Clinical Studies

16 May

A number of glutamate receptor ligands have been tested in humans and are in clinical trials as analgesics. A main focus has been on their therapeutic potential for neuropathic  pain, a condition that continues to be notoriously difficult to treat. Clinically tested compounds  include antagonists  for NMDA receptors and AMPA/kainate receptors. None of the mGluR compounds appear to have been studied clinically as potential  analgesics. However, a group II agonist (LY354740) has been successfully tested in clinical trials for generalized anxiety disorders, and mGluR5 antagonists such as MPEP are on their way to clinical trials as well (Swanson et al. 2005).

NMDA Receptor Antagonists

Commercially available NMDA receptor antagonists, including ketamine, me- mantine,  dextromethorphan, and its main metabolite dextrorphan, showed antinociceptive effects in preclinical studies (Sect. 3) and are analgesic in hu- mans (Parsons et al. 1999; Fisher et al. 2000; Weinbroum et al. 2000; Fundytus

2001; Parsons 2001; Kilpatrick and Tilbrook 2002; Henriksson and Sorensen

2002; Hewitt 2003; Carlsson et al. 2004). Evidence from preclinical and earlier clinical studies further suggested that NMDA receptor antagonists enhanced opioid analgesia and prevented the development of tolerance (Fundytus 2001; Parsons 2001), but a recent report  of three controlled clinical trials failed to demonstrate such effects of a combination of morphine and dextromethorphan (Galer et al. 2005).

Ketamine

The noncompetitive NMDA receptor antagonist ketamine has long been used to induce and maintain anesthesia. Ketamine, which has analgesic properties at subanesthetic  doses, is one of the most extensively studied NMDA recep- tor antagonists. The antinociceptive effects of ketamine in preclinical models of inflammatory  and neuropathic  pain have been well documented  (Sect. 3; Fundytus 2001; Parsons 2001; Hewitt 2003). Ketamine is also analgesic in ex- perimental pain induced in healthy human subjects by intradermal  capsaicin, ischemia, or burn (Fundytus 2001; Hewitt 2003). Interestingly, burn-induced pain was also inhibited by peripherally injected ketamine (Carlton 2001). In case reports and controlled studies, systemic (intravenous) ketamine produced relief of various forms of peripheral and central neuropathic  pain (including postherpetic  and posttraumatic neuralgias, phantom  limb pain, and spinal cord  injury),  cancer pain,  and  pain  in fibromyalgia  patients  (Fisher et al.

2000; Fundytus  2001; Parsons 2001; Henriksson  and Sorensen 2002; Hewitt

2003). Oral and epidural administrations of ketamine have also been reported to be effective. There is little evidence to support  long-term  treatment  of chronic pain with ketamine. The usefulness of perioperative ketamine for the treatment  of postoperative  pain is controversial. Some studies reported  ben- efits of preemptive  ketamine  analgesia such as reduced  postoperative  pain and/or  decreased analgesic consumption,  but others found little or no evi- dence (Fundytus 2001; McCartney et al. 2004; Ong et al. 2005). Likewise, post- operative  treatment  has produced  mixed results. Interestingly,  intravenous administration of ketamine may be used as a diagnostic test to predict the analgesic response of neuropathic  pain patients to dextromethorphan, which has a better  side effect profile (Cohen et al. 2004). Undesirable side effects of ketamine  include  dizziness, sedation,  perceptual  changes, and  dissocia- tive symptoms,  which typically disappear  fairly quickly (Fisher et al. 2000; Fundytus 2001; Parsons 2001; Henriksson and Sorensen 2002). In summary, ketamine  is effective in the treatment  of neuropathic  pain and perhaps  fi- bromyalgia but its usefulness is limited by the well-documented albeit tempo- rary side effects, abuse potential, and lack of evidence for long-term treatment benefits.

Memantine

A noncompetitive  NMDA receptor antagonist  memantine  has been used for many years in the treatment  of Parkinson’s disease and, more recently, de- mentia  (Parsons  et al. 1999; Kilpatrick and  Tilbrook  2002). Memantine  is clinically well tolerated  and  shows little of the  side effects typically seen

with NMDA receptor antagonists,  possibly because of the strong voltage de- pendence  and  rapid  kinetics  of its  NMDA channel-blocking  effects. Psy- chotomimetic  effects, agitation/excitation, increased motor  activity, and in- somnia have been reported  but appear to be sporadic and at doses outside the recommend  range (Parsons  et al. 1999; Kilpatrick and Tilbrook 2002). Preclinical studies  showed antinociceptive  effects in animal  models of in- flammatory and neuropathic  pain (see Sect. 3) although relatively high doses were used (Parsons et al. 1999). However, clinical trials have yielded less con- clusive data on its usefulness in the treatment  of neuropathic  pain (Parsons

2001; Kilpatrick and Tilbrook 2002). Memantine reduced nocturnal  pain in patients  with diabetic neuropathy  but was not effective on spontaneous  or evoked pain in patients with nerve injury from amputation or surgery (Kil- patrick and Tilbrook 2002). In summary, memantine  may still have a place in the treatment  of neuropathic  pain because it is well tolerated  and neu- ropathic  pain  represents  one of the therapeutically  most  challenging pain conditions.

Dextromethorphan

An orally available non-competitive NMDA receptor antagonist, dextromethor- phan,  has a long history as a safe cough suppressant  with few side effects (Fisher et al. 2000; Weinbroum  et al. 2000; Fundytus  2001; Carlsson et al.

2004). Dextromethorphan showed antinociceptive effects in preclinical mod- els of inflammatory  and neuropathic  pain (Sect. 3). In clinical studies, pre-

treatment  with dextromethorphan provided  preemptive  analgesia for acute postoperative  pain,  although  others  observed  no  such  effect (Weinbroum

et al. 2000; Fundytus  2001; McCartney et al. 2004; Ong et al. 2005). There is, however, little evidence for analgesic effects of dextromethorphan in exper- imental pain in healthy human volunteers and in neuropathic  pain, although a relatively high dose was analgesic in patients  with diabetic  or posttrau-

matic neuropathy  (Weinbroum  et al. 2000; Fundytus  2001; Henriksson  and Sorensen 2002; Hewitt 2003; Carlsson et al. 2004). Intravenous  ketamine has been proposed to have predictive value for the effectiveness of dextromethor-

phan in neuropathic  pain (Cohen et al. 2004). Dextromethorphan appeared to be effective in a subgroup of patients with fibromyalgia and again, intra- venous ketamine may help to select these patients (Henriksson and Sorensen

2002). It has also been suggested that dextromethorphan may enhance  the analgesic effects of opioids and prevent opioid tolerance, but a recent study failed to  show any clinical benefit  of MorphiDex  (Endo  Pharmaceuticals, Chadds Ford, PA), a combination of morphine and dextromethorphan (Galer et al. 2005).

NR2B-Selective Antagonists

Commercially available NR2B receptors antagonists such as CP-101606 (traxo- prodil) and ifenprodil were antinociceptive in preclinical models of inflamma- tory and neuropathic  pain (Sect. 3; Parsons 2001; Chizh et al. 2001; Nakazato et al. 2005). CP-101606 showed analgesic effects in pain patients with peripheral neuropathy and spinal cord injury (Nakazato et al. 2005). CP-101606 and ifen- prodil have also been tested in clinical trials for the treatment of ischemic brain injury or stroke. They were well tolerated and did not cause ataxia, sedation, or impaired learning and memory at therapeutic  concentrations,  suggesting a better therapeutic index than other NMDA receptor antagonists (Chizh et al.

2001; Wang and Shuaib 2005). Unfortunately,  some NR2B-selective antago- nists produced  electrocardiographic  abnormalities  such as a prolonged Q-T interval through blockade of potassium channels (Parsons 2001). There is not enough clinical evidence yet to suggest any therapeutic  advantages of NR2B antagonists in the treatment of pain.

4.1.5

GlycineB Site Antagonists

The presence of glycine at the strychnine-insensitive recognition site (glycineB) of the NMDA receptor is required for channel activation by glutamate or NMDA (Michaelis 1998; Dingledine et al. 1999; Wollmuth and Sobolevsky 2004; Mayer and Armstrong  2004; Mayer 2005). GlycineB site antagonists  have been re- ported  to lack the typical side effects of NMDA receptor  antagonists  (Par- sons 2001; Wallace et al. 2002). A glycineB antagonist  (GV196771) showed antinociceptive  effects in preclinical models of inflammatory  (formalin and carrageenan evoked) and neuropathic pain (Parsons 2001; Wallace et al. 2002). However, a clinical study found no significant effects of GV196771 on sponta- neous and mechanically or thermally evoked pain in patients with neuropathic pain associated with diabetic neuropathy, postherpetic neuralgia, complex re- gional pain syndrome, or peripheral nerve injury (Wallace et al. 2002). A sig- nificant decrease of the size of the allodynic area was observed but did not translate into a reduction of pain (Wallace et al. 2002). The therapeutic  value of glycineB antagonists for pain relief remains to be determined.

Side Effects

Side effects typically associated with NMDA receptor antagonists include mem- ory impairment,  psychomimetic effects, ataxia, and motor incoordination as well as neurotoxicity  (Parsons  2001; Haberny  et al. 2002; Low and Roland

2004). Noncompetitive  NMDA receptor antagonists  such as memantine  and

dextromethorphan are better tolerated and have fewer side effects, which has been explained by their relatively low affinity, fast kinetics, and strong voltage dependence (Parsons et al. 1999; Parsons 2001). GlycineB- and NR2B-selective antagonists  show a much  better  profile in animal  models of chronic  pain than high-affinity channel blockers and competitive NMDA receptor antago- nists (Parsons 2001; Chizh et al. 2001), but their clinical value as analgesics is not yet clear. Neurotoxic effects of NMDA receptor antagonists  such as vac- uolizations were observed with competitive and some noncompetitive NMDA receptor  antagonists  whereas glycineB and NR2B antagonists  did not show neurotoxicity  (Low and Roland 2004). They appear to be dose and time de- pendent.  Most studies, however, were done  in animals  (rats)  and it is not clear if NMDA receptor antagonists induce neurotoxic effects in humans. Fur- thermore, several compounds have been shown to prevent NMDA antagonist

induced neurotoxicity; these include GABAergic, α2-adrenergic, anticholiner- gic, serotonergic, antipsychotic, and antiepileptic drugs (Haberny et al. 2002; Low and Roland 2004).

Non-NMDA Receptor Antagonists

Non-NMDA receptor antagonists produce antinociceptive effects in preclinical pain models but also inhibit normal nociceptive and non-nociceptive process- ing, which would suggest a narrow therapeutic window and make them unlikely drug targets for pain relief. Still, a systemically active non-NMDA receptor an- tagonist  (LY293558, see the following section)  has been tested  in phase II clinical trials for pain. A selective AMPA receptor antagonist (YM872, zonam- panel) is being studied in phase II clinical trials for potentially neuroprotective effects in stroke. In preclinical studies, YM872 inhibited normal nociceptive responses and formalin-induced pain behavior (Nishiyama et al. 2004).

LY293558

LY293558 is a competitive AMPA(GluR2)/kainate(GluR5) antagonist that show- ed antinociceptive effects in a preclinical study of formalin-induced  pain be- havior (Simmons et al. 1998; Gilron 2001) but also inhibited nociceptive base- line responses (Von Bergen et al. 2002). In healthy human volunteers, systemic LY293558 significantly reduced capsaicin-evoked pain and mechanical hyper- algesia and allodynia but had no effect on mechanical or heat pain evoked from normal  skin (Sang et al. 1998). In clinical studies, LY293558 reduced spontaneous and movement-evoked postoperative pain following oral surgery (Gilron et al. 2000) and inhibited headache pain in patients with acute moder- ate or severe migraine attacks (Sang et al. 2004). It has been hypothesized that the analgesic effects of LY293558 involve its GluR5 antagonist action whereas GluR2 antagonism accounts for the side effects (see the following section).

Side Effects

In preclinical tests, LY293558 produced ataxia and motor deficits, but no serious side effects were observed in clinical studies involving humans.  Side effects included  a mild transient  visual impairment  (hazy vision), dizziness, and sedation (Gilron 2001). Although LY293558 was reported to be well tolerated, the therapeutic  range, duration  of drug action, and effect of repeated dosing remain to be determined.

5

Conclusions

Ionotropic and metabotropic glutamate receptors (iGluRs and mGluRs) regu- late and fine-tune neurotransmission and neuronal excitability throughout the nervous system and along the pain neuraxis through a variety of mechanisms. They are involved in a number  of physiological and pathological processes and are emerging as promising therapeutic targets for the treatment of certain pain conditions in preclinical and some clinical studies. Despite the diversity of iGluR and mGluR mediated effects, it appears that antagonists  for iGluRs and group I mGluRs and agonists for group II and III mGluRs can inhibit nociceptive processing in various parts  of the nervous  system. Among the iGluRs, NMDA and kainate receptors are more useful targets than AMPA re- ceptors. It has also been suggested that group I mGluR1 antagonists  may be better candidates for pain relief than mGluR5 antagonists particularly for the treatment of neuropathic pain. Group II agonists appear to hold more promise than group III agonists, but the latter have been not been studied extensively and subtype-selective agonists are still largely missing.

Although some evidence suggests distinct antinociceptive effects of subtype- selective agents on mechanical versus thermal and inflammatory  versus neu- ropathic pain and in different parts of the nervous system, a consistent pattern

has yet to emerge. The continued development of subtype-selective agents and analysis of their antinociceptive effects in different parts of the nervous system and in different pain models will provide answers in the near future. Of partic-

ular importance may be the fact that in the brainstem (PAG) some iGluRs and mGluRs produce effects opposite to those observed in the periphery and spinal cord. The role of glutamate receptors in higher brain centers in preclinical pain

models is still understudied and awaits a systematic and comparative analysis. The increasing availability of orally active compounds  that can be tested and used clinically is extremely promising  and suggests that  certain  iGluR and mGluR ligands can become novel pharmacological therapeutics for pain relief.

Glutamate receptor ligands may provide new alternatives or supplements  to currently available analgesics.

Acknowledgements   Work in the author’s laboratory is supported  by National Institutes of

Health (NIH) grants NS38261 and NS11255.

Random Posts

Comments are closed.