Pain control and anxiety management for periodontal therapies

Successful management of periodontal disease relies on a variety of relatively minor oral surgical procedures including dental prophylaxis, scaling and root planing, gingivectomies, gingival grafts, and various gingival flap procedures. Strategies for pain control and anxiety management in periodontics are tailored to address some of the unique features of these treatments. Local anesthesia and sedation are used extensively when providing periodontal therapies to help patients undergo painless surgical treatments with minimal physiological and psychological stress. Established techniques for sedation and anesthesia guidelines vary among countries and continents. Single- and multi-drug intravenous sedation techniques are employed using a number of different sedative drugs. A review of the pharmacology and clinical therapeutics of anesthetic and sedative agents used in the field of periodontology is presented. Alternative therapeutic strategies will also be addressed, including the use of nitrous oxide inhalation sedation and oral sedatives for enteral sedation. Two hundred years ago, surgical treatment of disease in medicine and dentistry was limited by the lack of effective means to control pain. The discovery of nitrous oxide by Joseph Priestley in 1776 fuelled the development of anesthetic and sedative techniques. Priestley realized that breathing nitrous oxide produced a very pleasurable effect and later described its analgesic properties, suggesting its potential use for surgical procedures. When a dentist in the USA, Horace Wells, successfully used nitrous oxide on himself to have a tooth extracted, this inhalation agent was further developed for use in all fields of medicine and anesthesiology. Carl Koller, at the Congress of Ophthalmologists in 1884, first officially demonstrated the local anesthetizing properties of cocaine (22). The efficacy of this first local anesthetic agent was rapidly accepted in medicine and dentistry. With the development of regional anesthetic techniques and Einhorn’s discovery in 1904 of procaine, a safer synthetic derivative of cocaine, local anesthesia became the foundation for pain control in dentistry and medicine. Intravenous sedation agents have also developed through the years with many having their original use in dental anesthesia. Many of the techniques employed ‘cocktails’ of drugs; most notably, the Jorgenson Technique, which included phenobarbitone, pethidine, and scopolamine (59). Techniques involving small incremental doses of thiopentine and methohexitone were also developed as popular methods. Often there was a fine line between general anesthesia and sedation, with the margin of safety of these techniques being very narrow. Modern sedation has evolved and developed over the last hundred years with the search for sedative agents that have a wide margin of safety and that provide conscious sedation as distinct from deep sedation/general anesthesia. The ideal drugs should be effective, acceptable to patients, easy to administer, and have a low potential for interaction with other prescribed systemic drugs. With the development of a class of drugs called the benzodiazepines, the sedation agent diazepam (Valium) was introduced in 1956. This paved the way for the provision of a safe form of sedation, permitting the relief of fear and anxiety while maintaining consciousness. With ongoing development and refinement of the benzodiazepine family of drugs, there is now sound evidence detailing their mode of action and use in the field of conscious sedation. Pharmacotherapy using a variety of central nervous system depressant agents is employed extensively to help patients undergo periodontal and restorative treatments with minimal physiological and psychological stress. The need for clear guidance on the appropriate use of a particular technique is essential to protect patient safety. Guidelines for dentists and other non-anesthetists have been developed in the USA, Australia, New Zealand, UK and other European countries (1, 2, 4, 6, 41, 51, 52, 63). The basic principles for all these guidelines are similar and vary only depending on the specific legislation for the country concerned. The Department of Health in the UK has endorsed the use of sedation as a safe alternative to general anesthesia and emphasized the importance of its development in the field of dentistry (63). The American Dental Association and the American Society of Anesthesiology also recognize that sedation is an integral part of dental practice and that it must be delivered safely and effectively (2, 4). In 2007, the American Dental Association guidelines for sedation and anesthesia were modified to address the increased use of enteral sedation and combined inhalational/enteral sedation (3). Categories of sedation and definitions of the level of consciousness were also modified to bring them into closer alignment with medical anesthesiology guidelines. Although the American Dental Association develops definitions and promotes guidelines and educational requirements, State laws control the various levels of anxiolysis, sedation, and anesthesia, and the anesthesia regulations in the USA The scope of practice established by individual State anesthesia laws has been found to vary significantly (7). Depending on the dose, route of administration, and agent(s) selected, the pharmacological strategies used to relieve fear and anxiety in ambulatory dental patients can produce the entire spectrum of central nervous system depression. Patient responses may range from minimal central nervous system depression, placing the patient at no significant risk, to complete loss of consciousness and loss of protective reflexes, as is seen when administering general anesthesia. Between these extremes, various levels of sedation have been described and categorized. By defining levels of sedation and anesthesia, regulations for training, monitoring, and medical emergency preparedness are promulgated. The boundaries between these discrete categories are often imprecise and are constantly being redefined. The American Dental Association’s 2007 revised guidelines for sedation and general anesthesia have redefined levels of anesthesia into the categories of minimal sedation, moderate sedation, deep sedation, and general anesthesia. The current categories of conscious sedation and deep sedation shown below are still used in many countries. Nevertheless, definitions of the level of sedation, central nervous system depression, and accompanying risk are essential in establishing the requirements for practice that will maximize the safety of sedation when used in dental practice. Conscious sedation has been defined as: ‘A technique in which the use of a drug or drugs produces a state of depression of the central nervous system enabling treatment to be carried out, but during which verbal contact with the patient is maintained throughout the period of sedation. The drugs and techniques used to provide conscious sedation for dental treatment should carry a margin of safety wide enough to render loss of consciousness unlikely. The level of sedation must be such that the patient remains conscious, retains protective reflexes, and is able to respond to verbal commands,’ (63). Deep sedation is defined as: ‘A drug-induced depression of consciousness during which patients cannot be easily aroused but respond purposefully following repeated or painful stimulation. The ability to independently maintain ventilatory function may be impaired. Patients may require assistance in maintaining a patent airway and spontaneous ventilation may be inadequate,’ (4). The most recent guidelines concerning the provision of conscious sedation for dental care in the UK were published in November 2003 by the Department of Health Standing Dental Advisory Committee (England and Wales) and the National Dental Advisory Committee 2006 document Conscious Sedation in Dentistry – Dental clinical guidance (Scotland) (51, 63). They have been ratified by the General Dental Council (UK) and accepted as the standard to be adhered to for those practicing sedation in the UK. The guidelines clearly state the standards that must be upheld with regard to sedation drugs and techniques, sedation and emergency equipment, staffing levels, training, and clinical governance. The established techniques for conscious sedation will vary on an international level. In the UK, for example, the recommended technique for adult dental patients is the single-drug technique using intravenous midazolam. This has a very high success rate and excellent safety profile when the standard technique is used and in patients who have been appropriately assessed. Where intravenous sedation is not indicated, inhalation and oral techniques may be considered. Outside the UK, however, other intravenous drugs, including propofol, ketamine, barbiturates, and opiates, used either individually or in combination, may be acceptable. It is important to be aware that these differences exist (6, 17, 60, 64). Anesthetic treatment modalities and specific drugs administered for third molar extraction have been recently surveyed in the USA to assess current office-based therapeutic practices. Questionnaires were mailed to a random national sample of 850 practitioners. Practicing oral and maxillofacial surgeons were estimated to perform an average of 53 third molar extraction surgery cases per month using either general anesthesia (46.3% of cases), intravenous conscious sedation (33.4% of cases), nitrous oxide sedation (5.8% of cases), oral sedation (1.7% of cases), or local anesthesia alone (12.9% of cases). For intravenous conscious sedation, a three-drug technique using midazolam, fentanyl, and propofol was most commonly reported. Ketamine and methohexital were commonly-used alternative agents for intravenous combinations (50). Because intravenous midazolam is the most universal agent employed for dental sedation, this article will concentrate on reviewing the pharmacology of midazolam. The technique of intravenous midazolam in the dental setting will be presented and its application in the field of specialist periodontal care will be discussed. Other sedation agents and techniques will be considered, including intravenous propofol, inhalation sedation with nitrous oxide and oxygen, and oral sedation techniques. Midazolam is an imidazobenzodiazepine derivative introduced into clinical practice in the UK in 1983. The unique chemical structure of midazolam confers a number of physiochemical properties that distinguish it from other benzodiazepines in terms of its pharmacological and pharmacokinetic characteristics (56). Midazolam has a fused imidazole ring that is different from other benzodiazepines such as diazepam. Midazolam’s imidazole ring helps to provide stability in solution as well as allowing for rapid metabolism. Unlike other benzodiazepines such as diazepam and lorazepam, midazolam is water-soluble because the imidazole ring is open at a pH under 4. However, when it is injected intravenously, the blood pH of 7.4 causes the imidazole ring to close and it becomes much more lipid-soluble, facilitating its rapid uptake into nerve tissue (Fig. 1). This, and the fact that it has an ionization constant (pKa) of 6.15 and is therefore poorly ionized at physiological pH, accounts for its rapid onset of action and its high protein binding in the blood (up to 97%). Metabolism includes its hydroxylation to the active metabolite 1-hydroxy-midazolam; it then undergoes glucuronidation before being renally excreted. Chemical structure of midazolam. Benzodiazepines affect γ-aminobutyric acid-mediated systems. The neurotransmitter γ-aminobutyric acid is an inhibitory neurotransmitter and controls the state of a chloride-ion channel. Activation of this chloride-ion channel results in neuronal hyperpolarization (an increased membrane potential in the direction away from the threshold potential) and it accounts for the classification of the γ-aminobutyric acid system as ‘inhibitory’. Benzodiazepines increase the inhibitory action at the γ-aminobutyric acid receptor. The γ-aminobutyric acid receptors are a group of receptors with γ-aminobutyric acid as their endogenous ligand. γ-Aminobutyric acid is the chief inhibitory neurotransmitter in the mammalian brain. Along with glycine, which primarily has effects in the spine, brainstem, and retina, it is responsible for the vast majority of all inhibitory neurotransmission in the central nervous system. Between 20% and 50% of all central synapses use γ-aminobutyric acid as their transmitter. The enzyme responsible for the formation of γ-aminobutyric acid from the amino acid glutamate is glutamic acid decarboxylase. γ-Aminobutyric acid receptors fall into two groups: ionotropic γ-aminobutyric acid A and C receptors (which are ligand-gated channels) and γ-aminobutyric acid B receptors (which are G protein-coupled receptors linked to the activation of potassium-ion channels and/or calcium-ion channels). The γ-aminobutyric acid A receptors are located postsynaptically and mediate fast synaptic inhibition (they are also known as fast receptors). These receptors are pentamers comprised of three different subunits (α, β, and γ) forming α-helices around a central ion channel. They are the targets of the actions of benzodiazepines, barbiturates, and neurosteroids and mediate sedation, excitation, and consciousness. The γ-aminobutyric acid B receptors are located pre- and postsynaptically and inhibit voltage-gated calcium-ion channels (and decrease neurotransmitter release) and open potassium-ion channels (and decrease postsynaptic membrane excitation). These receptors mediate spasticity and motor function. Similar to other benzodiazepines, midazolam produces anxiolytic, sedative, anticonvulsant, muscle relaxant, and amnesic effects. All these actions are clinically beneficial in patient management. Mild anxiolysis is the first sign to become apparent in patients receiving midazolam and with increasing drug levels the other effects become apparent. The amount of midazolam required to achieve the desired clinical effect varies on an individual basis between patients and the importance of slow titration cannot be over-emphasized. The safety profile of a drug depends on several factors, including the effects on other body systems. Midazolam exerts its main effect on the respiratory and cardiovascular systems. Respiratory system. In healthy humans midazolam may reduce the ventilatory response to carbon dioxide, leading to respiratory depression (60). However, at the dose levels used for conscious sedation only, limited effects of clinical significance have been reported (55). A respiratory effect of greater concern is apnea, the incidence being related to dose and speed of injection (56). It is essential, therefore, to communicate with the patient throughout the period of sedation to maintain respiratory function. As such, where midazolam is administered in a safe and effective way, the impact on the patient’s respiratory system will be limited. Cardiovascular system. Midazolam has been reported to produce a reduction in both systolic and diastolic blood pressure, with a simultaneous increase in heart rate (55). In a clinical setting, these changes are primarily the result of sedation and the subsequent reduction of cardiovascular function resulting from anxiety-induced sympathetic nervous system stimulation (17). The significance of these changes in healthy individuals is minimal, but does present as an issue in those with cardiovascular disease who demonstrate reduced physiological reserve. The importance of appropriate pretreatment assessment of patients for midazolam sedation cannot be over-emphasized. Once injected into the blood stream, at physiological pH, midazolam becomes lipid-soluble. This results in the drug rapidly crossing the blood–brain barrier to produce its effects on the central nervous system, which are seen as clinical signs in the patient. Midazolam has a high metabolic clearance and elimination rate, with the elimination half-life lying in the range of 1–4 hours. Both these properties result in midazolam having a relatively short duration of activity, approximately 30–40 minutes. This is an adequate period of time to allow most routine dental procedures to be carried out, although it is important to be aware that the time period will vary between individual patients. Factors influencing midazolam pharmacokinetics. The distribution and elimination of midazolam is influenced by a number of factors. Among these are age, obesity, and drug interactions. It has been demonstrated that total metabolic clearance time may increase with increasing age as a result of a slowing down of metabolism (24, 28). In obese patients, it was found that there was an increase in the deposition of midazolam into the fatty tissues, leading to an extended clearance time. The clinical impact of both these factors is that an extended recovery time is very often witnessed in such cases. An important consideration in pharmacokinetics is the effect of other drugs on the action and metabolism of midazolam. Metabolism occurs via the hepatic cytochrome p450 enzyme CYP3A4 (34). Consequently, inhibitors of CYP3A4, such as azole antifungal drugs, protease inhibitors, and erythromycin, will limit midazolam’s elimination and increase its sedative effects (47). Other drugs will enhance the sedative effect of midazolam including opioids, antidepressants, antipsychotics, and alcohol. When assessing a patient’s fitness for conscious sedation using a titrated dose of midazolam, it is important to take all these factors into consideration. One advantage of using midazolam and other benzodiazepines for sedation is the existence of an effective pharmacological reversal agent, should over-sedation occur. Flumazenil is a benzodiazepine antagonist used as a reversal agent in the treatment of benzodiazepine overdose. As this is the reversal agent for midazolam, it is important to consider its pharmacology at this stage. Flumazenil has no intrinsic activity of its own. It has a greater affinity for the benzodiazepine receptor than midazolam and reverses the effects of midazolam by competitive inhibition at the benzodiazepine-binding site on the γ-aminobutyric acid receptor. The result of this action is to reverse the sedative, respiratory depressant and cardiovascular effects of other benzodiazepines. Flumazenil is a true benzodiazepine, sharing the same basic structure as midazolam but lacking the ring structure attached to the diazepine part of the molecule. The chemical structure is illustrated in Fig. 2. Chemical structure of flumazenil. The onset of action is rapid and usually effects are seen within 1–2 minutes following intravenous administration (23). The peak effect is seen at 6–10 minutes. The recommended dose for adults is 200 μg every 1–2 minutes, until the effect is seen, to a maximum of 1 mg. It is available as a clear, colorless solution for intravenous injection, containing 500 μg in 5 ml. Many benzodiazepines have longer half-lives than flumazenil, therefore the patient must be warned of re-sedation occurring when the flumazenil has worn off (21). It is metabolized in the liver to inactive compounds, which are then excreted in the urine. Flumazenil should only be used to reverse the effects of midazolam in an emergency situation. It is worth noting that subjects who are physically dependent on benzodiazepines may suffer benzodiazepine withdrawal symptoms, including seizure upon administration of flumazenil. In such cases caution must be exercised in its use. Propofol, as an intravenous sedation agent for dental procedures, is widely used in the USA and is gaining popularity in the UK and Europe (12, 26, 38, 43, 50, 54). It is licensed as a general anesthetic agent and as such can only be administered by personnel qualified in anesthetic use. However, owing to its increasing use in the field of dentistry it is important to consider it at this point. Propofol (2, 6-diisopropylphenol) is a potent intravenous hypnotic agent that is widely used for the induction and maintenance of anesthesia and for sedation at sub-anesthetic doses in various fields of medicine. Propofol is an oil at room temperature and insoluble in aqueous solution. Present formulations consist of 1% or 2% (weight/volume) propofol, 10% soyabean oil, 2.25% glycerol, and 1.2% egg phosphatide. Propofol is a global central nervous system depressant. It directly activates γ-aminobutyric acid A receptors. Recent research has also suggested that the endocannabinoid system may contribute significantly to propofol’s anesthetic action and to its unique sedative properties (25). Propofol has a rapid onset of action with a dose-related hypnotic effect and recovery is rapid even after prolonged use. Propofol is highly protein-bound in vivo and is metabolized by conjugation in the liver. Its rate of clearance exceeds hepatic blood flow, suggesting an extrahepatic site of elimination as well. The half-life elimination of propofol has been estimated to be between 2 and 24 hours. However, its duration of clinical effect is much shorter because the drug is rapidly distributed into peripheral tissues, and its effects, therefore, wear off within even half an hour of injection. This, together with its rapid onset of action (within minutes of injection) and the moderate amnesia it induces, makes it an ideal drug for intravenous sedation when used in the appropriate environment. Ketamine is a dissociative anesthetic derived from phencyclidine and is in use for general anesthesia and sedation in the USA. However, as it is mainly used for pediatric patients, it is beyond the scope of this article. Readers are referred to textbooks on dental pharmacology and anesthesia for detailed presentations of the use of ketamine in dentistry (6, 30, 45). Inhalation sedation with nitrous oxide and oxygen is the mainstay of pediatric sedation in the UK (51, 63). However, where intravenous sedation with midazolam is contraindicated in some adults, this technique can be extremely valuable. The administration of inhalation sedation is a semi-hypnotic technique of conscious sedation in which nitrous oxide and oxygen are employed to produce physiological changes which enhance the patient’s suggestibility. The patient should remain conscious and co-operative throughout with all vital reflexes intact. The method uses a controlled mixture of nitrous oxide and oxygen, to a maximum of 70% nitrous oxide, to produce a level of sedation and anxiety control in the patient that will enable appropriate treatment to be carried out under local analgesia. A very low morbidity among dental patients has been reported with nitrous oxide sedation. Duncan & Moore (18) reviewed adverse reactions during dental treatment and found the most common problem, nausea, to be of minimal clinical significance. Nitrous oxide is a colorless, slightly sweet smelling gas. It is stored as a liquid at room temperature at a pressure of 750 psi. When the cylinder valve is opened, gaseous nitrous oxide is released. Nitrous oxide has a blood/gas solubility of 0.47 at 37 °C and as such is poorly soluble in blood. The rate of uptake of the gas into the circulation following inhalation is therefore very rapid. It does not enter any metabolic pathway and therefore is compatible with other prescribed drugs. As well as producing an anxiolytic and sedative effect, nitrous oxide produces a degree of vasodilatation and analgesia. These properties are extremely beneficial when providing dental care to patients with mild to moderate cardiovascular disease, for example controlled angina, with the added benefit of a high percentage of oxygen. As the drug is not metabolized and is removed from the body by exhalation, it is also a useful sedation technique for patients with liver and kidney disease. Temazepam is an active benzodiazepine with powerful hypnotic properties and acts in a similar manner to other benzodiazepines by enhancing the effects of γ-aminobutyric acid (Fig. 3). Its main use in the field of medicine is for short-term treatment of insomnia. Compared with other benzodiazepines, temazepam is relatively long acting and is useful for people who wake up too early. Its primary disadvantage is that it can cause a hangover, making the person using the drug feel drowsy and/or light-headed the following day. Chemical structure of temazepam. In dentistry, temazepam can be administered to help mildly anxious patients obtain a good night’s sleep before their treatment day, reducing the general level of anxiety. For severely anxious patients, the use of temazepam, either as the sole sedation agent or as a pre-medication before intravenous sedation, can be highly beneficial (62). Temazepam is available as capsules for oral administration and is well absorbed in humans. It has a half-life of about 8–10 hours in plasma. The usual adult dosage of temazepam is 10–15 mg taken before bedtime or 1 hour before their treatment session, if severely anxious. Dosages as small as 7.5 mg or as high as 30 mg may be appropriate for some people. As with all other sedative agents temazepam should not be used by people who know they are allergic to it or other benzodiazepines. When administering temazepam, similar caution should be taken as with midazolam, for example in people classified as category III by the American Society of Anesthesiology. Similar drug interactions will be noted as with other benzodiazepines. For example, temazepam may enhance the effect of other central nervous system depressants, including alcohol, opioids, antihistamines, and some antidepressants. Oral contraceptives, cimetidine, and erythromycin may increase blood levels of temazepam, potentially increasing the risk of its side effects. As one of the first benzodiazepines used for sedation in dentistry, diazepam has a long and successful record of relieving mild to moderate anxiety. Diazepam induces strong anti-anxiety effects with minimal somnolence and virtually no amnesia at orally prescribed doses. Diazepam is highly lipid soluble, which explains the sedative’s slow onset after oral and intramuscular administration. Diazepam has long-acting metabolites (oxazepam and desmethyldiazepam) that may have clinically significant sedative properties. Consequently, the clinical duration of diazepam sedation tends to be moderate to long. Diazepam readily redistributes into lipid structures, and a clinical ‘rebound’ effect can occur when this sequestered drug is re-released into the bloodstream after a meal. Diazepam is supplied in 5- and 10-mg tablets. The typical oral adult dosage is 5–10 mg administered 1 hour before the procedure. If patient sedation with this dosage range is not successful (e.g. patient experiencing minimal signs of sedation), the dosage can be cautiously increased to a total of 15–20 mg for subsequent sedations, paying close attention to the onset of unwanted side effects (e.g. unresponsive to verbal commands). Diazepam is classified as Pregnancy Risk Category D. It is a substrate of the cytochrome P450 isozymes 2C19 and 3A4, so medications that activate or retard the activity of those isozymes will affect the metabolism of diazepam (34). Like other oral benzodiazepines, diazepam is an excellent medication for patients with mild anxiety about a dental procedure. It will not cause significant somnolence or amnesia, and is a poor choice when those are the desired effects. Patients, especially the elderly and physically debilitated, should be warned that residual sedative effects are likely to last for the few days after the procedure. Accordingly, patients should exercise caution in making important decisions, and may wish to refrain from driving and operating machinery during this period (37). Triazolam is one of the more potent benzodiazepines. It has a short half-life because it is rapidly redistributed and rapidly metabolized. Similar to the other benzodiazepines, triazolam is a full agonist at the omega receptor and potentiates the central nervous system depression produced by others sedatives. Triazolam has a rapid onset, short duration of action, and profound anterograde amnesia. Originally developed as a medication for treating insomnia, it has the ability to induce a somnolent state. Unfortunately, the suggested dose of triazolam for treating insomnia was too high when the drug was first introduced to the market, and the importance of medical supervision was not emphasized adequately. Consequently, the early occurrence of unwanted side effects prompted many to question triazolam’s safety. Although commonly administered by dentists in the USA as a preoperative sedative, safety concerns have restricted its use in many countries. Triazolam is supplied in 0.125- and 0.25-mg tablets. The typical adult dosage is 0.250–0.375 mg administered orally or sublingually 30–45 minutes before the procedure. Clinical research suggests that the sublingual route for triazolam administration may be slightly more efficacious secondary to slightly higher plasma concentrations compared to the oral route. Triazolam carries a Pregnancy Risk Category X, and must not be used if there is any possibility that the patient might be pregnant. It is metabolized by the hepatic cytochrome P450 enzyme system (CYP3A4) and drug interactions involving coadministration of CYP3A4 inhibitors have been reported (34). Successful sedation requires profound local anesthesia. The local anesthestics available in dentistry, such as lidocaine, mepivacaine, prilocaine, and articaine, have proven to be effective agents for providing pain control for surgical procedures. Several advances in local anesthesia therapeutics have improved the options for the management of the periodontal patient. As discussed by Meechan (4