OFFICE OF THE PRIME MINISTER'S SCIENCE ADVISORY COMMITTEE Professor Peter Gluckman, DCNZM FRSNZ FMedSci FRS Chief Science Advisor Consideration of reduction of access to, or elimination of, pseudoephedrine in ‘cold and flu' preparations Report to the Prime Minister 30 July 2009 CSA-2009-01
Lwwus_aia_200329 117.133Multimodal Systemic and Adam Young, MDAsokumar Buvanendran, MDRush University Medical CenterChicago, Illinois Ambulatory surgery encompasses the majority of surgical proce- dures performed in the United States. The number of proceduresperformed on an ambulatory basis has increased owing to improve-ments in surgical technology, anesthetic techniques, and pharmacol-ogy—specifically analgesic agents. The latter is important as there is anincreasing trend of performing more painful procedures on anoutpatient Inadequate management of pain or side effects frommedications (such as opioids) can lead to decreased patient satisfactionand delayed discharge. Multimodal analgesia captures the effectivenessof individual agents in optimal dosages that maximize efficacy andminimize side effects. This important concept includes the theory thatagents with different mechanisms of may have synergisticeffects in preventing or treating pain. Joshi offered guidelines onconstructing a multimodal analgesia strategy that, in addition to regionalor local anesthesia, included scheduled administration of nonopioidanalgesics [eg, acetaminophen, nonsteroidal anti-inflammatory drugs(NSAIDs), or cyclooxygenase (COX)-2 inhibitors] using oral opioids onlyfor breakthrough pain.Successful regimens for outpatient (andinpatient) procedures have since been proposed that follow theseprinciples.These regimens must be tailored to individual patients,keeping in mind the procedure being performed, side effects ofindividual medications, and patients' preexisting medical conditions.
REPRINTS: ASOKUMAR BUVANENDRAN, MD, 1653 W. CONGRESS PARKWAY, 763 JELKE, RUSH UNIVERSITY MEDICALCENTER, CHICAGO, IL 60612, E-MAIL: [email protected] INTERNATIONAL ANESTHESIOLOGY CLINICSVolume 49, Number 4, 117–133 r 2011, Lippincott Williams & Wilkins 118 ' Young and Buvanendran Aniline Derivatives In 2005, Joshi commented on the underuse of acetaminophen in the perioperative Aniline derivatives have mild analgesic, anti-inflammatory, and antipyretic properties. The use of these compoundsin ambulatory surgery has gained interest of late owing to thedevelopment of intravenous formulations (just approved in the UnitedStates) and the favorable side effect profiles.
Paracetamol, the intravenous equivalent of acetaminophen, became available in 2002 and provides more predictable bioavailability andpredictable onset compared with enteral routes of administrationIt hasbeen researched for its ability to spare postoperative opioid use andconsequently decrease nausea, vomiting, and sedation. Concern still existsfor hepatotoxicity associated with aniline derivatives. A prospective studyby Gorocs et ademonstrated the safety and efficacy of preoperativeparacetamol when given alone or with other systemic analgesics. Onerandomized control trial of paracetamol as monotherapy demonstratedthe benefits of decreased pain scores, total morphine dose, and nauseapostoperatively.Two separate trials failed to validate these resultHowever, paracetamol appears to confer additional analgesic efficacywhen used in various combinations. Intravenous (IV) acetaminophen(OFIRMEV) is the first in the class of IV nonopioid, non-NSAIDanalgesics available in the United States. The safety and efficacy of IVacetaminophen as a parenteral analgesic agent has a wide array ofpostoperative settings, from minor outpatient to complicated or majorinpatient surgery. It has the potential to provide a significant therapeuticimprovement in the treatment of fever and acute postoperative pain.
As a combination, NSAIDs and paracetamol decrease pain s total opioid consumption,postoperative nausea and andsedationPatients expressed greater satisfaction when the combinationof NSAIDs and paracetamol was used versus por acetaminophenaloneAfter segmental mastectomy (with or without axillary lymph nodedissection), Ohnesorge et alfound that those who received paracetamol inthe perioperative period had shorter times to ambulation (around 4 h.) There appears to be much benefit to incorporating aniline derivatives as part of a multimodal analgesia regimen; as availability of intravenousformulations (such as IV acetaminophen: OFIRMEV) becomes morewidespread and anesthesiologists become more comfortable with theiradministration, their use should increase, which should lead to greaterpatient satisfaction and improved outcomes from ambulatory surgery.
Inhibition of the COX enzymes (COX-1 and COX-2) and subsequent modulation of the inflammatory response has proven to be an effective Multimodal Systemic and Intra-articular Analgesics ' 119 means to prevent and treat postoperative pain in ambulatory surgery. Inthe past there has been concern regarding nonselective COX inhibitorsand side effects that include renal toxicity, gastrointestinal toxicity,platelet inhibition, and exacerbation of asthma. COX-2 inhibitors havegained interest as they spare GI and renal side effects. However, use ofCOX-2 inhibitors is not without concern; valdecoxib and rofecoxib werewithdrawn from use because of serious side effects. Recent research oncelecoxib has defined its and safety.
In addition to decreasing pain scores, celecoxib has been associated with decreased opioid consumption, earlier return of bowel and physical activityand increased patient satisfaction. Time todischarge was decreased in groups that received ketorolac (P<0.05) forambulatory anorectal procedures.With regard to timing of dosing,Sun et alshowed there is no difference if celecoxib is given before orafter surgery.
Newer formulations of ketorolac include an intranasal (IN) spray.
Compared with placebo, patients receiving IN ketorolac had improvedpain scores in third molar extraction with bony impaction surgeryArandomized controlled trial in patients after abdominal surgery showed26% less morphine consumed in the first 48 hours postoperative.Bothstudies remarked on the rapid onset of analgesia, which lasted up to 8hours,and suggested its benefit in ambulatory or fast-track surgeryThe rapid onset and improved analgesia seen with IN ketorolac may bedue to higher penetration via the cribriform plate and into thecerebrospinal fluid. Higher cerebrospinal fluid levels of NSAIDs havebeen associated with greater analgesia.
Local injection of ketorolac mixed with lidocaine and bupivacaine mixture was first studied for ambulatory anorectal surgery in 2000 andhas not been widely used, despite oral analgesic-sparing properties,improved quality of recovery, and no untoward effects on postoperativebleeding in 1 studyThe local application of NSAIDs may preventsome of the systemic side effects seen with administration of these drugsvia the oral or injectable route. For patient populations able to tolerateNSAIDs, incorporating them as an oral adjunct has proven to beeffective and safe. Local injection or IN formulations appear to haveproperties that make them suitable for further investigation inambulatory surgery analgesia regimens.
Preoperative administration of glucocorticoids attenuates peripheral inflammatory pathways and has been shown to decrease postoperativepain for minor surgical Concern regarding side effects ofsteroid administration, such as gastrointestinal or wound complications,has limited widespread use.
120 ' Young and Buvanendran In a randomized controlled trial by Coloma et al,4 mg dexame- thasone administered preoperatively reduced time to discharge with noincrease in wound infections. Preoperative or intraoperative administra-tion of glucocorticoids seems to be sufficient timing to obtain the anti-inflammatory benefits. The onset of dexamethasone seems to be rapidwith duration of action of 24 to 48 hoursWhen Kjetil and colleadded dexamethasone 16 mg to a multimodal analgesia regimen(including paracetamol and COX-2 inhibitor), a prolonged analgesiceffect was observed. However, half that dose of dexamethasone did notdemonstrate the same effect in a study by Mathiesen and colleaAdditional benefits of dexamethasone administration include anti-emeticeffects. These properties make it an ideal adjunct for the ambulatorysetting. An extensive review by Salerno and concluded that‘‘the literature clearly reflects the safety of short-term use of corticosteroidsfor acute postoperative analgesia in relatively healthy individuals.'' The use of anticonvulsants, particularly gamma-aminobutyric acid analogs that bind to the a2d subunit of voltage-gated calcium channels,as an adjunct to multimodal regimens has increased in the past decade.
Presynaptic voltage-gated calcium channels are unregulated in thedorsal root ganglia and spinal cord after surgical trauma, which leads tocentral sensitization.
Some studies have indicated that the use of anticonvulsants decreases the incidence of opioid-related side effects (nausea, vomiting,and pruritis) and increases the incidence of sedation,whereasother studies have been A meta-analysis by Ho andconcluded that a single preoperative dose of gabapentin,1200 mg or less, reduces pain scores and opioid consumption in the first24 hours postoperatively. Half that dose, gabapentin 600 mg, given 2hours preoperatively was effective in reducing pain scores and tramadolconsumption by 33% after mini-laparotomy open cholecystectomy in thesame time frame; however, pain scores and tramadol consumptionreturned to similar levels on postoperative day 2.
Continuing administration of gabapentin, in addition to a single preoperative dose, appears to have benefit; when given 4 dayspostoperatively, opioid consumption and some opioid-related sideeffects were reduced after total knee arthroplasty.Of note, gabapentinhas been studied in the pediatric population and a single preoperativedose had similar effects to those seen in the adult population, that beinglower pain scores and decreased opioid consumption postoperatively.
Pregabalin has been shown to demonstrate a more favorable pharmacokinetic profile than gabapentin, including increased bioavailabil-ity, longer half-life, and increased potency.A single dose of pregabalin Multimodal Systemic and Intra-articular Analgesics ' 121 150 mg demonstrates similar efficacy to gabapentin in reducing post-operative pain and opioid consumption50% reduction in 24-hourmorphine consumption and decreased nausea and vomiting was observedafter a 1-time dose of pregabalin 300 mg in patients undergoing total hiparthroplasty.Buvanendran and colleaguesdemonstrated pregabalin(300 mg 1-time dose followed by 150 mg twice a day) administered in theperioperative period not only decreases the development of chronic pain,but improves surgical outcome as demonstrated with greater range onmotion after total knee arthroplasty. Clarke and colleaguehad similarfindings, along with improved range of motion after total knee arthroplasty,with a shorter course of postoperative gabapentin. Other studies with singledoses of pregabalin (75 mg or 150 mg) have shown improved immediatepostoperative analgesia, without opioid-sparing effects.
Precise dosing of pregabalin is undetermined, as higher doses of pregabalin (600 mg), though effective in decreasing postoperative opioidconsumption, are associated with increased incidence of dizziness, blurredvision, and headache.This dose-related increase in side effects was alsoobserved by White and collethough without analgesic benefit.
Lower doses of pregabalin, although with lower incidence of side effects,did not show any analgesic benefit after laparoscopic cholecystectomy(50 mor minor gynecologic procedures (100 mg.
Pregabalin 150 mg, acetaminophen, and celecoxib administered as a multimodal regimen decreased intraoperative and postoperative opioiduse in patients undergoing robotic-assisted laparoscopic prostatectomywithout an increase in somnolence or dizziness.A randomizedcontrolled trial by Sen et al,including gabapentin (1200 mg singledose preoperatively) plus intraoperative ketamine infusion, resulted indecreased pain scores, opioid consumption, and decreased chronic painafter total abdominal hysterectomy.
Incorporating anticonvulsants in a multimodal regimen seems to offer not only short-term benefits but long-term effects, such asdecreased chronic pain and improved functional outcomes, whencontinued throughout the immediate postoperative period for certainsurgical procedures such as orthopedic surgery. Although some of thestudies cited in this section involve inpatient surgical procedures, thesesame principles can be applied to procedures performed in anoutpatient setting. Larger clinical trials need to be carried out with thisgroup of drugs to determine if the incidence of chronic pain aftersurgery can be reduced in the outpatient setting after orthopedicsurgery such as carpal tunnel and minor knee scopes.
N-Methyl-D-Aspartate Receptor Antagonists N-methyl-D-aspartate (NMDA) receptor antagonists, such as keta- mine, dextromethorphan, or memantine, have been indicated as 122 ' Young and Buvanendran possible pharmacologic agents to prevent and treat postoperativepain.NMDA receptor antagonists have the ability to modulate paincentrally, and possibly preemptively, by limiting central sensitization. In2004, a review by McCartney et determined that blockade of theNMDA receptor has been shown to reduce pain scores and analgesicrequirements beyond the known duration of action of the substancesinvestigated (ketamine or dextromethorphan). The prolonged effect hasled to investigation of the interaction between opioids and dextro-methorphan.A precise dose of dextromethorphan necessary topotentiate opioid analgesia is yet to be determined. However, Yehet ademonstrated a single dose of dextromethorphan 40 mg intramus-cular before elective colonic surgery decreased the amount of epiduralanalgesics in the first 24 hours after surgery; that benefit was absent after24 hours. Ketamine has been used more frequently although side effectssuch as nausea, vomiting, and delirium are of concern. Intravenousketamine (0.5 mg/kg as a 1-time bolus) reduced pain scores and rescueanalgesia in children undergoing tonsillectomy compared with placeboin a study by Conceic¸a˘o and without increased incidence ofside effects. Administering ketamine before incision or at the conclusionof surgery had similar effects on postoperative analgesia.
Although an effect has been seen with single intravenous boluses as noted above, there is mixed evidence of perioperative ketamine infusions.
Ketamine infusions have been associated with opioid-sparinimproved rehabilitationand without increased side Otherstudies demonstrated no effect in reducing pain scores, opioid consump-tion, or chronic pain in and thoracotomy.Local injectionof ketamine (0.5 mg/kg) in the peritonsillar space during tonsillectomy wasshown to have equianalgesic effects as an intravenous 1-time dose ofketamine (0.5 mg/kg) during tonsillectomybut concern over possibleserious side effects, such as development of pseudoaneurysms, thrombi, ormortality, was voiced by Shah and Preciado.
Memantine, a noncompetitive NMDA receptor antagonist, may prove to be the most applicable for ambulatory surgery. Memantine,when orally administered, allows ease of administration postoperatively,is better tolerated, has a longer half-life, and is the most potent clinicallyavailable NMDA receptor antagonist.Daily doses of 30 mg memantinedecreased phantom pain by up to 80% at 1 month after amputations in astudy by Schley and colleagues. This improvement in phantom pain, wasnot long-lived as the prevalence of phantom pain approached similarrates as those in the control group at 12 months.Although NMDAreceptor antagonists have been shown to have a positive effect onpostoperative pain in many studies, the appropriate dose and timing isyet to be determined. Joshiand Suzukihave remarked that NMDAreceptor antagonists may have a beneficial role as an adjunct inmultimodal analgesia.
Multimodal Systemic and Intra-articular Analgesics ' 123 Alpha-2 Adrenergic Agonists Stimulation of the a2 adrenergic receptors has been known to produce a variety of favorable effects for anesthesiologists, such as analgesia,sedation, and anxiolysis. Clonidine and dexmedetomidine, commonlyused a2 agonists, have enteral, intravenous, and transdermal routes ofadministration. Side effects of these medications include bradycardia,hypotension, and excessive sedation. In 2005, White remarked thatintravenous clonidine was ‘‘apparently ineffective'' in treating post-operative pain.Owing to the aforementioned side effects, clonidinemay not be suitable for ambulatory analgesia except in combination withlocal anesthetics in peripheral nerve blockadedoses of less than 0.5 mg/kgperineurally are typically not associated with any hemodynamic sideeffects. However, one must be cautious using clonidine with subarachnoidblocks in the ambulatory setting owing to the concomitant side effects.
Dexmedetomidine is a highly selective a2 agonist with a short duration of action. Arain and colleagues found that a 4-hour infusionstarted 30 minutes before the conclusion of surgery was effective inreducing morphine consumption by 66% in the early postoperativeperiod. This was without an increase in sedation, hypotension, orchanges in nausea or vomiting.An intraoperative infusion ofdexmedetomidine produced reduced volatile anesthetic doses (by19% to 22%), reduced postoperative opioid needs (by 36% to 42%),decreased nausea and vomiting, and shorter postanesthesia care unitstay in patients undergoing laparoscopic bariatric surgery. Prolongedeffects (eg, opioid sparing or shorter hospital stay) were absent,attributable to dexmedetomidine's short half-life.In patients under-going laparoscopic gynecologic surgery, Salman and colleagues sug-gested that dexmedetomidine could be used as an alternative forremifentanil in ambulatory surgery, as a constant infusion reducedpostoperative analgesic requirements, nausea, and vomiting. The onlydrawback was a prolonged recovery, including time to extubation.
Although dexmedetomidine and clonidine possess many desired effects, current administration practices seem cumbersome for theambulatory setting. Dexmedetomidine infusions may have benefit inlonger, more painful procedures. Further research may provide newermethods or different formulations that address these limitations. Use ofa2 agonists as adjuncts in regional anesthesia should always beconsidered, as their safety profile and ability to prolong analgesia hasbeen demonstrated.
The use of b-adrenergic blocking agents as a method of preemptive or preventive analgesia has gained considerable interest in the past 5 124 ' Young and Buvanendran years. b-blockers have been associated with blunting the sympatheticresponse, opioid-sparing effects, and anticatabolic yet theexact mechanism of these effects is unknown. Incision at the beginningof surgery is associated with activation of the sympathetic nervoussystem; one thought is that the release of catecholamines enhancesexcitability of hippocampal NMDA receptors, which may play a role innociception.Another possible mechanism of analgesia is by decreasinghepatic blood flow, thereby decreasing the metabolism of circulatingopioids.Pranevicius and Pranevicius hypothesized that patients' painthresholds remain at a normal level with esmolol infusions, as opposedto intermittent fentanyl or remifentanil infusions that can lead to opioid-induced hyperalgesia and lower pain thresholds. They speculated thatthe absence of opioid-induced hyperalgesia in turn led to lowerpostoperative opioid use and faster recovery Esmolol is a lipophilic, ultra-short acting, b1-selective antagonist that has been studied in ambulatory surgery. Intraoperative esmolol bolusesfollowed by short-term infusions have led to opioid sparing intraopera-tivelyand postoperativelyHowever, this opioid-sparing effectseems to be limited to lasting from as little as 24 hours toas much as 3 days Coloma and reportedthis limited effect, noting increased use of hydrocodone after dischargein patients who received esmolol infusions in place of opioids. Despite itslimited duration of postoperative analgesia, esmolol is quite effectiveintraoperatively as it has been used successfully and safely in place of aremifentanil infusion in fast-track anesthesia.It has reliably beenassociated with decreased postoperative nausea and vomiting, presum-ably by sparing narcotic use.In addition, esmolol has beenreported to decrease time to emerand shorten time todischarge from the recovery Bilotta et al,were unable toreproduce any of these effects, albeit in patients undergoing craniotomyand using a lower dose of esmolol.
Local Anesthetics Local anesthetics have been found to have multiple mechanism of analgesia, including voltage-gated sodium channel blockade,inhibi-tion of G protein-coupled receptors,antagonism of NMDA recep-and modulation of the inflammatory response.In an inpatientsetting, patients undergoing laparoscopic colectomy, lidocaine bolusfollowed by 24-hour infusion resulted in anesthetic sparing (35% lessvolatile anesthetic) and a >50% reduction in intraoperative andpostoperative opioids. In addition patients receiving lidocaine infusionshad earlier return of bowel function, lower postoperative fatigue, and asa result 1 less day of hospitalization.Similar findings were observed inpatients undergoing laparoscopic cholecystectomy; lidocaine bolus Multimodal Systemic and Intra-articular Analgesics ' 125 followed by infusion for duration of case had anesthetic-sparing andopioid-sparing Other studies have confirmed opioid-sparingeffects,earlier return of bowel function,improved and shorter hospital stayThe anti-inflammatory effects of lidocaine,with attenuated levels of proinflammatory mediators [interleukin (IL)-6,IL-8, IL-1ra, complement C3a, integrins, and platelet leukocyteaggregates], have been demonstrated by Herroeder et and Yardeniet al.However, a study on patients undergoing total abdominalhysterectomy showed no difference in postoperative pain scores, a lackof opioid-sparing effect, and similar times to discharge as McCarthy and colleagues reviewed 16 studies with 764 total patients receiving lidocaine infusions. The dosage of lidocaine included bolusesof 100 mg (or 1.5 to 2 mg/kg) followed by infusions of 1.5 to 3 mg/kg/h(or 2 to 3 mg/min.) They determined a clear benefit in abdominalsurgery with less postoperative nausea/vomiting, earlier return of bowelfunction, earlier ambulation and rehabilitation, and shorter hospitaliza-tions. They concluded a ‘‘continuous infusion of perioperative lidocainehas a clear advantage in abdominal surgery.'' Plasma levels of lidocaineduring infusions have been measured within a safe (<5 mg/mL) rangeexcept in 1 patient who had a level of 5.8 mg/mL after the initial bolus.
However, these infusions seem to be safe; there are no reported cases ofCNS toxicity in patients undergoing lidocaine infusion.
Lidocaine infusions may provide benefit for ambulatory surgery patients as more invasive and extensive abdominal procedures areperformed on an outpatient basis. Dosing studies and research regardingthe duration of infusions should be a focus of future investigations.
Ease of administration, efficacy in achieving pain relief, and lack of systemic side effects are reasons intra-articular (IA) analgesia becamepopular for ambulatory surgeryProcedures in which this has beendemonstrated include knee and shoulder arthroscopy. However, for asmany studies that demonstrate a positive effect for IA analgesia thereseems to be several that demonstrate the contrary. In addition to this,very recent reports of chondrolysis after IA injections and infusions hasled to controversy A variety of substances, including local anesthetics, opioids, NSAIDs, corticosteroids, a2 agonists, and NMDA receptor antagonists, have beenused in IA analgesia as early as The many variables in IAanalgesia include varying pharmacokinetic profiles and dosages ofindividual agents; this has led to varying efficacy in pain relief andcreative combinations of drugs being used. One such combination thathas been investigated is a bupivacaine-morphine combination, whichdemonstrated positive effects on postoperative pain in multiple 126 ' Young and Buvanendran studies.After completing a systematic review, Kalso and colleaguesconcluded morphine 5 mg IA seemed to be an optimal dose and couldprovide as much as 27 hours of analgesia postoperatively.A dose-range effect of morphine was confirmed by Gupta et also notingthat the analgesic effect was ‘‘mild.'' Ketorolac IA has had analgesic properties when compared with low doses of bupivacaine or Some authors have includedketorolac as part of a combination IA injection; when used withbupivacaine and morphine, ketorolac 60 mg IA led to longer duration ofanalgesia after arthroscopic knee surgery with more patients wellenough to return to work on postoperative days 1 and 2.
Addition of a corticosteroid, methylprednisolone 40 mg, to a morphine-bupivacaine injection had a similar ability to further enhanceanalgesia and allow patients to return to work earlier in a study byRasmussen and colleaSide effects of steroids, such as delayedwound healing or infection, with steroid injections was not observed in astudy of 30 patients by Wang et alIn patients undergoing arthroscopicmeniscectomy, addition of clonidine 1 mg/kg to a mixture of bupivacaineand morphine injected intra-articularly resulted in significantly prolongedanalgesia and less opioid consumption postoperatively.
Finally, the use of IA ketamine 0.5 mg/kg was cited in a small study by Dal et to have analgesic effects when compared with placebo.
However, the study also compared ketamine to bupivacaine IA, whichhad greater analgesic effects as an individual agent.
Timing of IA injection may be important, as well. A single IA injection of morphine followed by another 10 minutes of tourniquettime improved postoperative analgesia in a study by Whitford andThis too, is controversial as other studies have found nodifference with varying tourniquet times,or after the tourniquet wasdeflated completely The type of procedure has also been linked to varying effects of IA agents. Patients undergoing knee procedures associated with ‘‘highinflammatory response'' (eg, anterior cruciate ligament reconstruction,lateral release, patellar shaving, and plica removal) had improvedanalgesia with morphine compared with bupivacaine. This was incontrast to patients undergoing diagnostic arthroscopy or partialmeniscectomy (associated with ‘‘low inflammation'') who had betterpain control with bupivacaine compared with Use ofregional, neuraxial, or systemic analgesia in addition to IA analgesia hasbeen noted as a possible confounding factor in evaluating efficacy of IAstudies. The exact mechanism is currently unknown.
IA analgesia in shoulder surgery has been compared with parenteral analgesics and interscalene brachial plexus blockade (ISB). In patientsundergoing arthroscopic acromioplasty, ISB is superior to IA orsuprascapular nerve blockade. When compared with controls, only Multimodal Systemic and Intra-articular Analgesics ' 127 patients receiving ISB had significant reductions in pain scores andmorphine consumption in the postanesthesia care unit.
To provide longer-lasting analgesia, continuous IA infusions may be necessary. After rotator cuff repair, implantation of an IA catheter withinfusion of ropivacaine led to an improvement in pain for 12 hourspostoperatively but no change in postoperative opioid consumption.
The authors argued that the use of continuous IA infusions were ‘‘notworth the substantial additional costs.''Similar findings occurredafter arthroscopic subacromial decompression with a catheter in thesubacromial space: improved pain scores but no change in opioidOther studies have shown neither a decrease in painscore nor opioid These findings have led Fredricksonet to question the practicality of IA analgesia in the recent times.
Earlier studies were conducted on less painful shoulder procedures(arthroscopic, nonrotator cuff) and may be the reason for thediscrepancy with contemporary findings.
Chondrolysis is defined as the disappearance of articular cartilage as a result of dissolution of cartilage matrix and chondrocytes in a shortperiod of time leading to severe osteoarthritis and long-term disability; itis considered to be a rare disease of the shoulderAnimal models haverecently indicated the chondrotoxicity of bupivacaine in rabbit Twenty-three cases of chondrolysis in young patients (aged 15 to 47)who underwent shoulder surgery were reviewed by Bailie andEllenbecker Various substances have been investigated for efficacy in relieving postoperative pain in arthroscopic surgery. With contradicting results, itis prudent to consider the variables mentioned here while evaluatingindividual studies' outcomes. IA injection of opioids and local anestheticsmay be safe in the knee. In theory, combinations of agents with differingmechanisms of action may allow for lower doses of individual drugs,while potentiating analgesic effects. Continuous and patient-controlledIA infusions are also discouraged as prolonged exposure to pharmaco-logic agents may be the trigger for development of chondrolysis. Largerscale studies are necessary to evaluate the benefit of substances otherthan opioids and local anesthetics. In addition, determining timing andoptimum dosages and establishing safety profiles are crucial if IAanalgesics are to evolve as a component of multimodal analgesicregimens.
The role of ambulatory analgesia has become an important focus of all providers in outpatient surgery. Coordinating a perioperativeregimen with the surgeon and recovery room staff will facilitate anexpedited, less painful recovery for the patient. By implementing 128 ' Young and Buvanendran multimodal regimens composed of NSAIDs, acetaminophen, and short-acting opioids, many patients will have improved analgesia after mild-to-moderate painful procedures. The use of steroids, anticonvulsants, andNMDA receptor antagonists should be considered based on the amountof postoperative pain anticipated and coexisting medical diseases.
Infusions, such as a2 agonists, b-blockers, and local anesthetics, mayalso prove useful in more painful procedures and in surgeries that maybe difficult to cover using RA techniques, but are likely to becumbersome in the fast-paced setting of an outpatient surgery center.
To facilitate quicker onset of analgesics, using new routes of adminis-tration (eg, IN ketorolac or ketamine) may become increasingly popular.
Their use should also be emphasized, as many studies alreadydemonstrate fewer side effects. As advancements in pharmacology andequipment improve, so should the anesthesiologist's ability to provide asafe, balanced, multimodal analgesic regimen for a variety of outpatientsurgical procedures.
Dr Buvanendran has been consultant for Pfizer and Cadence. He has received a Pfizergrant and lecture fees from Pfizer, Cadence and Johnson & Johnson.
The authors have no conflicts of interest to disclose.
1. Joshi GP. Multimodal Analgesia Techniques for Ambulatory Surgery. Int Anesthesiol 2. Woolf CJ. Pain: moving from symptom control towards mechanism-specific pharmacologic management. Ann Intern Med. 2004;140:441–451.
3. Bisgaard T. Analgesic treatment after laparoscopic cholecystectomy: a critical assessment of the evidence. Anesthesiology. 2006;104:835–846.
4. Rajpal S, Gordon DB, Pellino TA, et al. Comparison of perioperative oral multimodal analgesia versus IV PCA for spine surgery. J Spinal Disor Tech. 2010;23:139–145.
5. Rawlins MD, Henderson DB, Hijab AR. Pharmacokinetics of paracetamol (acetamin- ophen) after intravenous and oral administration. Eur J Clin Pharmacol. 1977;11:283–286.
6. Gorocs TS, Lambert M, Rinne T, et al. Efficacy and tolerability of ready-to use intravenous paracetamol solution as monotherapy or as an adjunct analgesic therapyfor postoperative pain in patients undergoing elective ambulatory surgery: open,prospective study. Int J Clin Pract. 2009;63:112–120.
7. Salihoglu Z, Yildirim M, Demiroluk S, et al. Evaluation of intravenous paracetamol administration on postoperative pain and recovery characteristics in patientsundergoing laparoscopic cholecystectomy. Surg Laparosc Endosc Percutan Tech.
8. Ohnesorge H, Bein B, Hanss H, et al. Paracetamol versus metamizol in the treatment of postoperative pain after breast surgery: a randomized, controlledtrial. Eur JAnaesthesiol. 2009;26:648–653.
9. Api O, Unal O, Ugurel V, et al. Analgesic efficacy of intravenous paracetamol for outpatient fractional curettage: a randomised, controlled trial. Int J Clin Pract.
Multimodal Systemic and Intra-articular Analgesics ' 129 10. Hong JY, Won Han S, Kim WO. Fentanyl sparing effects of combined ketorolac and acetaminophen for outpatient inguial hernia repair in children. J Urol.
11. Ong CK, Seymour RA, Lirk P. Combining paracetamol (acetaminophen) with nonsteroidal anti-inflammatory drugs: a qualitative systematic review of analgesicefficacy for acute postoperative pain. Anesth Analg. 2010;110:1170–1179.
12. Issioui T, Klein KW, White PF, et al. The efficacy of premedication with celecoxib and acetaminophen in preventing pain after otolaryngologic surgery. Anesth Analg.
with gabapentin, ketamine and dexamethasone in combination with paracetamoland ketorolac after hip arthroplasty: a preliminary study. Eur J Anaesthesiol.
14. Sun T, Sacan O, White PF, et al. Perioperative versus postoperative celecoxib on patient outcome after major plastic surgery procedures. Anesth Analg.
15. White PF, Sacan O, Tufanogullari B, et al. Effect of short-term postoperative celecoxib administration on patient outcome after outpatient laparoscopic surgery. Can JAnaesth. 2007;54:342–348.
16. Coloma M, White PF, Huber PJ Jr, et al. The effect of ketorolac on recovery after 17. Grant GM, Mehlisch DR. Intranasal ketorolac for pain secondary to third molar impaction surgery: a randomized, double-blind, placebo-controlled trial. J OralMaxillofac Surg. 2010;68:1025–1031.
18. Singla N, Singla S, Minkowitz HS, et al. Intranasal ketorolac for acute postoperative pain. Curr Med Res Opin. 2010;26:1915–1923.
19. Salerno A, Hermann R. Efficacy and safety of steroid use for postoperative pain relief. Update and review of the medical literature. J Bone Joint Surg Am.
20. Coloma M, Duffy LL, White PF, et al. Dexamethasone facilitates discharge after outpatient anorectal surgery. Anesth Analg. 2001;92:85–88.
21. Kjetil H, Sem TK, Ellen S, et al. The prolonged postoperative analgesic effect when dexamethasone is added to a nonsteroidal anti-inflammatory drug (rofecoxib) beforebreast surgery. Anesth Analg. 2007;105:481–486.
22. Mathiesen O, Jacobsen LS, Holm HE, et al. Pregabalin and dexamethasone for postoperative pain control: a randomized controlled study in hip arthroplasty.
Br J Anaesth. 2008;101:535–541.
23. Tiippana EM, Hamunen K, Kontinen VK, et al. Do surgical patients benefit from perioperative gabapentin/pregabalin? A systematic review of efficacy and safety.
Anesth Analg. 2007;104:1545–1556.
24. Ho KY, Gan TJ, Habib AS. Gabapentin and postoperative pain—a systematic review of randomized controlled trials. Pain. 2006;126:91–101.
25. Buvanendran A, Kroin JS, Della Valle CJ, et al. Perioperative oral pregabalin reduces chronic pain after total knee arthroplasty: a prospective, randomized, controlled trial.
Anesth Analg. 2010;110:199–207.
26. Agarwal A, Gautam S, Gupta D, et al. Evaluation of a single preoperative dose of pregabalin for attenuation of postoperative pain after laparoscopic cholecystectomy.
Br J Anaesth. 2008;101:700–704.
27. Srivastava U, Kumar A, Saxena S, et al. Effect of preoperative gabapentin on postoperative pain and tramadol consumption after minilap open cholecystect-omy: a randomized double-blind, placebo-controlled trial. Eur J Anaesthesiol.
130 ' Young and Buvanendran 28. Clarke H, Pereira S, Kennedy D, et al. Gabapentin decreases morphine consumption and improves functional recovery following total knee arthroplasty. Pain Res Manag.
29. Rusy L, Hainsworth K, Nelson T, et al. Gabapentin use in pediatric spinal fusion patients: a randomized, double-blind, controlled trial. Anesth Analg.
30. Baldini G, Carli F. Anesthetic and adjunctive drugs for fast-track surgery. Current Drug 31. Bryans JS, Wustrow DJ. 3-Substituted GABA analogs with central nervous system activity: a review. Med Res Rev. 1999;19:149–177.
32. Jokela R, Ahonen J, Tallgren M, et al. Premedication with pregabalin 75 or 150 mg with ibuprofen to control pain after day-case gynaecological laparoscopic surgery.
Br J Anaesth. 2008;100:834–840.
33. Jokela R, Ahonen J, Tallgren M, et al. A randomized controlled trial of perioperative administration of pregabaline for pain after laparoscopic hysterectomy. Pain. 2008;134: 106–112.
34. White PF, Tufanogullari B, Taylor J, et al. The effect of pregabalin on preoperative anxiety and sedation levels: a dose-ranging study. Anesth Analg. 2009;108:1140–1145.
35. Peng PW, Li C, Farcas E, et al. Use of low-dose pregabalin in patients undergoing laparoscopic cholecystectomy. Br J Anaesth. 2010;105:155–161.
36. Paech MJ, Goy R, Chua S, et al. A randomized, placebo-controlled trial of preoperative oral pregabalin for postoperative pain relief after minor gynecologicalsurgery. Anesth Analg. 2007;105:1449–1453.
37. Trabulsi EJ, Patel J, Vixcusi ER, et al. Preemptive multimodal pain regimen reduces opioid analgesia for patients undergoing robotic-assisted laparoscopic radicalprostatectomy. Urology. 2010;76:1122–1124.
38. Sen H, Sizlan A, Yanarates O, et al. A comparison of gabapentin and ketamine in acute and chronic pain after hysterectomy. Anesth Analg. 2009;109:1645–1650.
39. Suzuki M. Role of N-methyl-D-aspartate receptor antagonists in postoperative pain management. Curr Opin Anaesthesiol. 2009;22:618–622.
40. McCartney CJ, Sinha A, Katz J. A qualitative systematic review of the role of N-methyl-D-aspartate receptor antagonists in preventative analgesia. Anesth Analg.
41. Yeh CC, Jao SQ, Huh BK, et al. Preincisional dextromethorphan combined with thoracic epidural anesthesia and analgesia improves postoperative painand bowel function in patients undergoing colonic surgery. Anesth Analg.
42. Conceic¸a˘o MJ, Conceic¸a˘o DB, Lea˜o CC. Effect of an intravenous single dose of ketamine on postoperative pain in tonsillectomy patients. Paediatr Anaesth.
43. Remerand F, Tendre CL, Baud A, et al. The early and delayed analgesic effects of ketamine after total hip arthroplasty: a prospective, randomized, controlled, double-blind study. Anesth Analg. 2009;109:1963–1971.
44. Loftus RW, Yeager MP, Clark JA, et al. Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoingback surgery. Anesthesiology. 2010;113:639–646.
45. Duale C, Sibaud F, Guastella V, et al. Perioperative ketamine does not prevent chronic pain after thoracotomy. Eur J Pain. 2009;13:497–505.
46. Dal D, Celebi N, Elvan EG, et al. The efficacy of intravenous or peritonsillar infiltration of ketamine for postoperative pain relief in children followingadenotonsillectomy. Pediatr Anaesth. 2007;17:263–269.
Multimodal Systemic and Intra-articular Analgesics ' 131 47. Shah RK, Preciado DA. Reply: the efficacy of intravenous or peritonsillar infiltration of ketamine for postoperative pain relief in children following adenotonsillectomy.
Pediatr Anesth. 2007;17:1114–1115.
48. Schley M, Topfner S, Wiech K, et al. Continuous brachial plexus blockade in combination with the NMDA receptor antagonist memantine prevents phantom painin acute traumatic upper limb amputees. Eur J Pain. 2007;11:299–308.
49. White PF. The changing role of non-opioid analgesic techniques in the management of postoperative pain. Anesth Analg. 2005;101:S5–S22.
50. Lena P, Balarac N, Lena D, et al. Fast-track anesthesia with remifentanil and spinal analgesia for cardiac surgery: the effect on pain control and quality of recovery.
J Cardiothorac Vasc Anesth. 2008;22:536–542.
51. Arain SR, Ruehlow RM, Uhrich TD, et al. The efficacy of dexmedetomidine versus morphine for postoperative analgesia after major inpatient surgery. Anesth Analg.
52. Tufanogullari B, White PF, Peixoto MP, et al. Dexmedetomidine infusion during laparoscopic bariatric surgery: the effect on recovery outcome variables. Anesth Analg.
53. Salman N, Uzun S, Coskun F, et al. Dexmedetomidine as a substitute for remifentanil in ambulatory gynecologic laparoscopic surgery. Saudi Med J. 2009;30:77–81.
54. Sarvey JM, Burgard EC, Decker G. Long-term potentiation: studies in the hippocampal slide. J Neurosci Method. 1989;28:109–124.
55. Pranevicius M, Pranevicius O. Non-opioid anesthesia with esmolol avoids opioid- induced hyperalgesia and reduces fentanyl requirement after laparoscopy. AnesthAnalg. 2009;108:1048.
56. Ozturk T, Kaya H, Aran G, et al. Postoperative beneficial effects of esmolol in treated hypertensive patients undergoing laparoscopic cholecystectomy. Br J Anaesth.
57. Collard V, Mistraletti G, Taqi A, et al. Intraoperative esmolol infusion in the absence of opioids spares postoperative fentanyl in patients undergoing ambulatorylaparoscopic cholecystectomy. Anesth Analg. 2007;105:1255–1262.
58. White PF, Wang BG, Tang J, et al. The effect of intraoperative use of esmolol and nicardipine on recovery after ambulatory surgery. Anesth Analg. 2003;97:1633–1638.
59. Chia YY, Chan MH, Ko NH, et al. Role of beta-blockade in anaesthesia and postoperative pain management after hysterectomy. Br J Anaesth. 2004;93:799–805.
60. Coloma M, Chiu J, White P, et al. The use of esmolol as an alternative to remifentanil during desflurane anesthesia for fast-track outpatient gynecologic laparoscopicsurgery. Anesth Analg. 2001;92:352–357.
61. Bilotta F, Lam AM, Doronzio A, et al. Esmolol blunts postoperative hemodynamic changes after propofol-remifentanil total intravenous fast-track neuroanesthesia forintracranial surgery. J Clin Anesthesiol. 2008;20:426–430.
62. Hollmann MW, Durieux ME. Local anesthetics and the inflammatory response: a new therapeutic indication? Anesthesiology. 2000;93:858–875.
63. Sugimoto M, Uchida I, Mashimo T. Local anaesthetics have different mechanisms and sites of action at the recombinant N-methyl-D-aspartate (NMDA) receptors. Br JPharmacol. 2003;138:876–882.
64. Hollmann MW, Gross A, Jelacin N, et al. Local anesthetic effects on priming and activation of human neutrophils. Anesthesiology. 2001;95:113–122.
65. Kaba A, Laurent SR, Detroz BJ, et al. Intravenous lidocaine infusion facilitates acute rehabilitation after laparoscopic colectomy. Anesthesiology. 2007;106:11–18.
66. Lauwick S, Kim DJ, Michelagnoli G, et al. Intraoperative infusion of lidocaine reduces postoperative fentanyl requirements in patients undergoing laparoscopiccholecystectomy. Can J Anaesth. 2008;55:754–760.
132 ' Young and Buvanendran 67. Lauwick S, Kim DJ, Mistraletti G, et al. Functional walking capacity as an outcome measure of laparoscopic prostatectomy: the effect of lidocaine infusion. Br J Anaesth.
68. Herroeder S, Pecher S, Schonherr ME, et al. Systemic lidocaine shortens length of hospital stay after colorectal surgery: a double-blinded, randomized, placebo-controlled trial. Ann Surg. 2007;246:192–200.
intravenous lidocaine on postoperative pain and immune function. Anesth Analg.
70. Bryson G, Charapov I, Krolczyk G. Intravenous lidocaine does not reduce length of hospital stay following abdominal hysterectomy. Can J Anaesth. 2010;57:759–766.
71. McCarthy GC, Megalla SA, Habib AS. Impact of intravenous lidocaine infusion on postoperative analgesia and recovery from surgery: a systematic review ofrandomized controlled trials. Drugs. 2010;70:1149–1163.
72. Rawal N. Postoperative pain treatment for ambulatory surgery. Best Pract Res Clin 73. Fredrickson MJ, Krishnan S, Chen CY. Postoperative analgesia for shoulder surgery: a critical appraisal and review of current techniques. Anesthesia. 2010;65:608–624.
74. Hughes DG. Intra-articular bupivacaine for pain relief in arthroscopic surgery (letter). Anesthesia. 1985;40:821.
75. Senthilkumaran S, Tate R, Read JRM, et al. Intra-articular morphine and bupivacaine for post-operative analgesia in anterior cruciate ligament reconstruction:a prospective randomized controlled trial. Knee Surgery, Sports Traumatology.
76. Khoury GF, Chen ACN, Garland DE, et al. Intra-articular morphine, bupivacaine, and morphine/bupivacaine for pain control after knee videoarthroscopy. Anesthesi-ology. 1992;77:263–266.
77. Guler G, Karaoglu S, Akin A, et al. When to inject analgesic agents intra-articularly in anterior cruciate ligament reconstruction: before or after tourniquet releasing.
J Arthrosc Relat Surg. 2004;20:918–921.
78. Kalso E, Smith L, McQuay HJ et al. No pain, no gain: clinical excellence and scientific rigour—lessons learned from IA morphine. Pain. 2002;98:269–275.
79. Gupta A, Bodin L, Holmstro ¨m B et al. A systematic review of the peripheral analgesic effects of intra-articular morphine. Anesth Analg. 2001;93:761–770.
80. Calmet J, Esteve C, Boada S, et al. Analgesic effect of intra-articular ketorolac in knee arthroscopy: comparison of morphine and bupivacaine. Knee Surgery, SportsTraumatology. Arthoscopy. 2004;12:552–555.
81. Ng HP, Nordstro ¨m U, Axelsson K. Efficacy of intra-articular bupivacaine, ropivacaine or a combination of ropivacaine, morphine, and ketorolac on postoperative painrelief after ambulatory arthroscopic knee surgery: a randomized double-blind study.
Reg Anesth Pain Med. 2006;31:26–33.
82. Rasmussen S, Larsen AS, Thomsen ST, et al. Intra-articular glucocorticoid, bupivacaine and morphine reduces pain, inflammatory response and convalescenceafter arthroscopic meniscectomy. Pain. 1998;78:131–134.
83. Wang JJ, Ho ST, Lee SC, et al. Intraarticular triamcinolone acetonide for pain control after arthroscopic knee surgery. Anesth Analg. 1998;87:1113–1116.
84. Joshi W, Reuben SS, Kilaru PR, et al. Postoperative analgesia for outpatient arthroscopic knee surgery with intraarticular clonidine and/or morphine. AnesthAnalg. 2000;90:1102–1106.
85. Dal D, Tetik O, Altunkaya H, et al. The efficacy of intra-articular ketamine for postoperative analgesia in outpatient arthroscopic surgery. J Arthrosc Relat Surg.
Multimodal Systemic and Intra-articular Analgesics ' 133 86. Whitford A, Healy M, Joshi GP, et al. The effect of tourniquet release time on the analgesic efficacy of intraarticular morphine after arthroscopic knee surgery. AnesthAnalg. 1997;84:791–793.
87. Klinken C. Effects of tourniquet time in knee arthroscopy patients receiving intraarticular morphine combined with bupivacaine. CRNA. 1995;6:37–42.
88. Marchal JM, Delgado-Martinez AD, Poncela M, et al. Does the type of arthroscopic surgery modify the analgesic effect of intraarticular morphine and bupivacaine?A preliminary study. Clin J Pain. 2003;29:240–246.
89. Singelyn F, Lhotel L, Fabre B. Pain relief after arthroscopic shoulder surgery: a comparison of intraarticular analgesia, suprascapular nerve block, and interscalenebrachial plexus block. Anesth Analg. 2004;99:589–592.
90. Coghlan JA, Forbes A, McKenzie D, et al. Efficacy of subacromial ropivacaine infusion for rotator cuff surgery. J Bone Joint Surg. 2009;91:1558–1567.
91. Harvey GP, Chelly JE, AlSamsam T. Patient-controlled ropivacaine analgesia after arthroscopic subacromial decompression. J Arthrosc Relat Surg. 2004;20:451–455.
92. Boss AP, Maurer T, Seiler S, et al. Continuous subacromial bupivacaine infusion for postoperative analgesia after open acromioplasty and rotator cuff repair: preliminaryresults. J Shoulder Elbow Surg. 2004;13:630–634.
93. Bailie DS, Ellenbecker TS. Severe chondrolysis after shoulder arthroscopy: a case series. J Shoulder Elbow Surg. 2009;18:742–747.
94. Gomoll AH, Kang RW, Williams JM, et al. Chondrolysis after continuous intra- articular bupivacaine infusion: an experimental model investigating chondrotoxicityin the rabbit shoulder. J Arthrosc Relat Surg. 2006;22:813–819.
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