P&T News: January 1994, Volume 14, Number 7

Management of Postoperative Nausea and Vomiting: The Role of Droperidol, Metoclopramide, and Ondansetron

Douglas Morgan, R.Ph., M.S.
Peer Review Status: Internally Peer Reviewed by David J. Murray, M.D., Professor, Department of Anesthesia

Antiemetics may be administered preoperatively or intraoperatively to prevent PONV or given postoperatively to treat established PONV. The latter approach (i.e., the "rescue" strategy) is a satisfactory approach for patients undergoing surgical procedures with a low frequency of PONV, and for situations where PONV is generally mild or often self-limiting. In patients undergoing highly emetogenic surgical procedures, it is not uncommon for both prophylactic and rescue antiemetics to be used in the same patient during the perioperative period.

All perioperative antiemetics appear to have similar efficacy in both the prophylaxis and treatment of PONV, and carry acceptable side effect profiles. Antiemetic drugs available to treat or prevent PONV include: phenothiazines (chlorpromazine, prochlorperazine, and promethazine); antihistamines (hydroxyzine and diphenhydramine); anticholinergics (atropine, glycopyrrolate, and scopolamine); benzamides (metoclopramide, trimethobenzamide, and domperidone); butyrophenones (droperidol and haloperidol); and serotinin (5HT3) antagonists (ondansetron and granisetron).1 Droperidol, metoclopramide, and prochlorperazine are the best studied, while ondansetron has received considerable recent attention. However, ondansetron is an expensive therapy for PONV that should be reserved for settings where alternative antiemetics have failed or have caused unacceptable toxicity.

This review examines the efficacy of droperidol, metoclopramide, and ondansetron in the prevention and treatment of PONV in the perioperative period. The role of prophylactic versus rescue antiemetic strategies is briefly explored. Appropriate antiemetic selection strategies are outlined, and rational guidelines for the use of ondansetron, a new but expensive therapy for PONV, are provided (Table 1). Perioperative doses of these antiemetics and their acquisition costs are outlined in Table 2.

• In surgical settings at high risk for emesis, a prophylactic perioperative antiemetic is useful. Droperidol and metoclopramide are effective. A number of other antiemetics are also available. Depending upon the surgical setting, prophylactic droperidol can be given in doses of 0.625 to 2.5 mg IV in adults, and 10 to 75 mcg/kg IV in children. Metoclopramide doses of 20 mg IV in adults or 0.25 mg/kg IV in children may be more effective than the lower "traditional" doses of 5 to 10 mg in adults, and 0.1 to 0.15 mg/kg in children.

   

• Rescue antiemetic therapy of established PONV following surgery is an appropriate strategy for low risk surgeries where the frequency of PONV is expected to be low, or the severity is generally mild. Rescue antiemetics may also be required if prophylactic periopeative antiemetics fail to prevent PONV in high-risk settings. Failure of prophylactic therapy will often be obvious within the first two hours postoperatively. Metoclopramide, droperidol, prochlorperazine, and promethazine are commonly chosen rescue antiemetics.

   

• Prophylactic ondansetron should be reserved for use in two settings:[a]

1. Administration to patients with a past history of significant PONV who failed to respond to alternative intraoperative or rescue antiemetics, or who experienced unacceptable side effects from previous antiemetics;
2. Administration in high-risk patients for whom vomiting/retching would be detrimental, and for whom alternative intraoperative antiemetics have caused or would pose unacceptable side effects.

• Rescue ondansetron for established PONV is appropriate when:[a]

1. Prophylactic antiemetics (e.g., intraoperative metoclopramide or droperidol) have failed to prevent PONV. Ondansetron should be considered a first-line rescue therapy only when patient history reveals failure of alternative rescue (postoperative) antiemetics during prior surgical procedures. In high risk surgeries, a reasonable prophylactic dose of droperidol or metoclopramide can be followed 30 minutes postoperatively by the alternative antiemetic as a rescue antiemetic. If PONV continues after both the prophylactic and rescue antiemetic, then ondansetron may be considered as early as 60 minutes postoperatively.
2. Alternative rescue (i.e., postoperative) antiemetics have failed to adequately treat PONV, or when alternative antiemetics have caused or may cause unacceptable side effects. In most cases, the selection of a second rescue antiemetic can be made before ondansetron is considered. This insures a high chance for success, and eliminates unnecessary use of the extremely expensive ondansetron.

_________
[a] These guidelines reflect criteria reviewed and approved by the Drug Use Evaluation and Pharmacy and Therapeutics Subcommittee.

Preoperative or intraoperative medications also influence PONV. Opiates increase the risk of PONV. Anesthetic techniques using primarily opiates (fentanyl, sufentanil, or alfentanil) may increase the incidence of PONV two-to-five fold versus standard inhalation techniques.2 Short-acting barbiturates, etomidate, ketamine, and reversal of neuromuscular blockade may increase emetic risks, while midazolam and propofol have little influence or may decrease the risk of PONV.2 Recent studies suggest little difference in emetogenic risk among the inhalation anesthetics (isoflurane, enflurane, and halothane).1,2 Nitrous oxide does not appear to significantly influence the risk of PONV.1

TABLE 2. Perioperative Antiemetics
Antiemetic	Prophylactic Dose[a]	Rescue Dose[a]	Duration of Effective Dose
Droperidol Inj.	0.625 to 2.5 mg IV	0.625 to 1.25 mg IV	12 to 24 hrs (may repeat smaller doses every 15 to 30 min to total of 2.5 mg IV)
Metoclopramide Inj.	10 to 20 mg IV (0.1 to 0.25 mg/kg IV)	10 to 20 mg IV (0.1 to 0.25 mg/kg IV)	2 to 4 hrs (administer prophylactic dose near end of procedure)
Prochlorperazine Inj.	2.5 to 10 mg IV	2.5 to 10 mg IV/IM	4 to 6 hrs
Promethazine Inj.	12.5 to 50 mg IV (0.25 to 0.5 mg/kg IV)	12.5 to 50 mg IV (0.25 to 0.5 mg/kg IV)	4 to 6 hrs
Ondansetron Inj.	4 mg IV (0.06 to 0.15 mg/kg IV)d	1 to 4 mg IV (0.06 to 0.15 mg/kg IV)d	12 to 24 hrs (questionable benefit beyond 8 mg/24 hrs)
[a] Adult doses specified, pediatric doses noted in parentheses [c] Droperidol doses as high as 75 mcg/kg IV have been used in ambulatory pediatric strabismus surgery [d] Little experience available in pediatric PONV settings; dosing is derived from adult extrapolation and abstracted clinical experience

Droperidol
Droperidol, a butyrophenone with dopamine receptor blocking activity, is perhaps the most widely studied perioperative antiemetic, with proven efficacy as a prophylactic and a rescue antiemetic in PONV settings.1 In addition to its central antiemetic action, droperidol exhibits an intrinsic analgesic effect in the operative setting.1 Doses as low as 10 to 20 mcg/kg IV show efficacy in a variety of surgical settings, including laparoscopy, 1,11 while doses of 75 mcg/kg IV are often required for strabismus surgery. 12, 13 Droperidol 75 mcg/kg IV immediately after induction reduced the frequency of postoperative vomiting in patients undergoing strabismus surgery from 68% in controls to 16%.13 Droperidol has a relatively short half-life (2.5 to 3.5 hours), but has a prolonged duration of antiemetic effect. In many cases, a single 1.25 mg IV dose in adults appears to provide good control of PONV for 24 hours,14 permitting a straightforward single-dose strategy effective in preoperative or intraoperative prophylaxis strategies.

Droperidol is sometimes discouraged in ambulatory surgery on the basis of its sedative effects,1 and the possibility of akathisia (delayed-onset restlessness and anxiety).15, 16 However, a variety of studies strongly supports that droperidol is a highly effective antiemetic that shortens the time to discharge from the post-anesthetic recovery unit.17-20 Moderate doses of droperidol (e.g., 1.25 mg IV in adults, 5 to 20 mcg/kg IV in children) lead to mild, short-lived postoperative sedation,1 while large doses (e.g., 50 to 75 mcg/kg) cause relatively predictable sedation for periods that my not compromise the time to discharge when compared to placebo controls.21 The use of preoperative or intraoperative atropine may help to minimize the development of extrapyramidal side effects.1

Metoclopramide
Metoclopramide, a substituted benzamide derivative, is a dopamine receptor antagonist with intrinsic central antiemetic effects. It also demonstrates cholinomimetic activities which include enhanced gastric emptying and an increase in lower esophageal sphincter tone.1 Metoclopramide has shown exceptional antiemetic efficacy in the chemotherapy setting, where doses are escalated to as high as 3 mg/kg IV.22 Its antiemetic efficacy in the perioperative setting remains less proven, with conflicting findings of efficacyt.1-3 In the perioperative setting, doses of 10 to 20 mg IV has been used in adults, while in the pediatric patient, doses of 0.1 to 0.15 mg/kg IV are typical, although doses as high as 0.25 mg/kg IV has been employed.21 Prophylactic metoclopramide has been shown to reduce the frequency of PONV in a variety of settings and has been shown to shorten the time to discharge with little sedation at the doses typically employed.1

Late intraoperative use or immediate postoperative use of IV metoclopramide may be more appropriate than preoperative IV metoclopramide in the prophylaxis of PONV.1,24-29 The short duration of antiemetic effect of a typical 10 mg IV dose may explain this observation.1 Theoretically, larger doses of metoclopramide may offer greater effect, through a more prolonged duration of effect1 or through a dose-dependent serotinin receptor action previously noted in oncology settings.23 Lin et al found that metoclopramide 0.25 mg/kg IV administered immediately prior to induction reduced the frequency of postoperative vomiting from 88% in controls to 29% in 110 children undergoing strabismus surgery.21 Therefore, it is possible that 20 mg IV doses (0.25 to 0.3 mg/kg) in adults would show less variability in efficacy than the usually prescribed 10 mg IV dose.

Metoclopramide has been demonstrated to be effective in reducing nausea and vomiting associated with narcotic analgesics,1,3 and this action may provide more favorable antiemetic activity in postoperative settings where large doses of intraoperative or postoperative narcotics have been employed.1 It has also been shown that metoclopramide's action on smooth muscle of the gut can be reduced or abolished by atropine.30 If the antiemetic efficacy of metoclopramide is related to sensitizing muscarinic receptors on gastrointestinal smooth muscle, then the concurrent use of atropine or glycopyrrolate may reduce the effectiveness of metoclopramide.

At the doses employed in the perioperative setting (0.1 to 0.3 mg/kg IV), metoclopramide is rarely associated with significant sedation or extrapyramidal side effects. 1,21 The akathisia frequently seen with large metoclopramide doses (e.g., 2 mg/kg IV) in the oncology setting is rarely reported in the perioperative setting.1,3 If acute dystonic reactions occur, they usually respond promptly to administration of diphenhydramine 25 to 50 mg IV (0.5 to 1 mg/kg IV in children).

Ondansetron
Ondansetron is structurally related to serotinin and antagonizes the 5-hydroxytryptamine subtype 3 (5-HT3) receptor with no direct effect on dopamine, histamine, cholinergic, or adrenergic receptors. The precise mechanism of action is unclear, but the drug appears to inhibit emesis through receptors in the periphery and in the central nervous system, with primary effects in the gastrointestinal tract.31-33 Ondansetron may posses gastric prokinetic activity, 34 but it appears to have no effect on motion-sickenss.35 This "serotinin antagonist," introduced on the U.S. market in 1991 for management of chemotherapy related nausea and vomiting was approved for prophylaxis of PONV in August, 1993.

Randomized, blinded trials demonstrate that prophylactic ondansetron is superior to placebo controls in reducing the frequency and severity of PONV in high risk outpatient surgical procedures.36-39 One large clinical trial in ambulatory gynecologic surgery patients demonstrated that single ondansetron doses of 1 mg, 4 mg, or 8 mg IV offered comparable efficacy in PONV, and that all doses were superior to placebo controls.37 Ondansetron 1 mg IV reduced the frequency of postoperative vomiting from 54% in placebo controls to 38%, while single IV doses of 4 mg or 8 mg reduced the frequency to 24% and 23%, respectively. Even in patients with prior PONV (a more difficult group to manage), a single 8 mg dose offered no benefit over a 4 mg dose, strongly suggesting that a single 4 mg IV dose of ondansetron is the prophylactic dose of choice in PONV.

Several studies have shown ondansetron to be efficacious when 8 mg IV was administered immediately before induction of anesthesia and again 8 hours later. 36, 40, 41 However, the magnitude of effect against PONV was not different than the effects achieved with a single 4 to 8 mg dose reported in larger studies, 37,39,42 suggesting that the benefits of the repeat dose may be insignificant.

Adverse reactions attributed to ondansetron in the PONV setting have been similar in type and frequency to those associated with placebo controls. Adverse events reported in 5% or more of ondansetron recipients include: headache, dizziness, musculoskeletal pain, drowsiness/sedation, shivers, and malaise/fatigue.43 However, seizures and extrapyramidal-like reactions have recently been reported.44,45 In addition the FDA has received 24 reports of anaphylactoid reactions, including life-threatening symptoms.46

Prophylactic Antiemetics
Prophylactic antiemetics can reduce, but do not completely eliminate, PONV in "high risk" emetogenic circumstances. As early as 1960, Keats discouraged routine antiemetic prophylaxis in anesthesia.8 Adriana et al noted that only 3.5% of patients in their series had persistent vomiting that required treatment, and that a large fraction of PONV occurred at emergence from anesthesia and did not recur. Prophylactic antiemetics were regarded as unjustified.9 In many surgical procedures, PONV is a transient, self-limiting event carrying little morbidity. Of the 30% who develop PONV, many have transient nausea or only one to two episodes of emesis and do not require antiemetics.3,8 A smaller fraction will benefit from "rescue" antiemetics when nausea is severe or prolonged, or when more frequent vomiting or retching develop. Although the morbidity associated with nausea is probably very low, patient discomfort is an important factor, and should not be ignored or considered unavoidable.10 Conversely, antiemetic side effects and unnecessary expenses can be avoided if prophylactic antiemetics are used judiciously in the perioperative setting.

Antiemetic prophylaxis may be appropriate, however, in subgroups of patients at greater risk of PONV. A reasonable focus for routine perioperative antiemetic prophylaxis would include: 1) patients with a history of severe motion sickness or prior PONV; 2) gynecologic procedures (e.g., laparoscopy); and 3) children undergoing strabismus surgery, otoplasty, tonsilloadenoidectomy, and orchiopexy.1 Prophylactic antiemetics might be useful in preventing complications in intraocular, ear, plastic surgery, or neurosurgical procedures where increases in venous pressure associated with vomiting could lead to hematoma, or in preventing aspiration of emesis in patients with wired-jaw surgical procedures.

Effective doses of perioperative antiemetics are important in assuring success in the prevention of PONV or in ameliorating the severity of PONV once it is established. When effective intraoperative prophylactic doses of droperidol, 12,13,21 metoclopramide,21 or ondansetron 37-39 are given, the frequency of postoperative vomiting from highly emetic surgeries (typically 50 to 90%) is reduced by a factor of two-to-four fold. However, there are few direct comparative studies of perioperative antiemetics, and it is extremely difficult to compare results of antiemetic trials.

Comparative trials of droperidol with metoclopramide have usually shown consistent efficacy for droperidol, and variable efficacy for metoclopramide. 7,11,16,17,21,47 48 Alon and Himmelseher compared the prophylactic efficacy of ondansetron =(8 mg IV), droperidol (1.25 mg IV), and metoclopramide (10 mg IV) in a randomized, double-blind trial in 66 patients undergoing dilatation and curettage under general anesthesia.52 For the three-hour observation period, the frequency of vomiting was significantly less for ondansetron than for droperidol or metoclopramide (13%, 45%, and 54%, respectively). However, the "total effective antiemetic response," defined by the authors as no vomiting and no request for an antiemetic, was similar among the three groups (59%, 54%, and 36%, respectively).

Comparative trials of ondansetron (published in abstract form) provide mixed results regarding comparative prophylactic efficacy. 18,50-55 Roberson and Walker found ondansetron 8 mg IV equivalent to metoclopramide 10 mg IV in preventing PONV in 123 gynecologic laparoscopy patients.50 Lawhorn et al found prophylactic ondansetron 0.15 mg/kg IV to be as effective as droperidol 20 mcg/kg IV, when added to a routine regimen including oral preoperative midazolam and metoclopramide (0.15 mg/kg), in 120 children undergoing strabismus surgery or tonsillectomy.51,52 Furst et al demonstrated that ondansetron 0.15 mg/kg IV was superior to metoclopramide 0.5 mg/kg. droperidol 75 mcg/kg IV, or placebo given immediately after induction in 206 children undergoing outpatient tonsillectomy.53 Emesis following discharge (typically 6 to 7 hours following surgery) was infrequent and did not differ among antiemetic groups. Conroy et al found prophylactic droperidol 75 mg/kg IV to offer better acute and prolonged control of PONV than ondansetron 0.15 mg/kg IV, in a placebo-controlled study of 44 children undergoing strabismus surgery.18

Effective prophylactic antiemetic doses will not only reduce the frequency of PONV, but also its severity.1 Current literature suggests droperidol as a reasonable first choice for prophylaxis.1 Nonetheless, in high-risk settings, even appropriate doses of effective single antiemetics do not eliminate the need for rescue antiemetics.37,47,54 In many instances the antiemetic chosen for prophylaxis can be administered as a repeat dose intended for rescue purposes, particularly if the initial dose was not aggressive, or if the duration of time postoperatively has exceeded the typical duration of effect of the initial antiemetic. If the prophylactic doses used were generally consistent with maximum doses shown effective for PONV, or if the patient experiences significant adverse reactions to the prophylactic agent used, then use of an alternative antiemetic is a very logical strategy. While the role of combination prophylactic antiemetic regimens has proven highly successful in the oncology setting,56 this approach remains speculative in the perioperative setting. 7,17,57,58

Rescue Antiemetics
It is considered reasonable to employ rescue perioperative antiemetics as needed and to avoid routine prophylactic antiemetics except in very high risk situations.1,3 This strategy spares the patient the side effects and cost of unneeded antiemetic therapy, and still provides reasonable control of emesis.1 Studies 5,42,59 which have evaluated the effectiveness of rescue antiemetics in a systematic fashion are summarized in Table 3.

The lack of well-designed trials evaluating perioperative antiemetics for the rescue of established PONV is of concern. However, the widely accumulated clinical experience of rescue antiemetics in PONV supports this antiemetic strategy.1 Prochlorperazine, promethazine, metoclopramide, droperidol, and ondansetron have all demonstrated benefit as perioperative rescue antiemetics.1-3,4,42 In almost all cases, the rescue does is the same as the prophylactic dose. Dosing information is found on Table 2.

Early use of a rescue antiemetic substantially modifies the course of established, early-onset postoperative nausea and vomiting.5 The benefits of a rescue antiemetic administered intravenously are apparent within 30 minutes.5,14 Lack of response is an indicator to repeat the dose (particularly if a low dose was given and no side effects are present)54 or to consider an alternative antiemetic.42 An effective rescue antiemetic will eliminate the need for a subsequent alternative rescue antiemetic. It is clear that no single perioperative antiemetic can eliminate nausea and vomiting in all patients, and that in some cases, more than one rescue antiemetic may be required to achieve good control of established PONV. 5,42,59

TABLE 3. Rescue Antiemetic Therapy
Reference	Drug Dosage, and No. of Patients	Results
Scuderi et al[5]	Ondasetron 1 mg IV (n=130) Ondasetron 4 mg IV (n=119) Ondasetron 8 mg IV (n=122) Placebo (n=139)	Complete Response at 24 hours post dose:[a] Ondansetron 1 mg IV 41% Ondansetron 4 mg IV 49% Ondansetron 8 mg IV 47% Placebo 15%
Bodner and White[42]	Initial Rescue: Ondansetron 8 mg IV (n=35) Placebo (n=36)	Developed subsequent emetic episode: Ondansetron 8 mg IV 51% Placebo 92% Subsequent Rescue: Metoclopramide 20 mg IV plus hydroxyzine 25 mg IV used in 86% of placebo recipients and 43% of ondansetron recipients
Berghuis et al[59]	Ondansetron 0.16 mg/kg (n=57) Droperidol 20 mcg/kg (n=58) Ephedrine 0.1 mg/kg (n=49)	Droperidol = ondansetron greater than ephedrine in reducing severity of PONV
[a] No emesis and no subsequent rescue antiemetic

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2. Eur J Anaesthesiol 1992;9:25-31.
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18. Anesthesiology 1993;79:A10. Abstract.
19. Acta Anaesthesiol Scand 1982;26:48-52.
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29. Br J Clin Pract 1967;21:460-2.
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Drugs Added to Stock

MELPHALAL Injection: 50 mg Melphalan (Alkeran® - Burroughs Wellcome) injection is indicated for the palliative therapy of multiple myeloma.

PANCREATIN Capsules, enteric-coated microspheres: lipase 10,000 U.S.P. units, amylase 33,200 U.S.P. units, and protease 37,500 U.S.P. units Pancreatin enteric-coated microsphere capsules (Creon-10® - Solvay) are indicated for the management of pancreatic exocrine insufficiency.

APRACLONIDINE Ophthalmic Solution: 0.5% Apraclonidine (Iopidine® - Alcon) 0.5% ophthalmic solution is indicated for the short-term, adjunctive treatment of glaucoma.

REGULAR HUMAN BUFFERED INSULIN Injection: 100 units per ml Regular human buffered insulin (Velosulin Human® - Novo Nordisk) injection is used for the management of diabetes mellitus, particularly for use in subcutaneous insulin pumps.

ONDANSETRON Tablets: 4 mg and 8 mg Ondansetron (Zofran® - Glaxo) tablets are indicated for the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy. The prescribing of ondansetron tablets is limited to the UIHC criteria published in "Guide to Ondansetron Use in Oncology Settings."

CYCLOBENZAPRINE Tablets: 10 mg Cyclobenzaprine (Flexeril® - Merck Sharp Dohme, generic) tablets are indicated for relief of muscle spasm associated with acute, painful musculoskeletal conditions.

BOVINE DERMAL COLLAGEN IMPLANT Injection: 0.1 ml (skin test) and 2.5 ml Bovine dermal collagen implant (Contigen Implant® - Bard) is indicated for the treatment of urinary incontinence due to intrinsic sphincter deficiency. The use of this product is restricted to urologists.

GRISEOFULVIN Tablets, ultamicrosize: 125 mg, 250 mg, 330 mg Griseofulvin ultramicrosize (Fulvicin P/G® - Schering, Gris - PEG® - Herbert) tablets are indicated for the treatment of cutaneous fungal infections.

HOLOBETASOL PROPIONATE Cream and Ointment: 0.05% Halobetasol propionate (Ultravate® - Westwood) is a super-high potency topical corticosteroid indicated for the relief of the inflammatory and pruritic manifestations of steroid-responsive dermatoses. The prescribing of halobetasol propionate is limited to quantities less than 50 grams per week and to a two-week supply; additionally open-ended prescriptions (i.e., multiple refills) will not be dispensed.

Drugs Deleted from Stock
REGULAR HUMAN BUFFERED (HUMULIN® BR) INSULIN INJECTION Discontinued by the manufacturer. Velosulin® - Human is available.

PANCREATIN (Creon®) enteric-coated microsphere capsules (lipase 8000 U.S.P. units, amylase 13,000 U.S.P. units, and protease 30,000 U.S.P. units) Discontinued by the manufacturer. Creon® - 10 in available.

GRISEOFULVIN MICROSIZE TABLETS This product will be phased-out during the next six-months. The replacement product, griseofulvin ultramicrosize tablets, is more bioavailable even when taken with a low-fat meal. The equivalent ratio of ultramicrosize to microsize is 2:3.

PHOSPHATES, INORGANIC ORAL SOLUTION Extemporaneously prepared inorganic phosphates oral solution is being replace with commercially available sodium phosphate and sodium biphosphate oral solution (Fleet Phospho-Soda®). Inorganic phosphates oral solution provides 30.4 mg (1mM) of phosphorous per ml; sodium phosphate and sodium biphosphate solution provides 126 mg (4.15mM) of phosphorous per ml. The Pharmacy and Therapeutics Subcommittee considers these products to be therapeutically interchangeable at a ratio of 0.25 ml of sodium phosphate and sodium biphosphate oral solution for each 1 ml of inorganic phosphates oral solution ordered.

Because serious or life-threatening hypoventilation could occur, Duragesic® is contraindicated:

• In the management of acute or post-operative pain, including use in outpatient surgeries
• In the management of mild or intermittent pain responsive to PRN or non-opioid therapy
• In doses exceeding 25 mcg/hour at the initiation of opioid therapy

Duragesic® should not be administered to children under 12 years of age or patients under 18 years of age who weigh less than 50 kg (110 lbs) except in an authorized investigational research setting.

Duragesic® is indicated for treatment of chronic pain (such as that of malignancy) that:

• cannot be managed by lesser means such as acetaminophen-opioid combinations, non-steroidal analgesics, or PRN dosing with short-acting opioids and;
• requires continuous opioid administration.

The 50, 75, and 100 mcg/hour dosages should ONLY be used in patients who are already on and are tolderant to opioid therapy.

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