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Opioids: Other Routes for Use in Recovery Room Juan-Francisco Asenjo* and Krista M. Brecht# *Department of Anesthesia and Acute Pain Service and #Department of Nursing, The Montreal General Hospital, McGill University, Montreal, Canada Abstract: Opioids remain the main pharmacological tools for pain control in the postoperative patient. Recent concerns about chronic use of non-steroidal anti-inflammatory drugs have put extra pressure on health care workers to device and develop new medications and delivery methods to provide patients with appropriate pain relief after surgery. New technologies and better understanding of the pharmacology of the opioids administered by non-traditional ways will be reviewed in this manuscript. Understanding the anatomy of the nose cavity is important to use the inhaled way to deliver fentanyl, sufentanyl or butorphanol in surgical patients. High concentration and small volume are keys to good absorption and effect by nasal administration. Transdermal delivery of fentanyl has been used in chronic pain for some years. A new fentanyl self-administration method is in advanced trials for clinical use. It has a huge potential in giving good pain relief with lower side effects and more patient independence because of its reduced size and lack of tubing attached to it. Day surgery patients could be great candidates for this therapeutic alternative. Finally, oral transmucosal fentanyl is also in the market. Better suited to be used in controlling breakthrough pain in chronic settings, it has been so far marketed in the perioperative period. Side effects are a concern in its use for preoperative sedation in children. Large studies are now required for drugs approval and for new indications at regulatory agencies level. Good clinical judgment is more relevant now than ever before to avoid complications and new withdraw of old good medications inappropriately prescribed from the market place.

Key Words: Opioids, pain, post anesthesia care unit (PACU), nasal, transdermic, oral transmucosal, iontophoresis. INTRODUCTION In October 2002 the international community suddenly became aware of new “indications” and ways to deliver opioids to human beings. The Russian military used a special gas to incapacitate Chechen rebels that had taken a group of 800 hostages in a Moscow theater. Later analysis of blood samples from foreign tourist at their own countries showed a combination of fentanyl (or carfentanyl) and possibly halothane [1, 2]. In spite of the visit to several hospital in Moscow by military physicians in the hours prior to the army assault to the theater requesting to increase the supply of naloxone, 127 hostage (16%) and all the rebels perished in the action. A number of factors may explain the resulting casualties: individual variability in the uptake of the aerosolized opioids introduced through the ventilation system, the high therapeutic index of carfentanyl might have lulled Russian scientist in believing that the gas would not kill people inside the theater also. This assumption would have been a wrong and dangerous one since only animal studies have been done to test ED50 and ED95 with carfentanyl. Combining carfentanyl with halothane poses another hurdle to calculate the “appropriate” dose of both medications to subdue the rebels. Present standard of care [3] in Post Anesthesia Care Unit (PACU) calls for quick recovery from anesthesia/surgery, fast titration of pain therapy, control of side effects and discharge home or to the ward. Multimodal analgesia involving non-steroidal anti-inflammatory drugs (NSAIDs), opioids, *Address correspondence to this author at the Department of Anesthesia and Acute Pain Service, Montreal, Canada; E-mail: [email protected] 1389-4501/05 $50.00+.00

α−agonists, ketamine and local anesthetics are widely utilized to achieve a dynamic Visual Analog Score (VAS) < 3-4 in order to consider patients fit to move out of the PACU. Opioids are classically administered in PACU by intravenous, neuroaxial, subcutaneous and intramuscular routes. However, the complexity of the surgery or the patient’s condition, the new technologies ready available and the pressure on care givers for early discharge with efficient and less invasive pain control methods generates an interest for new ways to help patients to cope with good pain control after surgery. However, because opioids adverse effects when used in the perioperative period are accountable for at least 16% increase in hospital cost and prolonged the hospital stay by 0.5 days, an effort is required to refine our postoperative pain relief strategies incorporating new medications and techniques [4]. The aim of this review is to look into recent data pertaining “non-traditional” ways to administer opioids to patients in the PACU, the pharmacokinetic and pharmacodynamic data. Nasal and aerosolized, oral transmucosal, percutaneous transdermal route will be reviewed. Patient controlled analgesia (PCA) by some of these approaches will be described also. NASAL ADMINISTRATION OF OPIOIDS The primary functions of the nose are olfaction, transfer, humidification, heating and filtration of air in and out from the pharynx. The mucosal surface has an area of 150 cm2, with 5 -10 cm2 for olfactory functions and the balance for respiratory activity. The olfactory epithelium covers the cephalic part, with 15 ml of volume of the nasal cavity. It ap© 2005 Bentham Science Publishers Ltd.

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pears that there may be an intimate contact between the olfactory mucosa and the subarachnoidal space (Fig. 1). Bundles of olfactory sensory neurons from the olfactory epithelium pass though these holes surrounded by a prolongation of the subarachnoid space [5]. Studies in human autopsy material have demonstrated that the olfactory perineural space provides an efficient drainage route from the subarachnoid space to the nasal mucosa [6]. In man only a small fraction of an administered dose will reach this area by conventional methods used for nasal administration. Evidence from animal studies has shown that drugs may enter the cerebrospinal fluid via the olfactorial mucosa without the restrictions usually linked to the blood–brain barrier. Human nasal mucosa is capable of metabolizing xenobiotics in vitro [7]. Cytochrome P450 isoforms CYP2C and CYP3A in serous cells of glands of the human nasal mucosa have been demonstrated. Other CYPs such as CYP2A are also found in human nasal mucosa. It is not known whether these enzymes are inducible in nasal mucosa, although they are inducible in other tissues. In addition to the demonstration of oxidative phase 1 enzymes in human nasal mucosa, significant amounts/activity of phase 2 enzymes (with the exception of UDP-glucuronyl transferase) has been shown. Thus, human nasal mucosa contains drug metabolizing enzymes, which might (especially if induced) catalyze first-pass drug metabolism, however, the extent and clinical significance of such metabolism is unknown, and actual human nasal first-pass drug metabolism has not been investigated [8]. The venous drain of the nose is via the ophthalmic veins to the cavernous sinuses and by veins going to the external and internal jugular veins. Blood supply to the nose is under influence of the sympathetic nervous system and is provided by internal maxillary and ophthalmic arteries. DEVICES FOR ANALGESICS

NASAL

ADMINISTRATION

OF

For many years the market presented us with nasal spray dispensers to deliver local vasoconstrictors, steroids, calcitonin, sumatriptan and others. The maximum volume to avoid run-off into the pharynx by a single administration in

one nostril in man is 150 ul. Thus, the therapeutic dose should ideally be contained in 150ul or 2 x 150ul formulations, if both nostrils are used to administer the therapeutic dose in a single session. Striebel and O’Neil have published Patient Controlled Analgesia (PCA) Intranasal Administration Devices (PCINA) that deliver 0.5 and 0.18 ml respectively with lock out times of 6 or 15 vs. 4 min each. Regular nasal sprayers are produced by many companies. (GoMedical in Australia and others in Europe); they deliver 0.180 ml boluses to each nostril with less than 2% inter dose volume variation [9]. PHARMACOKINETICS OF NASAL ADMINISTRATION Stadol® (butorphanol) has been well studied and it has been available in the US market for a number of years [10]. Butorphanol shows a linear kinetic profile with accumulation of an apparently non-active metabolite. In healthy volunteers bioavailability for both, butorphanol and fentanyl is 71%, whereas sufentanyl is 78% (Table 1). Butorphanol does not require dose adjustment in elderly, but liver dysfunction increases bioavailability to 89%. Creatinine clearance lower than 30 ml/min doubles the elimination time so that dosing interval must be increased. No drug interaction at Cytochrome level was shown with cimetidine or metoclopramide [11, 12]. Bioavailability and pharmacokinetics of butorphanol suffer no change in individual with ongoing rhinitis, except for an increase in the Tmax when oximetazolin treatment preceded the opiate. NASAL OPIOIDS FOR PAIN CONTROL IN THE PACU Nasal administrations of fentanyl, meperidine and butorphanol have been studied in PACU patients. Studies have compared nasal vs. intravenous fentanyl for general surgery and discectomy. Pain relief and timing to obtain pain control was similar in both groups. The dose requirement was about 30% higher in the nasal administration patients. These findings make sense since the bioavailability of the nasal formulation is only 70% as mentioned above. Striebel [9, 11, 13] looked at the PCINA with fentanyl in orthopedic and

Fig. (1). Direct-to-brain delivery of intranasal drugs may be facilitated by incomplete blood-brain-barrier in the olfactory region.

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Table 1.

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Nasal Pharmacokinetics of Some Opioids [8]

Drug

Design

n

Dose/volume

Tmax (min)

Cmax (ng/ml)

Bioavailability (%)

Alfentanyl

R, CO, DB

10

0.54 mg/1.08 ml both nostrils

9 ± 2.1

20.1 ± 7.3

65 ± 26

Fentanyl

R, CO, DB

8

0.054 mg/1.08 ml both nostrils

5

0.29 ± 0.076

71

Butorphanol

R, CO

11

2 mg/0.2 ml both nostrils

49 ± 30

1.68 ± 0.36

71 ± 9

Buprenorphine

CO

9

0.3 mg/0.150 ml

30.6 ± 6.6

1.77 ± 0.45

48.2 ± 8.3

R: randomized, CO: cross-over, DB: double blind

general surgery with nasal boluses of 25 ug. and lock out of 6 min vs. standard ward treatment. His study showed better patient’s satisfaction with nasal fentanyl. Results are consistent with equivalent analgesia and a 30% extra dose of fentanyl in the PCINA. Meperidine has been compared between PCINA and subcutaneous administration for the first 8 hours post orthopedic surgery (Table 2). Pain relief was significantly better in the PCINA group, but dose requirements were similar [14, 15]. Butorphanol IV versus nasal route was compared prospectively by Abboud in post cesarean pain control [16]. The IV formulation produced a faster onset (5 vs. 15 min); however nasal administration gave longer relief. In the post episiotomy pain model butorphanol was compared with placebo at different doses. Only 2 mg displayed consistently better pain control than placebo. In Day Surgery patients Stadol was used with 0.5 mg per dose at a minimum 1 hour interval and follow up for three days. Eighty percent of patients reported good pain relief the first day and 90% the next 2 days with doses below 3 mg/day. Side effects were considered mild and 90% of patients would request the same medication in future surgeries [17]. COMMENTS ON NASAL OPIOIDS ADMINISTRATION When reviewing studies on nasal administration of opioids it is important to bear in mind that maximum volume to be administered should not exceed 150 ul. Because of that limitation, some drugs have to be more concentrated than the IV preparations in order to reach the effective dose with 150 ul. or 2 x 150 ul. For instance, to deliver 60 ug of fentanyl (with 70% bioavailability) the drug would need to be formulated in a 400 ug/ml concentration. In summary, nasal administration results in onset times between 10 and 25 min and peak effect at 60 min for most Table 2.

patients and all drugs studied in these trials. Nasal administration compares favorably with IV PCA and regular ondemand opioid regimen in the postoperative period. The clinical experience is greater with fentanyl and butorphanol in good quality studies. Both medications are very well tolerated and side effects depend on the drug itself rather than the way of administration with only 8 – 14% mild nasal irritation in patients using it for less than 3 days. There seems to be huge potential for PCINA in ambulatory settings. PERCUTANEOUS (PCTF)

TRANSDERMAL

FENTANYL

PCTF has been in use for chronic pain for the last 10 years. This is not a primary therapy for post operative pain relief because of the pharmacokinetic/dynamic considerations highlighted below. However in patients having surgery and already using this modality as a result of chronic pain conditions it may become a valuable alternative. In PACU these patients usually require IV bolusing or other modalities until reaching a level of comfort. Fentanyl’s low molecular weight, high potency and lipid solubility make it suitable for delivery by the percutaneous transdermal therapeutic system (the “patches”, see Fig. 2). These patches are designed to deliver fentanyl at a constant rate (25, 50, 75 and 100 µg/h), and require replacement every 3 days [18]. As a consequence of the formation of a fentanyl depot in the skin tissue, serum fentanyl concentrations gradually increase following initial application, generally plateauing between 12 and 24 hours. Thereafter, they remain relatively constant, with minimal fluctuation, for the remainder of the 72-hour period. Mean maximum plasma concentration (Cmax) values are 0.6, 1.4, 1.7 and 2.5 µg/L at delivery rates of 25, 50, 75 and 100 µg/h, respectively. Once achieved, steady-state plasma fentanyl concentrations can be maintained for as long as the patches are renewed. Peng and

Intravenous vs. Nasal Opioids in Postoperative Pain Relief [8]

Drug

Design

Dose (mg)

Onset (min) Nasal

IV

Tmax (min) Nasal

IV

Fentanyl n=112

R, DB

0.027 Q5 min until satisfactory effect

16 ± 12.6

10.8 ± 9.0

26.3 ± 15

20.2 ± 12.0

Fentanyl n=48

R, DB

0.025 nasal 0.0175 IV Q6 PCA/PCINA

21 ± 11

22 ± 16

106 ± 67

107 ± 47

Demerol n=60

R, DB

27 Q5 min until satisfactory effect

12 ± 5.9

9.7 ± 3.6

32.6 ± 9.4

23.8 ± 9.5

R: randomized, DB: double blind, IV: intravenous

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Fig. (2). Transdermal fentanyl patch.

Sandler [19] have suggested a “minimum fentanyl analgesic concentration” in post operative pain relief around 1.5 ng/ml, with a wide range between 0.2 and 8 ng/ml. The observed variability in the analgesic CP reported for fentanyl in large part is caused by differences in study design and in individual pharmacodynamic responses. Analgesic requirements of individual patients and different surgical populations vary over a six-fold range for fentanyl and other opioids. Higher plasma levels correlates with lower VAS at rest but they increase with VAS on movement. Neither local blood flow nor anatomical site of application seems to affect fentanyl delivery. Nonetheless, a rise in body temperature at or above 40°C may increase the absorption rate by about 30%. Pharmacokinetics of transdermal fentanyl show inter individual variability and an average bioavailability of 92% has been estimated in surgical patients. Fentanyl is mainly metabolized by Cytochrome P450 (CYP) 3A4. The major metabolite is norfentanyl and minor metabolites include despropionylfentanyl, and other hydroxy metabolites none of which show clinically relevant pharmacological activity. Elimination of fentanyl after patch removal is slow and elimination half-life values of 13 to 22 hours have been reported. The slow elimination is likely to be due to the slow release of the drug from the skin depot [18]. ADVERSE EFFECTS WITH FENTANYL PATCHES They are similar to opioids administered by any other route and the more frequent are nausea, vomiting and constipation. Randomized trials suggest that constipation occurs less frequently in patients receiving transdermal fentanyl than in those given sustained-release oral morphine. More uncommon are myoclonus, blurred vision, hallucinations, respiratory depression (with concentrations over 1 ng/ml), skin rush and seizures. Like any other opioid, withdrawal symptoms may occur after discontinuation of transdermal fentanyl. Consideration should be given to the slow decrease in plasma levels when stopping and removing the patch in case of overdose and respiratory depression.

IMPORTANCE OF CONTINUATION OF CHRONIC PAIN THERAPY WITH FENTANYL PATCHES IN THE EARLY PACU PERIOD Transdermal fentanyl is indicated in patients with acute postoperative pain when they have been on the patch before surgery. These patients have a high degree of tolerance (with hyperalgesia sometimes also present) to opioids and usually require higher doses than a regular opioid naïve postoperative patient [20]. So the clinical experience indicates that a significant increase in the preoperative dose will be seen in the first 24-48 hours following surgery. In particular this phenomenon can be observed when mayor procedures are performed and no continuous regional blockades with local anesthetics are added to the pain control regimen. In this situation the patch will serve the purpose of contributing to pain relief but also to blunt the potential for a withdraw reaction. IONTOPHORESIS SYSTEM Passive transdermal fentanyl is an effective method of providing stable long-term opioid analgesia [21]. However, slow onset time, inability to change quickly the amount of delivered drug, and prolonged drug elimination make this delivery system unsatisfactory for some patients. Iontophoresis is a method of transdermal administration of ionizable drugs in which the electrically charged components are propelled through the skin by an external electric field. In iontophoresis, sweat gland ducts and hair follicles provide the preexisting aqueous pathways that potentially allow the passage of water-soluble molecules upon the application of low voltages across the skin. However, the permeation flux provided by iontophoresis is often much smaller than what is desirable. For transdermal delivery, the interest lies primarily in electroporating human skin, and this has been done using high voltage pulses. Electroporation within the stratum corneum results in new aqueous pathways and a driving force for ionic and molecular transport across the skin. Scientists have shown that pulses of high voltage create aqueous pathways penetrating the multi-lamellar lipid bilayer membranes

Opioids

of the stratum corneum. In this process, adjacent corneocytes become connected, and pathways spanning the stratum corneum result. Studies have shown that pulses lasting as short a time as 1 ms causes up to four orders of magnitude increase in the transdermal transport of charged molecules up to 1, 000 grams/mol (most pharmaceutical compounds fall within this range of sizes). The E-TRANS® system uses low-level electrical energy to transport drugs like fentanyl and other compounds that previously could not be delivered by passive transdermal systems. Additionally, this system can control precisely the amount of drug delivered, as well as provide pulsatile or patient-controlled delivery. Complex delivery patterns, including ascending, descending, or variable, can be emulated using these systems. The fentanyl hydrochloride transcutaneous iontophoretic PCA system (FTIPCA) is manufactured to function within preset dosing specifications. It operates for 24 hours after the first dose is delivered or delivers a maximum of 80 doses and shuts off. The dose, controlled by the amount of electrical current, is fixed to not exceed 40 µg, the dosing interval is 10 minutes, and each dose is a 10-minute infusion. Drug delivery begins when the electrical current is activated by pressing the dosing button twice within 3 seconds. It can deliver up to 6 doses per hour. The 40 ug dose has been chosen after studies that tried 20, 25, 40 and 60 ug. 20 and 25 ug were insufficient and 40 was as good as 60 ug but with less side effects. During delivery of the dose, the FTIPCA cannot deliver additional doses, and delivery of the dose cannot be interrupted or extended. The system provides an audible (beep) and visual indication (red light from a light-emitting diode) that a dose has begun (Fig. 3). The light turns off momentarily when the dose has been completed and then flashes to indicate the

Fig. (3). E-Trans system for FTICA.

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approximate number of doses delivered. One flash represents delivery of 1 to 5 doses, 2 flashes represent delivery of 6 to 10 doses, and so on. Because the maximum number of doses allowed by the system is 80, the corresponding maximum number of flashes is 16. Alerts for nonfunctioning conditions are a short series of beeps (the FTIPCA should be restarted) and continuous beeping (the system has shut down and should be removed). Thus, the audible and visual signals provide information on dosing similar to that of standard IV PCA. In 2004 Viscusi [22] published results of a prospective randomized trial comparing FTIPCA against standard IV PCA with morphine in post operative settings. They enrolled 636 patients that were allocated to both groups after surgery. Main outcome was patient global assessment of the method of pain control. Good or excellent ratings in the first 24 hours were around 75% for patients in each group and it increased to 80% in days 2 and 3. Early patient discontinuation remained at 25% in both groups and last VAS score was similar at 30 points. The large inter patient (up to 5-fold) variability in plasma levels required to achieve pain control in post op period make this approach very attractive. Chelly also reported interesting results with FTIPCA in post operative usage in abdominal, thoracic and orthopedic cases [23]. COMMENTS OF SYSTEMS IN PACU

TRANSDERMAL

DELIVERY

Utilization of this route seems promising. Possibly the combination of a constant delivery patch with a FTIPCA might become a very useful tool in the next few years, but trials will be needed to compare it with present ”standard”

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alternatives. Other potent and lipophilic drugs perhaps could have a place in this approach. To prove enhanced outcome could be more difficult, but in terms of comfort and convenience for the patients this route is very interesting. In the ever-expanding ambulatory surgical setting the FTIPCA with or without the baseline provided by the constant delivery patch might quickly find a large niche for development. Some questions need to be answered regarding suitability of the iontophoretic system in patients with skin diseases, chronic use of opioids or at high risk for nausea and vomiting. ORAL TRANSMUCOSAL OPIOIDS ADMINISTRATION (OTMF) OTMF has been used mainly as premedication and procedure sedative/analgesic in children [24] and more recently as a breakthrough medication in cancer patients. Ten ug/kg OTMF in children produces good sedation with minimal respiratory side effects [25]. PHARMACOKINETIC AND PHARMACODYNAMIC STUDIES Fenatnyl is highly liposoluble and has a relatively low molecular weight that allows them to readily cross mucosa membranes. Single dose pharmacokinetics of OTMF in adults showed that doses between 800 and 1600 ug are required to achieve plasma levels within the range of 1 – 2 ng/ml necessary to produce analgesia [26]. A dose of 1600 ug produced peak levels near 2.5 ng/ml with a decay to 1 ng/ml at about 5 hours. Nausea and pruritus presented in almost every volunteer receiving 1600 ug, but headaches and vertigo were also prominent. Intense respiratory depression requiring supplemental Oxygen occurs in almost all individuals with 800 and 1600 ug. A two-compartment population pharmacokinetic model represented the data from subjects in other study by the same group [27] using 800 ug OTMF repeated three times at 6 hours intervals. These models demonstrated rapid and substantial absorption of OTMF that did not changed with time and multiple doses. No accumulative effect was observed therefore the authors suggested that OTMF could safely used in multiple doses as an alternative to more invasive routes in the treatment of acute pain. Kharasch et al. [28] demonstrated no effect of aging (age average 26 vs. 67 years) on the pharmacokinetic parameters of 10 ug/kg of OTMF and its metabolite norfentanyl. They also found very limited differences in pharmacodynamic parameters like sedation, energy level, confusion and nausea, except for pupil diameter that changed less in the elderly group. Peak plasma fentanyl concentrations, time to peak, and maximum pupil diameter change from baseline were unchanged after rifampin, troleandomycin, and grapefruit juice used to manipulate the hepatic and intestinal Cytochrome P450 (CYP3A). Nonetheless, Fentanyl metabolism, elimination, and duration of effects were significantly affected [29]. When treating breakthrough pain, with careful attention to maximal mucosal absorption and minimal swallowing, CYP3A variability and drug interactions are unlikely to affect the onset or magnitude of OTF analgesia; however, duration may be affected. Bioavailability seems to change from

Asenjo and Brecht

33% in children 2-10 years old to around 60% in adults. This spread could be related to a better understanding and compliance among the adults of the importance of keeping the drug in the mouth avoiding swallowing it [24-26]. In fact bioavailability of single dose of oral fentanyl in adults is about the same as in children 2- 10 years old. CLINICAL USE IN POSTOPERATIVE PAIN OTMF was studied for post operative pain relief by Lichtor et al. [30] They compared in an elegant randomized, prospective and double blind fashion 200 and 800 ug of OTMF vs. 2 and 10 mg of IV morphine in day 1 after lower abdominal surgery and morphine PCA. Results showed insufficient pain relief with 200 ug OTMF and 2 mg IV morphine, but 10 mg IV morphine and 800 ug OTMF depicted equivalent and effective analgesic action (in 64 and 74% of patients (respectively) for about 3 hours. Very small incidence of side effects was registered in this study, which correlates well with the fact that patients in variable levels of pain tolerate much better opioids. Lind [31] reported using OTMF in acute pain patients in the Emergency Room as well as post operatively. Patients received 14 ug/kg of OTMF over 12 min. reaching satisfactory pain relief with low profile of side effects. Onset of action for OTMF is similar to morphine around 10 min. Some reduce experience has been reported with OTM Sufentanyl in cancer patients. It was considered fast, effective and void of side effects when the concentrated (50 ug/ml) IV solution was used [32]. OTMF is effective and safe in children having dressing changes in burn units, both to control anxiety before the procedure as well as to help with pain during the wound care [33]. In these studies OTMF compared slightly better than hydromorphine and morphine [34]. Malviya [35] studied the effect of the anesthesia technique on the side effects of the Oralet® 5-10 ug/kg premedication in peds average 9 years old. They showed an increase in post operative pruritus and vomiting in the groups with OTMF premedication and a statistically significant, but clinically mild improvement in preoperative behavior. COMMENTS ON OTMF Oralet displays a 50% bioavailability and an onset around 10 min. OTMF exist in 200, 400, 600, 800, 1200 and 1600 ug lollipops. Probably a good niche for this medication is in pain control after surgery or in cancer/chronic patients that are already in Fentanyl patches. Also, for those patients with an expected short period of pain after surgical procedures. It seems to be suitable for breakthrough pain. The high incidence of side effects is a source of concern. REFERENCES [1] [2] [3]

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