Douglass L. Jackson

Adrenergic regulation of capsaicin-sensitive neurons in dental pulp

Alpha adrenergic agonists (e.g. vasoconstrictors) represent one of the most commonly used drug classes in dentistry. Although adrenergic agonists have potent vascular effects, recent studies suggest that capsaicin-sensitive nociceptors may express adrenoceptors, suggesting that these drugs may directly modulate the function of an important class of pain-signaling neurons in peripheral tissues. In this study, we tested the hypothesis that adrenergic agonists inhibit activation of peripheral terminals of capsaicin-sensitive fibers innervating dental pulp. Pretreatment with epinephrine or clonidine significantly inhibited capsaicin-evoked release of immunoreactive calcitonin gene-related peptide from superfused bovine dental pulp. These studies suggest that adrenergic agonists may reduce postoperative pain in part via a direct inhibition of capsaicin-sensitive nociceptors. This finding may lead to the development of selective, peripherally acting, adrenergic analgesics. Moreover, because neuropeptide release alters blood flow, it is possible that the vascular effects of these drugs are caused by both vasoconstriction and inhibition of peripheral neuropeptide release.

Tramadol Hydrochloride: Analgesic Efficacy Compared with Codeine, Aspirin with Codeine, and Placebo after Dental Extraction

Tramadol hydrochloride is a novel, centrally acting analgesic with two complementary mechanisms of action: opioid and aminergic. Relative to codeine, tramadol has similar analgesic properties but may have fewer constipating, euphoric, and respiratory depressant effects. A two‐center randomized double‐blind controlled clinical trial was performed to assess the analgesic efficacy and reported side effects of tramadol 100 mg, tramadol 50 mg, codeine 60 mg, aspirin (ASA) 650 mg with codeine 60 mg, and placebo. Using a third molar extraction pain model, 200 healthy subjects were enrolled in a 6‐hour evaluation after a single dose of drug. Of the 200 patients enrolled, seven provided incomplete efficacy data or discontinued prematurely and one was lost to follow‐up. Using standard measures of analgesia, including total pain relief score (TOTPAR), maximum pain relief score (MaxPAR), sum of pain intensity difference scores (SPID), peak pain intensity difference (Peak PID), remedication, and global evaluations, all active treatments were found to be numerically superior to placebo. ASA/codeine was found to be statistically superior to placebo for all measures of efficacy. Tramadol 100 mg was statistically superior to placebo for TOTPAR, SPID, and time of remedication, whereas tramadol 50 mg was statistically superior to placebo only for remedication time. Codeine was not found to be statistically superior to placebo for any efficacy measure. A greater TOTPAR response compared with all other active measures was seen for ASA/codeine during the first 3 hours of study. The 6‐hour TOTPAR scores for the tramadol groups and ASA/codeine group were not significantly different. Gastrointestinal side effects (nausea, dysphagia, vomiting) were reported more frequently with tramadol 100 mg, ASA/codeine, and codeine 60 mg than with placebo.

Glial cell line‐derived neurotrophic factor (GDNF) from adult rat tooth serves a distinct population of large‐sized trigeminal neurons

Glial cell line‐derived neurotrophic factor (GDNF) mediates trophic effects for specific classes of sensory neurons. The adult tooth pulp is a well‐defined target of sensory trigeminal innervation. Here we investigated potential roles of GDNF in the regulation of adult trigeminal neurons and the dental pulp nerve supply of the rat maxillary first molar. Western blot analysis and radioactive 35S‐UTP in situ hybridization revealed that GDNF in the dental pulp and its mRNAs were localized with Ngf in the coronal pulp periphery, in particular in the highly innervated subodontoblast layer. Retrograde neuronal transport of iodinated GDNF and Fluorogold (FG) from the dental pulp indicated that GDNF was transported in about one third of all the trigeminal dental neurons. Of the GDNF‐labelled neurons, nearly all (97%) were large‐sized (≥35 µm in diameter). Analysis of FG‐labelled neurons revealed that, of the trigeminal neurons supporting the adult dental pulp, ≈ 20% were small‐sized, lacked isolectin B4 binding and did not transport GDNF. Of the large‐sized dental trigeminal neurons ≈ 40% transported GDNF. About 90% of the GDNF‐accumulating neurons were negative for the high‐temperature nociceptive marker VRL‐1. Our results show that a subclass of large adult trigeminal neurons are potentially dependent on dental pulp‐derived GDNF while small dental trigeminal neurons seems not to require GDNF. This suggests that GDNF may function as a neurotrophic factor for subsets of nerves in the tooth, which apparently mediate mechanosensitive stimuli. As in dorsal root ganglia both small‐ and large‐sized neurons are known to be GDNF‐dependent; these data provide molecular evidence that the sensory supply in the adult tooth differs, in some aspects, from the cutaneous sensory system.

Pharmacokinetics and clinical effects of multidose sublingual triazolam in healthy volunteers.

Triazolam is increasing in popularity as a premedication prescribed by dentists to help their fearful and anxious patients tolerate the potentially aversive nature of some dental procedures. Recent anecdotal reports suggest that incremental sublingual dosing of triazolam may be an effective technique for producing conscious sedation in the dental setting. Although promising, no laboratory or clinical data have been available to evaluate the efficacy or safety of this approach. This study was designed to determine the pharmacokinetics and sedative effects of incremental sublingual dosing of triazolam (total, 1.0 mg) in healthy adults. Ten healthy adult volunteers received sublingual triazolam (0.25 mg) followed by additional doses after 60 (0.50 mg) and 90 (0.25 mg) minutes. Plasma triazolam concentrations, clinical effects (Observers Assessment of Alertness/Sedation score), and processed electroencephalogram (bispectral index score) were measured intermittently for 3 hours. Plasma triazolam concentrations (mean ± SD, 5.1 ± 1.1 ng/mL) and drug effects (Observers Assessment of Alertness/Sedation score, 2 ± 1; and the bispectral index score, 62 ± 16) were greatest in all subjects at the end of the 3-hour evaluation period. Eight of the subjects had Observers Assessment of Alertness/Sedation scores consistent with the definition of deep sedation or general anesthesia (Observers Assessment of Alertness/Sedation score, <3) at some of the later time points in the 180 minutes of data collection. In comparison, 4 of the subjects had bispectral index scores less than 60 during these later time points of data collection. Given the considerable intersubject variability in triazolam concentrations and effects, additional research is needed to assess this multidosing strategy before it can be endorsed as a useful and safe sedation technique for managing fearful and anxious patients in dental practice.

Inhalational and enteral conscious sedation for the adult dental patient

There are clearly many safe and effective sedatives available to the dental practitioner for reducing patient fear and improving their level of comfort. Careful consideration needs to be given to the objectives of the sedation when deciding which pharmacologic agents to use because they all possess slightly different clinical characteristics and various degrees of risk. Patient selection also is critical when making decisions about sedation because the patients expectations and general health status factor into keeping the procedure safe. N2O/O2 sedation is an excellent choice for managing the mildly fearful dental patient or when minimal sedation is desirable. Among the sedatives administered enterally, the benzodiazepines are the most commonly used, and for good reason. These drugs are safe, effective, and offer a host of different personalities from which the dentist can choose. If used wisely and thoughtfully, the dentist can tailor the effects and duration of onset and recovery to the needs of the patient and the expected parameters of the appointment. When N2O/O2 sedation is combined with a single enteral sedative, a more profound level of CNS depression is achieved that can be modestly altered by changing the concentration of inhaled nitrous oxide. With these many pharmacologic alternatives, many different dental patient populations can be sedated in a safe, effective manner, thus allowing the delivery of most dental treatments in a setting of reduced psychologic and physiologic stress. These pharmacologic sedatives have truly opened up a wonderful world of possibilities for the comfortable delivery of dental care, and should be integrated into every offices repertoire for delivery of care.

β2-Adrenoceptor Regulation of CGRP Release from Capsaicin-sensitive Neurons

Previous studies have suggested that neurotransmitter substances from the sympatho-adrenomedullary system regulate pulpal blood flow (PBF), in part, by the inhibition of vasoactive neuropeptide release from pulpal sensory neurons. However, no study has evaluated the role of β-adrenoceptors. We evaluated the hypothesis that activation of β-adrenoceptors inhibits immunoreactive calcitonin gene-related peptide (iCGRP) release from capsaicin-sensitive nociceptive neurons via in vitro superfusion of bovine dental pulp. Either norepinephrine or epinephrine inhibited capsaicin-evoked iCGRP. The norepinephrine effect was blocked by the selective β2-adrenoceptor antagonist, ICI 118,551, but not by pre-treatment with the selective β1-adrenoceptor antagonist, atenolol. In addition, application of albuterol, a selective β2-adrenoceptor agonist, significantly blocked capsaicin-evoked release of iCGRP. Collectively, these studies demonstrate that activation of β2-adrenoceptors in dental pulp significantly reduces exocytosis of neuropeptides from capsaicin-sensitive nociceptors. This effect may have physiologic significance in regulating PBF. Moreover, since capsaicin selectively activates nociceptors, β2-adrenoceptor agonists may have clinical utility as peripherally acting therapeutics for dental pain and inflammation.

Multidrug intravenous sedation : Determinants of the sedative dose of midazolam

OBJECTIVES The efficacy of multidrug intravenous sedation regimens in oral surgery is based on the ability to titrate opioids, benzodiazepines, and barbiturates to a desired level of relaxation. Dosage requirements to reach the initial sedation end points of slurred speech and ptosis of eyelids vary widely from one patient to another. STUDY DESIGN An assessment of physical, cardiovascular, behavioral, and pharmacologic factors that might predict midazolam dosage requirements for the initial sedation titration was carried out with data collected from a large controlled clinical trial of fentanyl, midazolam, and methohexital sedation for third molar surgery. RESULTS Dosage requirements for the initial titration of midazolam were found to be significantly higher when fentanyl was not included in the sedation regimen and when presedation heart rate and presedation systolic blood pressure were elevated.

Intrinsic Regulation of CGRP Release by Dental Pulp Sympathetic Fibers

Neurotransmission from sympathetic and peptidergic afferent fibers participates in the regulation of pulpal blood flow (PBF) via opposing effects. In this study, we directly tested the hypothesis that activation of pulpal sympathetic terminals inhibits exocytosis of immunoreactive calcitonin gene-related peptide (iCGRP) from peptidergic afferents innervating bovine dental pulp. The results demonstrate that norepinephrine inhibits capsaicin-evoked iCGRP release. The application of α-adrenergic antagonists (phentolamine or phenoxybenzamine) increased spontaneous release of iCGRP. Moreover, administration of agents that evoke the release of sympathetic neurotransmitters (guanethidine or reserpine) inhibited capsaicin-evoked iCGRP release. Collectively, these results indicate that sympathetic neurotransmission inhibits exocytosis from pulpal peptidergic afferent fibers. Analysis of these data supports the hypothesis that peripheral sympathetic vasomotor control may operate by a direct mechanism (vasoconstriction) as well as by an indirect mechanism (e.g., inhibition of exocytosis from afferent fibers). Since capsaicin-sensitive neurons are nociceptors, it is possible that certain sympathetic neurotransmission may modulate pain.

Expanded studies of the pharmacokinetics and clinical effects of multidose sublingual triazolam in healthy volunteers.

Abstract Previous work described the pharmacokinetics and clinical effects of multidose sublingual triazolam (Halcion; Pharmacia & Upjohn Co, Kalamazoo, Mich). This laboratory study evaluated the hypothesis that incremental dosing of triazolam produces dose-dependent central nervous system depression that is profound and long lasting. Forty-nine healthy adults between the ages of 21 and 39 years, not receiving dental treatment, were randomly assigned to placebo (n = 12) or 1 of 3 triazolam groups (0.25-mg single dose, n = 12; 0.5 mg divided between 2 equal doses for 60 minutes, n = 12; or 0.75 mg divided among 3 doses for 90 minutes, n = 13). Plasma triazolam concentrations were determined. Bispectral index (BIS) and the Observer Assessment of Alertness/Sedation scale were used to assess sedation. Plasma triazolam concentrations increased with time in all subjects, with Tmax and Cmax both increasing dose dependently. Compared with placebo, all dosing paradigms produced dose-dependent BIS suppression and sedation. The single dose of 0.25 mg reached its peak BIS suppression at 90 (81 ± 7) minutes and sedation at 120 (3.6 ± 0.5) minutes and returned to baseline before 360 minutes. In contrast, incremental dosing of 0.5 and 0.75 mg produced profound and long-lasting BIS suppression and sedation that did not plateau until either 180 or 210 minutes as measured by the BIS index (67 ± 14 and 60 ± 16 at 0.5 and 0.75 mg, respectively) and 150 minutes as measured by the Observer Assessment of Alertness/Sedation scale (3.2 ± 1.0 and 2.7 ± 0.4 at 0.5 and 0.75 mg, respectively). These data more fully characterize the effects of incremental dosing with sublingual triazolam and provide additional insight for discharge safety recommendations.