chapter 9 Sublingual, Transdermal, and Intranasal Sedation
In recent years, efforts have been directed at seeking alternative routes of drug administration for use where traditional routes are unavailable or where patient cooperation is lacking. Such situations include younger children or infants (the “precooperative patient”), where cooperation does not exist; older patients requiring long-term drug therapy, where noncompliance with administration recommendations is a significant problem; and victims of burns, trauma, or life-threatening emergencies, where other routes of administration are not present, yet rapid onset of drug action is necessary.
Three routes of drug administration, sublingual (SL), transdermal, and intranasal (IN), are discussed. These techniques are becoming increasingly popular in many areas of medicine. The IN route, in particular, has seen a dramatic increase in popularity in medicine and, to a lesser degree, in dentistry. IN midazolam has become a commonly employed drug in the management of status epilepticus in infants and smaller children.1–3
Transdermal drug administration is most often used for sustained-action drug administration (e.g., scopolamine as an antimotion sickness therapy), whereas SL and IN drug administration provide a considerably more rapid onset of clinical action.
SL drug administration has a long history. Indeed, SL administration of nitroglycerin tablets has been the recommended route for management of anginal pain for decades. SL placement of nitroglycerin tablets usually provides relief from anginal discomfort within 2 minutes.
An advantage of SL drug administration is that the drug enters directly into the systemic circulation, almost entirely bypassing the enterohepatic circulation. This avoids the hepatic first-pass effect, in which a percentage of the drug is biotransformed before ever having the opportunity to enter the general circulation and to reach its target organ (e.g., brain).4–6 Harris and Robinson7 have stated that SL drug delivery provides rapid absorption and good bioavailability for some drugs, although this site is not well suited to sustained-delivery systems. Patient cooperation is important to the success of the SL route of administration, which minimizes its use in many pediatric and other uncooperative patients.8
Among the drugs that have been used sublingually are nitroglycerin in the management of angina pectoris, acute pulmonary edema, and acute myocardial infarction9; heparin in the prophylaxis of atherosclerotic disease10; nifedipine, a calcium channel blocker, for the management of acute hypertensive urgencies and emergencies11–17; opioids, such as meperidine and buprenorphine, for relief of pain in cancer18,19 or following abdominal or gynecologic surgery8,20; and sedatives for premedication and sedation.21–23
Nitroglycerin is administered sublingually in the management of anginal discomfort. Rapid SL absorption provides venodilation within 2 minutes. The rapidity of onset and degree of vasodilation observed make nitroglycerin the drug of choice for the management of angina pectoris. Side effects of SL nitroglycerin are few and usually not severe. However, in certain individuals, SL nitroglycerin has provoked severe side effects. Brandes, Santiago, and Limacher24 report on 35 cases of nitroglycerin-induced hypotension, bradycardia, apnea, and unconsciousness and conclude that this is a drug-induced effect of nitroglycerin that is independent of the route of administration and is unpredictable. They recommend close monitoring whenever nitroglycerin is administered.
Therapeutic advantage may be taken of the hypotensive side effect of nitroglycerin in the management of acute hypertensive episodes. Acute hypertensive episodes are classified as either “urgencies” or “emergencies,” the level of blood pressure elevation determining the classification. Hypertensive emergencies involve significantly greater blood pressure elevations and require more aggressive and immediate treatment than do hypertensive urgencies.11 Although nitroglycerin has been used effectively sublingually, the calcium channel blocker nifedipine has received considerably more attention in management of both hypertensive urgencies and emergencies. SL nifedipine is rapidly absorbed, leading to improved myocardial perfusion, increased coronary blood flow, and decreased coronary vascular resistance.12 A capsule of nifedipine is punctured several times (in the dental office an explorer or small round bur will be sufficient for this purpose), placed under the tongue, and sucked on by the patient. Nifedipine SL has been used in the management of clonidine overdose, which produces severe hypertension and altered mental status. SL nifedipine (20 mg) produces a rapid decline in blood pressure and improved mental status.13 As with nitroglycerin, SL nifedipine used for management of acute hypertensive episodes may produce symptomatic hypotension in some patients.16 Vital signs should be monitored closely whenever SL nifedipine is used. Recent evidence has demonstrated that SL nifedipine may cause serious dose-dependent adverse effects.17
Four studies have reported on the efficacy of SL administration of opioids. Korttilla and Hovorka20 compared SL buprenorphine with intramuscular (IM) oxycodone as a preanesthetic medication. Preoperatively the SL opioid produced less drowsiness and sedation and alleviated patients’ apprehension significantly less than oxycodone. However, in the recovery room, moderate to severe pain was more common with oxycodone than with SL buprenorphine. SL buprenorphine was as effective as IM oxycodone for pain relief. However, two patients receiving SL opioids developed severe respiratory depression postoperatively. The authors concluded that SL opioids can provide good postoperative pain relief for gynecologic procedures performed under anesthesia but that patients must be monitored because of the potential for respiratory depression. In a similar study, Carl et al8 compared SL and IM buprenorphine and IM meperidine for pain control following major abdominal surgery. Patients receiving SL buprenorphine were significantly more conscious in the immediate postoperative period than either IM group, yet all three groups demonstrated equal pain relief. Sedation and nausea were the most common complications in all three groups. Three cases of IM meperidine and one of IM buprenorphine required intermittent positive-pressure ventilation (IPPV) for respiratory depression. They concluded that SL opioids are useful for postoperative pain and exhibited administrative advantages when patients were able to cooperate. Two studies have looked at the use of opioids for the long-term relief of cancer pain, concluding that SL morphine has enabled patients whose cancer pain is refractory to traditional methods of drug delivery to obtain satisfactory control of their symptoms.18,19
Oral Transmucosal Fentanyl Citrate (Fentanyl “Lollipop”)
Fentanyl has also been formulated as a lozenge or lollipop (Fentanyl Oralet, Abbott Laboratories). Originally designed for use in long-term pain management in cancer patients,25,26 oral transmucosal fentanyl citrate (OTFC) has recently demonstrated advantages in the management of moderate to severe postoperative pain27 and as a preoperative sedative in children.28,29 The use of OTFC has been studied as an alternative to oral and parenteral medication in younger or older patients who are unwilling or unable to tolerate orally administered drugs.30–37 Although several doses have been evaluated, most studies indicated that a dose of 15 to 20 µg/kg provides the optimal sedation and anxiolysis preoperatively.30,31 Acceptance of the lollipop was reported as universal in most studies, a significant advantage over most other forms of drug administration.30–34 The objective onset of sedation was noted to develop from 10 minutes32 to 30 minutes30 following administration of the lollipop. After beginning OTFC, 60% of patients became drowsy or sedated in 12 to 30 minutes.34 When volunteers were asked to rapidly suck the lollipop (as opposed to permitting it to passively dissolve), a more rapid onset of a pleasant feeling (the first subjective sensation) was observed. However, the onset of subjective sedation or analgesia was no more rapid than with passive dissolution.31
The use of fentanyl lollipops is not without the potential for side effects. Significant decreases in respiratory rate and arterial oxygen saturation (Spo2) have been reported.5,30,32,36 Management of these episodes of opioid-induced respiratory depression was simple: reminding the patient to breathe.30 Other side effects noted with some frequency included pruritus30,33,36 in 80%30 to 90%33 of patients preoperatively and 33% to 70% postoperatively30; postoperative nausea (30% to 58%30); and vomiting (50% to 83%),30,33,35–36 which was not significantly reduced by the prophylactic administration of the antiemetic droperidol.35
The conclusion reached by most authors is that OTFC is a reliable means of inducing rapid, noninvasive preoperative sedation for pediatric outpatients undergoing short operations35,37 or in the emergency room.31 They further observe that OTFC use is associated with potentially significant reductions in respiratory rate and Spo2 and a high incidence of postoperative nausea and vomiting and pruritus.32 In the absence of controlled clinical trials in dental outpatients, it seems prudent, at this time, to withhold recommendation of this method of opioid administration for preoperative sedation in dentistry.
Several studies have reported on the use of the SL route for preoperative sedation. Two have compared the SL administration of a benzodiazepine with oral administration. Gram-Hansen and Schultz,21 administering 2.5 mg lorazepam either orally or sublingually before gynecologic surgery, found a maximal plasma concentration at 40 minutes orally and 60 minutes after SL administration. Garzone and Kroboth,22 looking at alprazolam and triazolam, found peak concentrations that occurred earlier and were higher following SL versus oral administration. SL lormetazepam (2.5 mg) followed in 35 minutes by intravenous (IV) diazepam (10 mg) was compared with SL placebo followed in 35 minutes by IV diazepam (10 mg) in patients undergoing surgical removal of impacted third molars.23 A rapid onset of sedation was noted after SL lormetazepam administration, whereas the course and duration of postoperative sedation, measured using standard psychometric tests, were similar following both treatments. Surgeons’ ratings indicated that SL lormetazepam was comparable with IV diazepam, but patients’ ratings indicated greater satisfaction with and preference for IV diazepam. Significant anterograde amnesia was found following both treatments. The authors indicate that SL lormetazepam may have a role in anesthesia as a premedicant and for minimal or moderate sedation.
SUMMARY (SUBLINGUAL SEDATION)
The SL route of drug administration possesses possible uses in dentistry in two distinct areas. First, for the management of preoperative fears and anxiety, the use of certain drugs, such as benzodiazepines, appears to provide a level of sedation comparable with that achieved with orally administered drugs. The onset of action also appears comparable with that of oral drugs. The second possible use for SL administration in dentistry is in management of postoperative pain. SL opioid administration appears to provide adequate pain relief with less sedation than IM opioids. The potential for opioid-induced respiratory depression is still present; therefore the usual postoperative monitoring practices must be continued when SL opioids are used. Patient cooperation is essential for SL delivery of drugs to be effective. Therefore the use of SL administration in younger children or any uncooperative patient is not recommended.
The administration of drugs through the skin (transdermally) has existed for a long time. In the past, the most commonly applied systems were topically applied creams and ointments for dermatologic disorders. The occurrence of systemic side effects with some of these formulations is indicative of absorption through the skin. In a broad sense, the term transdermal delivery system includes all topically administered drug formulations intended to deliver the active ingredient into the general circulation.38 Serious consideration for the transdermal delivery of drugs for systemic therapy began with a number of revolutionary ideas in the early 1970s.39 It is only since the 1980s, however, that modern transdermal therapeutic systems (TTS) have been successfully marketed.40 Drugs such as nitroglycerin (angina),41 scopolamine (antimotion sickness),42,43 clonidine (high blood pressure),44 estradiol (postmenopause),45 and nicotine (smoking cessation)46 are the current prominent representatives that have met expectations regarding therapeutic benefits based on TTS applications. The use of opioids via TTS for pain management has also met with considerable clinical success.47,48
A major advantage of TTS is the avoidance of the hepatic first-pass effect. Other advantages include simplified dosage regimens, enhanced compliance, reduced side effects, and improved disease therapy.49
The intact skin provides an efficient barrier against percutaneous absorption of drug/>