The ionotropic glutamate receptors are ligand-gated ion channels that mediate the vast majority of excitatory neurotransmission in the brain. The cloning of cDNAs encoding glutamate receptor subunits, which occurred mainly between 1989 and 1992 ([Hollmann and Heinemann, 1994][1]), stimulated this

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The glutamate receptor ion channels

Peripheral tissue damage or nerve injury often leads to pathological pain processes, such as spontaneous pain, hyperalgesia and allodynia, that persist for years or decades after all possible tissue healing has occurred. Although peripheral neural mechanisms, such as nociceptor sensitization and neuroma formation, contribute to these pathological pain processes, recent evidence indicates that changes in central neural function may also play a significant role. In this review, we examine the clinical and experimental evidence which points to a contribution of central neural plasticity to the development of pathological pain. We also assess the physiological, biochemical, cellular and molecular mechanisms that underlie plasticity induced in the central nervous system (CNS) in response to noxious peripheral stimulation. Finally, we examine theories which have been proposed to explain how injury or noxious stimulation lead to alterations in CNS function which influence subsequent pain experience.

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Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence

Repetitive stimulation of small diameter primary afferent fibres produces a progressive increase in action potential discharge (windup) and a prolonged increase in the excitability of neurones in the spinal cord following the stimulus. Previous studies have demonstrated that windup is the consequence of the temporal summation of slow synaptic potentials and that the slow potentials and windup are reduced by pretreatment with N-methyl-D-aspartic acid (NMDA) antagonists. We have now examined whether primary afferent induced hypersensitivity states in flexor motoneurones are also dependent on the activation of NMDA receptors and whether windup is a possible trigger for the production of the central hypersensitivity. Both a non-competitive (MK-801) and a competitive (D-CPP) NMDA antagonist, at doses that did not modify the baseline reflex, reduced the facilitation of the flexor reflex produced by either brief electrical stimulation of the sural nerve (1 Hz for 20 sec at C-fibre strength), or by the cutaneous application of the chemical irritant mustard oil. These antagonists also prevented windup from occurring in the motoneurones. When the the MK-801 and the D-CPP were administered once a state of central facilitation had been induced by prior treatment with mustard oil, they returned the facilitated reflex to its pretreatment level. These results indicate that NMDA receptors are involved in the induction and maintenance of the central sensitization produced by high threshold primary afferent inputs. Because central sensitization is likely to contribute to the post-injury pain hypersensitivity states in man, these data have a bearing both on the potential role of NMDA antagonists for pre-emptive analgesia and for treating established pain states.

The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states.

Statistical Methods in Medical Research.

Ketamine, a racemic mixture consisting of (S)- and (R)-ketamine, has been in clinical use since 1970. Although best characterized for its dissociative anesthetic properties, ketamine also exerts analgesic, anti-inflammatory, and antidepressant actions. We provide a comprehensive review of these therapeutic uses, emphasizing drug dose, route of administration, and the time course of these effects. Dissociative, psychotomimetic, cognitive, and peripheral side effects associated with short-term or prolonged exposure, as well as recreational ketamine use, are also discussed. We further describe ketamine’s pharmacokinetics, including its rapid and extensive metabolism to norketamine, dehydronorketamine, hydroxyketamine, and hydroxynorketamine (HNK) metabolites. Whereas the anesthetic and analgesic properties of ketamine are generally attributed to direct ketamine-induced inhibition of N-methyl-D-aspartate receptors, other putative lower-affinity pharmacological targets of ketamine include, but are not limited to, γ-amynobutyric acid (GABA), dopamine, serotonin, sigma, opioid, and cholinergic receptors, as well as voltage-gated sodium and hyperpolarization-activated cyclic nucleotide-gated channels. We examine the evidence supporting the relevance of these targets of ketamine and its metabolites to the clinical effects of the drug. Ketamine metabolites may have broader clinical relevance than was previously considered, given that HNK metabolites have antidepressant efficacy in preclinical studies. Overall, pharmacological target deconvolution of ketamine and its metabolites will provide insight critical to the development of new pharmacotherapies that possess the desirable clinical effects of ketamine, but limit undesirable side effects.

https://pharmrev.aspetjournals.org/content/pharmrev/70/3/621.full.pdf

Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms

We examined the analgesic effect of racemic ketamine and its 2 enantiomers in 16 female patients (age: 20-29 years) suffering acute pain after oral surgery and in 7 female patients (age: 42-79 years) suffering chronic neuropathic orofacial pain. All 3 forms of ketamine consistently relieved postoperative pain, (S)-ketamine being 4 times more potent than (R)-ketamine. The analgesic effect was maximal 5 min after i.m. injection and lasted for about 30 min. The 7 patients with neuropathic pain received ketamine at one or several occasions. Four patients (age: 54-79 years) who had suffered pain for more than 5 years did not experience an analgesic effect, whereas 3 patients (age: 42-53 years) who had suffered pain for less than 3 years reported pain relief lasting from 24 h to 3 days. The individual type of response did not depend on the form of ketamine used. The mental side effects were qualitatively similar for the 3 forms of ketamine. Relative to the analgesic effect (S)-ketamine caused more disturbing side effects than did (R)-ketamine. The mean serum concentration of each form of ketamine at the time of maximal effect was close to the approximate Kd value for PCP site occupancy by that particular form. This is in concert with the hypothesis that the effect of ketamine on acute nociceptive pain is due to N-methyl-D-aspartate (NMDA) receptor inhibition and adds to the evidence that NMDA receptors are important for the perception of acute, nociceptive pain in humans.(ABSTRACT TRUNCATED AT 250 WORDS)

https://rsds.org/wp-content/uploads/2015/06/2015-effect-ketamine.pdf

Effect of ketamine, an NMDA receptor inhibitor, in acute and chronic orofacial pain

Background The purpose of this randomized double-blind study was to compare the efficacy and safety of propacetamol 2 g (an i.v. acetaminophen 1 g formulation) administered as a 2-min bolus injection (n=50) or a 15-min infusion (n=50) with oral acetaminophen 1 g (n=50) or placebo (n=25) for analgesia after third molar surgery in patients with moderate to severe pain after impacted third molar removal. Methods All patients were evaluated for efficacy during the initial 6 h period after treatment administration (T0) and for safety during the entire week after T0. Results The onset of analgesia after propacetamol was shorter (3 min for bolus administration, 5 min for 15-min infusion) than after oral acetaminophen (11 min). Active treatments were significantly better for all parameters (pain relief, pain intensity, patient's global evaluation, duration of analgesia) than placebo (P Conclusion I.V. propacetamol, administered as a 15-min infusion, is a fast-acting analgesic agent. It is more effective in terms of onset of analgesia than a similar dose of oral acetaminophen.

Onset of acetaminophen analgesia: comparison of oral and intravenous routes after third molar surgery

The analgesic efficiency of ketamine and pethidine was compared in experimental ischemic pain and postoperative pain after oral surgery. Naloxone 1.6 mg or placebo was given 5 min before the analgesic drug. The subjects recorded their pain on a visual analogue scale. Both ketamine 0.3 mg/kg and pethidine 0.7 mg/kg were effective as analgesics against the two types of pain studied. Naloxone prevented the analgesic effect of pethidine, but had no effect on ketamine analgesia. The results are in accordance with the hypothesis that the analgesic effect of ketamine is mediated by a non-opioid mechanism, possibly involving PCP-receptor-mediated blockade of the NMDA-receptor-operated ion channel.

Comparison of ketamine and pethidine in experimental and postoperative pain.

Two nickel-titanium arch-wire types commonly used for initial tooth alignment were compared with regard to the pain/discomfort patients experience during the initial phase of tooth movement. The two arch wires used were a superelastic nickel-titanium alloy, 0.014 inch Sentalloy, Light (GAC International Inc. Central Islip, NY, USA) and a 0.014 inch Nitinol (Unitek, Monrovia, CA, USA), a conventional nickel-titanium aligning archwire. One hundred and twenty-eight consecutive patients attending an orthodontic university clinic and 2 private practices for routine placement of a fixed appliance were randomly assigned one of these 2 initial arch wires. Assessments of pain/discomfort were made daily by means of a 100 mm visual analog scale (VAS) over the first 7-day period after bonding. On the first day, recordings were made every hour for the first 11 hours. The results showed that the level of discomfort increased continuously every hour after the insertion of either a Sentalloy or a Nitinol as first arch wires, with a peak in the first night, remaining high on the second day and decreasing thereafter to baseline level after 7 days. During the first 10 hours it was apparent that the pain/discomfort experienced after placement of a Sentalloy was less than that found with the Nitinol archwire, although a significant difference could be found at 4 hours only. No significant gender-specific differences were found in either archwire group. A significant difference between the upper and lower dental arches was observed during the first 11 hours after placement of either a Sentalloy or a Nitinol arch wire, with the lower arch having the higher pain experience.

Pain and discomfort experienced after placement of a conventional or a superelastic NiTi aligning archwire. A randomized clinical trial

We compared an acetaminophen (paracetamol) 1 g (n = 51) formulation for infusion with propacetamol 2 g (n = 51) and placebo (n = 50) in a randomized, controlled, double-blind, parallel group trial in patients with moderate-to-severe pain after third molar surgery. Treatment efficacy was assessed in house for 6 h after starting the 15-min infusion. Significant effects versus placebo (P < 0.01) were obtained with both active treatments on pain relief, pain intensity difference on a 100-mm visual analog scale, and on a categorical scale (except for propacetamol at 6 h). No significant differences were noted between active groups except at 1 h. Six-hour weighted sums of primary assessments showed significantly better efficacy than placebo (P < 0.0001) and no difference between active treatments. Median stopwatch time to onset of pain relief for active treatment was 6-8 min after infusion start. Active treatments showed comparable efficacy with a significantly longer duration of analgesia and better patients' global evaluation compared with placebo. The incidence of patients reporting local pain at the infusion site was significantly less frequent after IV acetaminophen or placebo (0%) in comparison with propacetamol (49%). In conclusion, acetaminophen 1 g and propacetamol 2 g were superior to placebo regarding analgesic efficacy, with a more frequent incidence of local pain at the infusion site for propacetamol.

Intravenous acetaminophen (paracetamol): comparable analgesic efficacy, but better local safety than its prodrug, propacetamol, for postoperative pain after third molar surgery.

L.A. Skoglund

Papers

Effect of ketamine, an NMDA receptor inhibitor, in acute and chronic orofacial pain

Onset of acetaminophen analgesia: comparison of oral and intravenous routes after third molar surgery

Comparison of ketamine and pethidine in experimental and postoperative pain.

Pain and discomfort experienced after placement of a conventional or a superelastic NiTi aligning archwire. A randomized clinical trial

Intravenous acetaminophen (paracetamol): comparable analgesic efficacy, but better local safety than its prodrug, propacetamol, for postoperative pain after third molar surgery.