabapentin, rofecoxib and their combination for spontaneous and movement evoked pain after abdominal hysterectomy. Pain 2005;113:191200.

    • Search Google Scholar
    • Export Citation
  • 78

    Suarez LM, Suarez F, Del Olmo N, et al. Presynaptic NMDA autoreceptors facilitate axon excitability: a new molecular target for the anticonvulsant gabapentin. Eur J Neurosci 2005;21:197209.

    • Search Google Scholar
    • Export Citation
  • 79

    Dirks J, Fredensborg BB, Christensen D, et al. A randomized study of the effects of single-dose gabapentin versus placebo on postoperative pain and morphine consumption after mastectomy. Anesthesiology 2002;97:560564.

    • Search Google Scholar
    • Export Citation
  • 80

    Fassoulaki A, Patris K, Sarantopoulos C, et al. The analgesic effect of gabapentin and mexiletine after breast surgery for cancer. Anesth Analg 2002;95:985991.

    • Search Google Scholar
    • Export Citation
  • 81

    Turan A, Karamanlioglu B, Memis D, et al. Analgesic effects of gabapentin after spinal surgery. Anesthesiology 2004;100:935938.

  • 82

    Turan A, Karamanlioglu B, Memis D, et al. The analgesic effects of gabapentin after total abdominal hysterectomy. Anesth Analg 2004;98:13701373.

    • Search Google Scholar
    • Export Citation
  • 83

    Deleu D, Northway MG, Hanssens Y. Clinical pharmacokinetic and pharmacodynamic properties of drugs used in the treatment of Parkinson's disease. Clin Pharmacokinet 2002;41:261309.

    • Search Google Scholar
    • Export Citation
  • 84

    Vernier VG, Harmon JB, Stump JM, et al. The toxicologic and pharmacologic properties of amantadine hydrochloride. Toxicol Appl Pharmacol 1969;15:642665.

    • Search Google Scholar
    • Export Citation
  • 85

    Palmer GC. Neuroprotection by NMDA receptor antagonists in a variety of neuropathologies. Curr Drug Targets 2001;2:241271.

  • 86

    Bouza C, Magro A, Munoz A, et al. Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review. Addiction 2004;99:811828.

    • Search Google Scholar
    • Export Citation
  • 87

    Wesemann W, Sontag KH, Maj J. Pharmacodynamics and pharmacokinetics of memantine. Arzneimittelforschung 1983;33:11221134.

  • 88

    Snijdelaar DG, Koren G, Katz J. Effects of perioperative oral amantadine on postoperative pain and morphine consumption in patients after radical prostatectomy: results of a preliminary study. Anesthesiology 2004;100:134141.

    • Search Google Scholar
    • Export Citation
  • 89

    Fukui S, Komoda Y, Nosaka S. Clinical application of amantadine, an NMDA antagonist, for neuropathic pain. J Anesth 2001;15:179181.

  • 90

    Fisher K, Coderre TJ, Hagen NA. Targeting the N-methyl-D-aspartate receptor for chronic pain management. Preclinical animal studies, recent clinical experience and future research directions. J Pain Symptom Manage 2000;20:358373.

    • Search Google Scholar
    • Export Citation
  • 91

    Zhang GH, Min SS, Lee KS, et al. Intraarticular pretreatment with ketamine and memantine could prevent arthritic pain: relevance to the decrease of spinal c-fos expression in rats. Anesth Analg 2004;99:152158.

    • Search Google Scholar
    • Export Citation
  • 92

    Maier C, Dertwinkel R, Mansourian N, et al. Efficacy of the NMDA-receptor antagonist memantine in patients with chronic phantom limb pain: results of a randomized double-blinded, placebo-controlled trial. Pain 2003;103:277283.

    • Search Google Scholar
    • Export Citation
  • 93

    Pud D, Eisenberg E, Spitzer A, et al. The NMDA receptor antagonist amantadine reduces surgical neuropathic pain in cancer patients: a double blind, randomized, placebo controlled trial. Pain 1998;75:349354.

    • Search Google Scholar
    • Export Citation
  • 94

    Amin P, Sturrock ND. A pilot study of the beneficial effects of amantadine in the treatment of painful diabetic peripheral neuropathy. Diabet Med 2003;20:114118.

    • Search Google Scholar
    • Export Citation
  • 95

    Berrino L, Oliva P, Massimo F, et al. Antinociceptive effect in mice of intraperitoneal N-methyl-D-aspartate receptor antagonists in the formalin test. Eur J Pain 2003;7:131137.

    • Search Google Scholar
    • Export Citation
  • 96

    Eide PK, Stubhaug A, Oye I, et al. Continuous subcutaneous administration of the N-methyl-D-aspartic acid (NMDA) receptor antagonist ketamine in the treatment of post-herpetic neuralgia. Pain 1995;61:221228.

    • Search Google Scholar
    • Export Citation
  • 97

    Dich-Nielsen JO, Svendsen LB, Berthelsen P. Intramuscular low-dose ketamine versus pethidine for postoperative pain treatment after thoracic surgery. Acta Anaesthesiol Scand 1992;36:538587.

    • Search Google Scholar
    • Export Citation
  • 98

    Bhattacharya A, Gurnani A, Sharma PK, et al. Subcutaneous infusion of ketamine and morphine for relief of postoperative pain: a double-blind comparative study. Ann Acad Med Singapore 1994;23:456459.

    • Search Google Scholar
    • Export Citation
  • 99

    Silvasti M, Karttunen P, Happonen P, et al. Pharmacokinetic comparison of a dextromethorphan-salbutamol combination tablet and a plain dextromethorphan tablet. Int J Clin Pharmacol Ther Toxicol 1990;28:268272.

    • Search Google Scholar
    • Export Citation
  • 100

    Katz J. Pre-emptive analgesia: evidence, current status and future directions. Eur J Anaesthesiol Suppl 1995;10:813.

  • 101

    Moiniche S, Kehlet H, Dahl JB. A qualitative and quantitative systematic review of preemptive analgesia for postoperative pain relief: the role of timing of analgesia. Anesthesiology 2002;96:725741.

    • Search Google Scholar
    • Export Citation
  • 102

    Woolf CJ. Somatic pain pathogenesis and prevention. Br J Anaesth 1995;75:169176.

  • 103

    Fu ES, Miguel R, Scharf JE. Preemptive ketamine decreases postoperative narcotic requirements in patients undergoing abdominal surgery. Anesth Analg 1997;84:10861090.

    • Search Google Scholar
    • Export Citation
  • 104

    Eisenach JC. Preemptive hyperalgesia, not analgesia? Anesthesiology 2000;92:308309.

  • 105

    Lamont LA, Tranquilli WJ, Grimm KA. Physiology of pain. Vet Clin North Am Small Anim Pract 2000;30:703728.

  • 106

    Schulte H, Sollevi A, Segerdahl M. The synergistic effect of combined treatment with systemic ketamine and morphine on experimentally induced windup like pain in humans. Anesth Analg 2004;98:15741580.

    • Search Google Scholar
    • Export Citation
  • 107

    Bossard AE, Guirimand F, Fletcher D, et al. Interaction of a combination of morphine and ketamine on the nociceptive flexion reflex in human volunteers. Pain 2002;98:4757.

    • Search Google Scholar
    • Export Citation
  • 108

    Menigaux C, Guignard B, Fletcher D, et al. Intraoperative small dose ketamine enhances analgesia after outpatient knee arthroscopy. Anesth Analg 2001;93:606612.

    • Search Google Scholar
    • Export Citation
  • 109

    Lauretti GR, Lima IC, Reis MP, et al. Oral ketamine and transdermal nitroglycerin as analgesic adjuvants to oral morphine therapy for cancer pain management. Anesthesiology 1999;90:15281533.

    • Search Google Scholar
    • Export Citation
  • 110

    Schmid RL, Sandler AN, Katz J. Use and efficacy of low-dose ketamine in the management of acute postoperative pain: a review of current techniques and outcomes. Pain 1999;82:111125.

    • Search Google Scholar
    • Export Citation
  • 111

    Nemmani KVS, Grisel JE, Stowe J, et al. Modulation of morphine analgesia by site specific N-methyl-D-aspartate receptor antagonists: dependence on sex, site of antagonism, morphine dose, and time. Pain 2004;109:274283.

    • Search Google Scholar
    • Export Citation
  • 112

    Chia YY, Liu K, Liu YC, et al. Adding ketamine in a multimodal patient-controlled epidural regimen reduces post-operative pain and analgesic consumption. Anesth Analg 1998;86:12451249.

    • Search Google Scholar
    • Export Citation
  • 113

    Subramaniam K, Subramaniam B, Steinbrook RA. Ketamine as adjuvant analgesic to opioids: a quantitative and qualitative systematic review. Anesth Analg 2004;99:482495.

    • Search Google Scholar
    • Export Citation
  • 114

    Wiesenfeld-Hallin Z. Combined opioid-NMDA antagonist therapies. What advantages do they offer for the control of pain syndromes? Drugs 1998;55:14.

    • Search Google Scholar
    • Export Citation
  • 115

    Heiskanen T, Hartel B, Dahl ML, et al. Analgesic effects of dextromethorphan and morphine in patients with chronic pain. Pain 2002;96:261267.

    • Search Google Scholar
    • Export Citation
  • 116

    Mao J, Price DD, Mayer DJ. Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Pain 1995;62:259274.

    • Search Google Scholar
    • Export Citation
  • 117

    Kissin I, Bright CA, Bradley EL Jr. The effect of ketamine on opioid-induced acute tolerance: can it explain reduction of opioid consumption with ketamine-opioid analgesic combinations? Anesth Analg 2000;91:14831488.

    • Search Google Scholar
    • Export Citation
  • 118

    Kochs E, Scharein E, Möllenberg O, et al. Analgesic efficacy of low dose ketamine. Somatosensory evoked responses in relation to subjective pain ratings. Anesthesiology 1996;85:304314.

    • Search Google Scholar
    • Export Citation
  • 119

    Lees P, Landoni MF, Giraudel J, et al. Pharmacodynamics and pharmacokinetics of nonsteroidal anti inflammatory drugs in species of veterinary interest. J Vet Pharmacol Ther 2004;27:479490.

    • Search Google Scholar
    • Export Citation
  • 120

    Herrero JF, Headley PM. Reversal by naloxone of the spinal antinociceptive actions of a systemically administered NSAID. Br J Pharmacol 1996;118:968972.

    • Search Google Scholar
    • Export Citation
  • 121

    Lees P, Landoni MF, Giraudel J, et al. Pharmacodynamics and pharmacokinetics of nonsteroidal anti-inflammatory drugs in species of veterinary interest. J Vet Pharmacol Ther 2004;27:479490.

    • Search Google Scholar
    • Export Citation
  • 122

    Kelly DJ, Ahmad M, Brull SJ. Preemptive analgesia I: physiological pathways and pharmacological modalities. Can J Anaesth 2001;48:10001010.

    • Search Google Scholar
    • Export Citation
  • 123

    Samad TA, Sapirstein A, Woolf CJ. Prostanoids and pain: unraveling mechanisms and revealing therapeutic targets. Trends Mol Med 2002;8:390396.

    • Search Google Scholar
    • Export Citation

Appendix

Appendix

N-methyl-D-aspartate receptor antagonists that are available for clinical use in dogs and cats and their doses.33–41,a,b

NMDAR antagonistDose   
DogsCats  
KetamineFor mild to moderate pain:

0.1–1.0 mg/kg; IV, IM, or SC; q 8 h

For moderate to severe pain:

0.5–4.0 mg/kg; IV, IM, or SC; q 8 h

0.01 mg/kg/min* via constant rate infusion

2–10 mg/kg, PO, q 6–8 h

2.5 mg/kg, epidural injection
For mild to moderate pain:

0.1–1.0 mg/kg; IV, IM, or SC; q 8 h

For moderate to severe pain:

0.5–4 mg/kg; IV, IM, or SC; q 8 h

0.01 mg/kg/min* via constant rate

infusion 2–10 mg/kg, PO, q 8 h
  
Drugs that may be combined with ketamine    
   Morphine0.1–1.0 mg/kg, IV, IM, SC0.05–1 mg/kg, IM, SC  
   Lidocaine25–75 μg/kg/min* via constant rate infusion25–75 μg/kg/min* via constant rate infusion  
   Hydromorphone0.05–0.1 mg/kg, IM or IV, q 4–6 h0.05–0.1 mg/kg; IV, IM, or SC; q 4–6 h  
   Carprofen2.2 mg/kg; IV, IM, SC, or PO; q 12 h2.2 mg/kg; IV, IM, SC, or PO; q 12 h  
   Deracoxib1–4 mg/kg, PO, q 24 h  
   Methadone0.1–0.3 mg/kg; IV or IM; q 2–4 h

0.1–0.2 mg/kg, epidural injection, q 6–7 h
0.1–0.3 mg/kg; IV or IM; q 2–4 h

0.1–0.2 mg/kg, epidural injection, q 6–7 h
  
   Gabapentin3 mg/kg, PO, q 24 h3 mg/kg, PO, q 24 h  
   Dextromethorphan2 mg/kg, PO, q 6–8 h2 mg/kg; PO, IV, or SC; q 6 h  
   Amantadine2–10 mg/kg, PO, q 8–12 h2 mg/kg, PO, q 24 h  
   Tramadol1–2 mg/kg, PO, q 6–12 h2–4 mg/kg, PO, q 12 h  
   Acamprosate or memantineNANA  

Greater infusion dosages have been suggested.

NA = Not available.

  • Figure 1

    Schematic diagram of the structures and processes involved in sensitization and wind-up of the CNS in mammals. During physiologic pain, most NMDARs are blocked by Mg2+. Consequently, there is no postsynaptic cumulative depolarization or wind-up of the CNS. During somatic and visceral pathologic pain conditions, C fibers become sensitized by inflammatory mediators (peripheral sensitization); the lower threshold and spontaneous impulse generation result in persistent release of glutamate and substance P in the C fibers of the dorsal horns of the spinal cord. These substances cause increases in intracellular Ca2+ and Na+ concentrations in the dorsal horn neurons of the spinal cord and trigger the activation of PKC, phosphorylates, and NMDARs, leading to removal of the Mg2+ block and to the wind-up phenomenon. I, II, III, IV, V, and VI = Various laminae of the dorsal horn of the spinal cord. Aβ, Aδ, and C = Sensory nerve fibers. SP = Substance P. GLU = Glutamate. KAR = Kainate receptors. P = Phosphorylation.

  • 1

    Meranda C, Di Virgilio M, Selleri S, et al. Novel pathogenic mechanism of congenital insensitivity to pain with anhidrosis genetic disorders unveiled by functional analysis of neurotropic tyrosine receptor kinase type 1/nerve growth factor mutations. J Biol Chem 2002;277:64556462.

    • Search Google Scholar
    • Export Citation
  • 2

    Craig AD. Interoception: the sense of the physiological condition of the body. Curr Opin Neurobiol 2003;13:500505.

  • 3

    Muir WW III, Woolf CJ. Mechanisms of pain and their therapeutic implications. J Am Vet Med Assoc 2001;219:13461356.

  • 4

    Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000;288:17651769.

  • 5

    Petrenko AB, Yamakura T, Baba H, et al. The role of N-methyl-D-aspartate (NMDA) receptors in pain: a review. Anesth Analg 2003;97:11081116.

    • Search Google Scholar
    • Export Citation
  • 6

    Woolf CJ. Pain: moving from symptom control towards mechanism-specific pharmacologic management. Ann Intern Med 2004;140:441451.

  • 7

    Pogatzki EM, Niemeier JS, Sorkin LS, et al. Spinal glutamate receptor antagonists differentiate primary and secondary mechanical hyperalgesia caused by incision. Pain 2003;105:97107.

    • Search Google Scholar
    • Export Citation
  • 8

    Kawamata M, Watanabe H, Nishikawa K, et al. Different mechanisms of development and maintenance of experimental incision-induced hyperalgesia in human skin. Anesthesiology 2002;97:550559.

    • Search Google Scholar
    • Export Citation
  • 9

    Baranauskas G, Nistri A. Sensitization of pain pathways in the spinal cord: cellular mechanism. Prog Neurobiol 1998;54:349365.

  • 10

    Carroll RC, Zukin RS. NMDA-receptor trafficking and targeting: implications for synaptic transmission and plasticity. Trends Pharmacol Sci 2002;25:571577.

    • Search Google Scholar
    • Export Citation
  • 11

    Ji RR, Kohno T, Moore KA, et al. Central sensitization and LPT: do pain and memory share similar mechanism? Trends Neurosci 2003;26:696705.

    • Search Google Scholar
    • Export Citation
  • 12

    Pogatzki EM, Vandermeulen EP, Brennan TJ. Effect of plantar local anesthetic injection on dorsal horn neuron activity and pain behaviors caused by incision. Pain 2002;97:151161.

    • Search Google Scholar
    • Export Citation
  • 13

    Siddall PJ, Cousins MJ. Persistent pain as a disease entity: implications for clinical management. Anesth Analg 2004;99:510520.

  • 14

    Nagy J. Renaissance of NMDA receptor antagonists: do they have a role in the pharmacotherapy for alcoholism? IDrugs 2004;7:339350.

  • 15

    Li J, McRoberts JA, Nie J, et al. Electrophysiological characterization of N-methyl-D-aspartate receptors in rat dorsal root ganglia neurons. Pain 2004;109:443452.

    • Search Google Scholar
    • Export Citation
  • 16

    Kakinohana M, Kakinohana O, Jun JH, et al. The activation of spinal N-methyl-D-aspartate receptors may contribute to degeneration of spinal motor neurons induced by neuraxial morphine after a noninjurious interval of spinal cord ischemia. Anesth Analg 2005;100:327334.

    • Search Google Scholar
    • Export Citation
  • 17

    Olivar T, Laird JMA. Differential effects of N-methyl-D-aspartate receptor blockade on nociceptive somatic and visceral reflexes. Pain 1999;79:6773.

    • Search Google Scholar
    • Export Citation
  • 18

    Willert RP, Woolf CJ, Hobson AR, et al. The development and maintenance of human visceral pain hypersensitivity is dependent on the N-methyl-D-aspartate. Gastroenterology 2004;126:683692.

    • Search Google Scholar
    • Export Citation
  • 19

    Ossipov MH, Lai J, King T, et al. Antinociceptive and nociceptive actions of opioids. J Neurobiol 2004;61:126148.

  • 20

    Chizh BA, Headley PM, Tzschentke TM. NMDA receptor antagonists as analgesics: focus on the NR2B subtype. Trends Pharmacol Sci 2001;22:636641.

    • Search Google Scholar
    • Export Citation
  • 21

    McCartney CJL, Sinha A, Katz J. A qualitative systematic review of the role of N-methyl-D-aspartate receptor antagonists in preventive analgesia. Anesth Analg 2004;98:13851400.

    • Search Google Scholar
    • Export Citation
  • 22

    Ilkjaer S, Petersen Kl, Brennum J, et al. Effect of systemic N-methyl-D-aspartate receptor antagonist (ketamine) on primary and secondary hyperalgesia in humans. Br J Anaesth 1996;76:829834.

    • Search Google Scholar
    • Export Citation
  • 23

    Callahan RJ, Au JD, Paul M, et al. Functional inhibition by methadone of N-methyl-D-aspartate receptors expressed in xenopus oocytes: stereospecific and subunit effects. Anesth Analg 2004;98:653659.

    • Search Google Scholar
    • Export Citation
  • 24

    Chen L, Huang LYM. Protein kinase C reduces Mg2+ block of NMDA-receptor channels as a mechanism of modulation. Nature 1992;356:521523.

    • Search Google Scholar
    • Export Citation
  • 25

    Brenner GJ, Ji RR, Shaffer S, et al. Peripheral noxious stimulation induces phosphorylation of the NMDA receptor NR1 subunit at the PKC-dependent site, serine-896, in spinal cord dorsal horn neurons. Eur J Neurosci 2004;20:375384.

    • Search Google Scholar
    • Export Citation
  • 26

    Guo W, Zou S, Guan Y, et al. Tyrosine phosphorylation of the NR2B subunit of the NMDA receptor in the spinal cord during the development and maintenance of inflammatory hyperalgesia. J Neurosci 2002;22:62086217.

    • Search Google Scholar
    • Export Citation
  • 27

    Petrenko AB, Yamakura T, Baba H, et al. Unaltered pain-related behavior in mice lacking NMDA receptor GluRepsilon 1 subunit. Neurosci Res 2003;46:199204.

    • Search Google Scholar
    • Export Citation
  • 28

    Olney JW, Labruyere J, Price MT. Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science 1989;244:13601362.

    • Search Google Scholar
    • Export Citation
  • 29

    Eisenach JC. Preemptive hyperalgesia, not analgesia? Anesthesiology 2000;92:308309.

  • 30

    Bowen JM, Blackmon DM, Heavner JE. Neuromuscular transmission and hypocalcemic paresis in the cow. Am J Vet Res 1970;31:831839.

  • 31

    Sobow T. The clinical relevance of memantine use [in Polish]. Psychiatr Pol 2004;38:321330.

  • 32

    Wiech K, Kiefer RT, Topfner S, et al. A placebo-controlled randomized crossover trial of the N-methyl-D-aspartic acid receptor antagonist, memantine, in patients with chronic phantom limb pain. Anesth Analg 2004;98:408413.

    • Search Google Scholar
    • Export Citation
  • 33

    Lin HC, Thurmon JC, Benson GJ, et al. Telazol: a review of its pharmacology and use in veterinary medicine. J Vet Pharmacol Ther 1993;16:383418.

    • Search Google Scholar
    • Export Citation
  • 34

    Amarpal GR, Aithal HP, Singh GR, et al. Pre-emptive effects of epidural ketamine for analgesia in dogs. Indian Vet J 1999;76:300302.

  • 35

    Wagner AE, Walton JA, Hellyer PW, et al. Use of low doses of ketamine administered by constant rate infusion as an adjunct for postoperative analgesia in dogs. J Am Vet Med Assoc 2002;221:7275.

    • Search Google Scholar
    • Export Citation
  • 36

    Jones RS. Epidural analgesia in the dog and cat. Vet J 2001;161:123131.

  • 37

    Martin DD, Tranquilli WJ, Olson WA, et al. Hemodynamic effects of epidural ketamine in isoflurane-anesthetized dogs. Vet Surg 1997;26:505509.

    • Search Google Scholar
    • Export Citation
  • 38

    Muir WW III, Wiese AJ, March PA. Effects of morphine, lidocaine, ketamine and morphine-lidocaine-ketamine drug combination on minimum alveolar concentration in dogs anesthetized with isoflurane. Am J Vet Res 2003;64:11551160.

    • Search Google Scholar
    • Export Citation
  • 39

    Schwieger IM, Szlam F, Hug CC Jr. The pharmacokinetics and pharmacodynamics of ketamine in dogs anesthetized with enflurane. J Pharmacokinet Biopharm 1991;19:145156.

    • Search Google Scholar
    • Export Citation
  • 40

    Joubert K. Ketamine hydrochloride—an adjunct for analgesia in dogs with burn wounds. J S Afr Vet Assoc 1998;69:9597.

  • 41

    Slingsby LS, Waterman-Pearson AE. The post-operative analgesic effects of ketamine after canine ovariohysterectomy: a comparison between pre- or post-operative administration. Res Vet Sci 2000;69:147152.

    • Search Google Scholar
    • Export Citation
  • 42

    Woolf CJ, Chong MS. Preemptive analgesia—treating post-operative pain by preventing the establishment of central sensitization. Anesth Analg 1993;77:362379.

    • Search Google Scholar
    • Export Citation
  • 43

    Woolf CJ, Max MB. Mechanism-based pain diagnosis. Anesthesiology 2001;95:241249.

  • 44

    Zahn PK, Pogatzki-Zahn EM, Brennan TJ. Spinal administration of MK-801 and NBQX demonstrates NMDA-independent dorsal horn sensitization in incisional pain. Pain 2005;114:499510.

    • Search Google Scholar
    • Export Citation
  • 45

    De Kock M, Lavand'homme P, Waterloos H. ‘Balanced analgesia’ in the perioperative period: is there a place for ketamine? Pain 2001;92:373380.

    • Search Google Scholar
    • Export Citation
  • 46

    Grant IS, Nimmo WS, Clements JA. Lack of effect of ketamine analgesia on gastric emptying in man. Br J Anaesth 1981;53:13211323.

  • 47

    Amarpal GR, Aithal HP, Kinjavdekar P, et al. Interaction between epidurally administered ketamine and pethidine in dogs. J Vet Med 2003;50:254258.

    • Search Google Scholar
    • Export Citation
  • 48

    Dal D, Tetik O, Altunkaya H, et al. The efficacy of intraarticular ketamine for postoperative analgesia in outpatient arthroscopic surgery. Arthroscopy 2004;20:300305.

    • Search Google Scholar
    • Export Citation
  • 49

    Redua MA, Valadao CAA, Duque JC, et al. The pre-emptive effect of epidural ketamine on wound sensitivity in horses tested by using von-Frey filaments. Vet Anesth Analg 2002;29:200206.

    • Search Google Scholar
    • Export Citation
  • 50

    Schmid RL, Sandler AN, Katz J. Use and efficacy of low-dose ketamine in the management of acute postoperative pain: a review of current techniques and outcomes. Pain 1999;82:111125.

    • Search Google Scholar
    • Export Citation
  • 51

    Hirota K, Lambert DG. Ketamine: its mechanism(s) of action and unusual clinical uses. Br J Anesth 1996;77:441444.

  • 52

    Scheller M, Bufler J, Hertle I, et al. Ketamine blocks currents through mammalian nicotinic acetylcholine receptor channels by interaction with both the open and the closed state. Anesth Analg 1996;83:830836.

    • Search Google Scholar
    • Export Citation
  • 53

    Smith DJ, Pekoe GM, Martin LL, et al. The interaction of ketamine with the opiate receptor. Life Sci 1980;26:789795.

  • 54

    Willetts J, Balster RL, Leander JD. The behavioral pharmacology of NMDA receptor antagonists. Trends Pharmacol Sci 1990;11:423428.

  • 55

    Stubhaug A, Breivik H, Eide PK, et al. Mapping of punctuate hyperalgesia around a surgical incision demonstrates that ketamine is a powerful suppressor of central sensitization to pain following surgery. Acta Anaesthesiol Scand 1997;41:11241132.

    • Search Google Scholar
    • Export Citation
  • 56

    Schwinn DA, Leslie JB, Watkins WD. Basic principles of pharmacology and anesthesia. In: Miller RD, ed. Anesthesia, 1. New York: Churchill Livingstone Inc, 1994;4366.

    • Search Google Scholar
    • Export Citation
  • 57

    Enarson MC, Hays H, Woodroffe MA. Clinical experience with oral ketamine. J Pain Symptom Manage 1999;17:384386.

  • 58

    Hocking G, Cousins MJ. Ketamine in chronic pain management: an evidence based review. Anesth Analg 2003;97:17301739.

  • 59

    Weinbroum AA, Ben-Abraham R. Dextromethorphan and dexmedetomidine: new agents for the control of perioperative pain. Eur J Surg 2001;167:563569.

    • Search Google Scholar
    • Export Citation
  • 60

    Ebert B, Andersen S, Krogsgaard-Larsen P. Ketobemidone, methadone and pethidine are non-competitive N-methyl-D-aspartate (NMDA) antagonists in the rat cortex and spinal cord. Neurosci Lett 1995;187:165168.

    • Search Google Scholar
    • Export Citation
  • 61

    Ebert B, Thorkildsen C, Andersen S, et al. Opioid analgesics as noncompetitive N-methyl-D-aspartate (NMDA) antagonists. Biochem Pharmacol 1998;56:553559.

    • Search Google Scholar
    • Export Citation
  • 62

    Manfredi PL, Foley KM, Payne R, et al. Parenteral methadone: an essential medication for the treatment of pain. J Pain Symptom Manage 2003;26:687688.

    • Search Google Scholar
    • Export Citation
  • 63

    Manfredi PL, Gonzales GR, Cheville AL, et al. Methadone analgesia in cancer pain patients on chronic methadone maintenance therapy. J Pain Symptom Manage 2001;21:169174.

    • Search Google Scholar
    • Export Citation
  • 64

    Mercadante S. Methadone in cancer pain. Eur J Pain 1997;1:7785.

  • 65

    McDonnell FJ, Sloan JW, Hamann SR. Advances in cancer pain management. Curr Oncol Rep 2000;2:351357.

  • 66

    Scott LJ, Perry CM. Tramadol: a review of its use in perioperative pain. Drugs 2000;60:139176.

  • 67

    Sindrup SH, Andersen G, Madsen C, et al. Tramadol relieves pain and allodynia in polyneuropathy: a randomised, double-blind, controlled trial. Pain 1999;83:8590.

    • Search Google Scholar
    • Export Citation
  • 68

    Hara K, Minami K, Sata T. The effects of tramadol and its metabolite on glycine, gamma-aminobutyric acid, and N-methyl-D-aspartate receptors expressed in Xenopus oocytes. Anesth Analg 2005;100:140014015, table of contents.

    • Search Google Scholar
    • Export Citation
  • 69

    Sang CN. NMDA-receptor antagonists in neuropathic pain: experimental methods to clinical trials. J Pain Symptom Manage: 2000;19 (suppl 1):S21S25.

    • Search Google Scholar
    • Export Citation
  • 70

    Taylor CP, Gee NS, Su TZ, et al. A summary of mechanistic hypotheses of gabapentin pharmacology. Epilepsy Res 1998;29:233249.

  • 71

    Serpell MG, Neuropatic Pain Study Group. Gabapentin in neuropathic pain syndromes: a randomized, double-blind, placebo-controlled trial. Pain 2002;99:557566.

    • Search Google Scholar
    • Export Citation
  • 72

    Maneuf YP, Gonzalez MI, Sutton KS, et al. Cellular and molecular action of the putative GABA-mimetic, gabapentin. Cell Mol Life Sci 2003;60:742750.

    • Search Google Scholar
    • Export Citation
  • 73

    Gottrup H, Juhl G, Kristensen AD, et al. Chronic oral gabapentin reduces elements of central sensitization in human experimental hyperalgesia. Anesthesiology 2004;101:14001408.

    • Search Google Scholar
    • Export Citation
  • 74

    Gu Y, Huang LY. Gabapentin actions on N-methyl-D-aspartate receptor channels are protein kinase C-dependent. Pain 2001;93:8592.

  • 75

    Dirks J, Petersen KL, Rowbotham MC, et al. Gabapentin suppresses cutaneous hyperalgesia following heat-capsaicin sensitization. Anesthesiology 2002;97:102107.

    • Search Google Scholar
    • Export Citation
  • 76

    Harding LM, Kristensen JD, Baranowski AP. Differential effects of neuropathic analgesics on wind-up–like pain and somatosensory function in healthy volunteers. Clin J Pain 2005;21:127132.

    • Search Google Scholar
    • Export Citation
  • 77

    Gilron I, Orr E, Tu D, et al. A placebo-controlled randomized clinical trial of perioperative administration of gabapentin, rofecoxib and their combination for spontaneous and movement evoked pain after abdominal hysterectomy. Pain 2005;113:191200.

    • Search Google Scholar
    • Export Citation
  • 78

    Suarez LM, Suarez F, Del Olmo N, et al. Presynaptic NMDA autoreceptors facilitate axon excitability: a new molecular target for the anticonvulsant gabapentin. Eur J Neurosci 2005;21:197209.

    • Search Google Scholar
    • Export Citation
  • 79

    Dirks J, Fredensborg BB, Christensen D, et al. A randomized study of the effects of single-dose gabapentin versus placebo on postoperative pain and morphine consumption after mastectomy. Anesthesiology 2002;97:560564.

    • Search Google Scholar
    • Export Citation
  • 80

    Fassoulaki A, Patris K, Sarantopoulos C, et al. The analgesic effect of gabapentin and mexiletine after breast surgery for cancer. Anesth Analg 2002;95:985991.

    • Search Google Scholar
    • Export Citation
  • 81

    Turan A, Karamanlioglu B, Memis D, et al. Analgesic effects of gabapentin after spinal surgery. Anesthesiology 2004;100:935938.

  • 82

    Turan A, Karamanlioglu B, Memis D, et al. The analgesic effects of gabapentin after total abdominal hysterectomy. Anesth Analg 2004;98:13701373.

    • Search Google Scholar
    • Export Citation
  • 83

    Deleu D, Northway MG, Hanssens Y. Clinical pharmacokinetic and pharmacodynamic properties of drugs used in the treatment of Parkinson's disease. Clin Pharmacokinet 2002;41:261309.

    • Search Google Scholar
    • Export Citation
  • 84

    Vernier VG, Harmon JB, Stump JM, et al. The toxicologic and pharmacologic properties of amantadine hydrochloride. Toxicol Appl Pharmacol 1969;15:642665.

    • Search Google Scholar
    • Export Citation
  • 85

    Palmer GC. Neuroprotection by NMDA receptor antagonists in a variety of neuropathologies. Curr Drug Targets 2001;2:241271.

  • 86

    Bouza C, Magro A, Munoz A, et al. Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review. Addiction 2004;99:811828.

    • Search Google Scholar
    • Export Citation
  • 87

    Wesemann W, Sontag KH, Maj J. Pharmacodynamics and pharmacokinetics of memantine. Arzneimittelforschung 1983;33:11221134.

  • 88

    Snijdelaar DG, Koren G, Katz J. Effects of perioperative oral amantadine on postoperative pain and morphine consumption in patients after radical prostatectomy: results of a preliminary study. Anesthesiology 2004;100:134141.

    • Search Google Scholar
    • Export Citation
  • 89

    Fukui S, Komoda Y, Nosaka S. Clinical application of amantadine, an NMDA antagonist, for neuropathic pain. J Anesth 2001;15:179181.

  • 90

    Fisher K, Coderre TJ, Hagen NA. Targeting the N-methyl-D-aspartate receptor for chronic pain management. Preclinical animal studies, recent clinical experience and future research directions. J Pain Symptom Manage 2000;20:358373.

    • Search Google Scholar
    • Export Citation
  • 91

    Zhang GH, Min SS, Lee KS, et al. Intraarticular pretreatment with ketamine and memantine could prevent arthritic pain: relevance to the decrease of spinal c-fos expression in rats. Anesth Analg 2004;99:152158.

    • Search Google Scholar
    • Export Citation
  • 92

    Maier C, Dertwinkel R, Mansourian N, et al. Efficacy of the NMDA-receptor antagonist memantine in patients with chronic phantom limb pain: results of a randomized double-blinded, placebo-controlled trial. Pain 2003;103:277283.

    • Search Google Scholar
    • Export Citation
  • 93

    Pud D, Eisenberg E, Spitzer A, et al. The NMDA receptor antagonist amantadine reduces surgical neuropathic pain in cancer patients: a double blind, randomized, placebo controlled trial. Pain 1998;75:349354.

    • Search Google Scholar
    • Export Citation
  • 94

    Amin P, Sturrock ND. A pilot study of the beneficial effects of amantadine in the treatment of painful diabetic peripheral neuropathy. Diabet Med 2003;20:114118.

    • Search Google Scholar
    • Export Citation
  • 95

    Berrino L, Oliva P, Massimo F, et al. Antinociceptive effect in mice of intraperitoneal N-methyl-D-aspartate receptor antagonists in the formalin test. Eur J Pain 2003;7:131137.

    • Search Google Scholar
    • Export Citation
  • 96

    Eide PK, Stubhaug A, Oye I, et al. Continuous subcutaneous administration of the N-methyl-D-aspartic acid (NMDA) receptor antagonist ketamine in the treatment of post-herpetic neuralgia. Pain 1995;61:221228.

    • Search Google Scholar
    • Export Citation
  • 97

    Dich-Nielsen JO, Svendsen LB, Berthelsen P. Intramuscular low-dose ketamine versus pethidine for postoperative pain treatment after thoracic surgery. Acta Anaesthesiol Scand 1992;36:538587.

    • Search Google Scholar
    • Export Citation
  • 98

    Bhattacharya A, Gurnani A, Sharma PK, et al. Subcutaneous infusion of ketamine and morphine for relief of postoperative pain: a double-blind comparative study. Ann Acad Med Singapore 1994;23:456459.

    • Search Google Scholar
    • Export Citation
  • 99

    Silvasti M, Karttunen P, Happonen P, et al. Pharmacokinetic comparison of a dextromethorphan-salbutamol combination tablet and a plain dextromethorphan tablet. Int J Clin Pharmacol Ther Toxicol 1990;28:268272.

    • Search Google Scholar
    • Export Citation
  • 100

    Katz J. Pre-emptive analgesia: evidence, current status and future directions. Eur J Anaesthesiol Suppl 1995;10:813.

  • 101

    Moiniche S, Kehlet H, Dahl JB. A qualitative and quantitative systematic review of preemptive analgesia for postoperative pain relief: the role of timing of analgesia. Anesthesiology 2002;96:725741.

    • Search Google Scholar
    • Export Citation
  • 102

    Woolf CJ. Somatic pain pathogenesis and prevention. Br J Anaesth 1995;75:169176.