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DISCLAIMER: These guidelines were prepared by the Department of Surgical Education, Orlando Regional Medical Center. Theyare intended to serve as a general statement regarding appropriate patient care practices based upon the available medical literatureand clinical expertise at the time of development. They should not be considered to be accepted protocol or policy, nor are intendedto replace clinical judgment or dictate care of individual patients.PAIN MANAGEMENT IN THE SURGICAL PATIENTSUMMARYAdequate pain relief is essential to not only patient comfort, but also pulmonary toilet and wound healing.In the surgical patient, pain is best relieved using a combination of pharmacologic agents including opioidanalgesics, non-opioid analgesics (such as non-steroidal anti-inflammatory drugs or NSAIDS), localanesthetics, and analgesic adjuvants.RECOMMENDATIONS Level 1 None Level 2 A patient’s pain medication regimen should be constantly evaluated and adjusted asneeded to achieve appropriate pain control while avoiding oversedation. For enteral opioid therapy, a combination of a sustained-release formulation for longacting pain control and an immediate-release formulation for breakthrough pain ispreferred. For parenteral opioid therapy, morphine, fentanyl or hydromorphone should be utilizedin titrated doses as indicated. Enteral pain medication therapy should be initiated as soon as the patient is able totolerate such medications. COX-2 inhibitors and non-selective NSAIDS should be avoided in patients with or at highrisk for thrombotic cardiovascular events (see Appendix I). Level 3 NSAIDS and COX-2 inhibitors should not be used in patients with renal dysfunction,hypovolemia, or active gastrointestinal hemorrhage. NSAIDS and COX-2 inhibitors should not be used in patients with acute orthopedicfractures unless the benefit outweighs the potential risk.INTRODUCTION“Pain” may be defined as “an unpleasant sensory and emotional experience associated with actual orpotential tissue damage, or described in terms of such damage”. “Analgesia” is defined as the blunting orabsence of sensation of pain or noxious stimuli. Pain and physical discomfort is common in the surgicalpatient as a result of injury, invasive procedures, or preexisting illnesses. It may also be caused bymonitoring and therapeutic devices (such as invasive catheters, drains, and tubes), routine patient care(such as airway suctioning, physical therapy, dressing changes, and patient mobilization), and prolongedimmobility (1). Unrelieved pain may contribute to patient discomfort, anxiety, exhaustion, disorientation,agitation, tachycardia, increased myocardial oxygen consumption, pulmonary dysfunction,immunosuppression, and persistent catabolism. Effective pain control, in addition to improving patientEVIDENCE DEFINITIONS Class I: Prospective randomized controlled trial. Class II: Prospective clinical study or retrospective analysis of reliable data. Includes observational, cohort, prevalence, or casecontrol studies. Class III: Retrospective study. Includes database or registry reviews, large series of case reports, expert opinion. Technology assessment: A technology study which does not lend itself to classification in the above-mentioned format. Devicesare evaluated in terms of their accuracy, reliability, therapeutic potential, or cost effectiveness.LEVEL OF RECOMMENDATION DEFINITIONS Level 1: Convincingly justifiable based on available scientific information alone. Usually based on Class I data or strong Class IIevidence if randomized testing is inappropriate. Conversely, low quality or contradictory Class I data may be insufficient to supporta Level I recommendation. Level 2: Reasonably justifiable based on available scientific evidence and strongly supported by expert opinion. Usually supportedby Class II data or a preponderance of Class III evidence. Level 3: Supported by available data, but scientific evidence is lacking. Generally supported by Class III data. Useful foreducational purposes and in guiding future clinical research.1Approved 5/08/2001Revised 4/08/2003, 6/21/2005, 10/11/2009, 09/30/2015

comfort, may also decrease the incidence of many complications (such as pulmonary dysfunction) in thepostoperative patient.The patient’s perception of pain plays a major role in its control. A realistic goal for pain management inthe surgical patient is to minimize the sensation of pain rather than eliminate it. Pain may be alleviatedthrough the combined use of analgesics (addressed in this evidence-based medicine guideline) andsedatives (addressed in the guidelines on control of agitation and delirium). Patient education and patientphysician communication can play as important and effective a role in relieving pain as the actualpharmaceutical agents prescribed. No medication regimen can overcome the unrealistic expectations ofthe uninformed patient.A patient senses pain through the afferent pain pathway in the peripheral tissues whose signal ends in thesomatosensory cortex. Tissue injury leads to a release of inflammatory mediators (i.e. substance p, PGEs,serotonin, & ACH) which activate this pathway. These various substances and pathways are the targets ofmany of the pharmacologic agents that follow.Pain can be divided into two types based upon its etiology. Acute pain follows injury and generally resolveswhen the bodily injury heals. It is commonly associated with physical signs such as tachycardia,hypertension, diaphoresis, mydriasis, and pallor. Chronic pain may be acute, chronic, or intermittent, isusually associated with a definable etiology, and is rarely associated with physical signs.Although controversial due to its subjective nature, pain can be considered the “fifth vital sign” as quotedby JCAHO in 2001, and should be documented during each patient assessment. These standards aroseas a multitude of studies demonstrated that hospitals were grossly undertreating pain. A variety of tools andassessment scales have been advocated to document the degree of pain. The most reliable and validindicator of pain has been shown to be the patient’s self-report. In the comatose or unresponsive patient,however, the physician must infer the patient’s level of pain based upon clinical experience andinterpretation of the patient’s physiologic parameters.Perhaps the most widely known scale is the Visual Analog Scale for pain or VAS. The drawback to thisscale is that it requires written responses. The Numeric Rating Scale or NRS, however, can be completedverbally or graphically. It is similar to the VAS, but utilizes a scale from 0 to 10 with zero representing “nopain” and ten being “the worst pain imaginable”2Approved 5/08/2001Revised 4/08/2003, 6/21/2005, 10/11/2009, 09/30/2015

Pain is prevented and/or treated using various pharmaceutical agents. These medications can be dividedinto four general categories:1. Non-opioid analgesics (aspirin, acetaminophen, NSAIDS)2. Opioid analgesics (morphine, hydromorphone, fentanyl, oxycodone, hydrocodone)3. Local anesthetics (lidocaine, bupivacaine)4. Analgesic adjuvants (tricyclic antidepressants, antihistamines, benzodiazepines, steroids,phenothiazines, anticonvulsants, clonidine)Non-opioid AnalgesicsAspirin and other salicylates, acetaminophen, and NSAIDS are useful for treating both acute and chronicpain due to a variety of etiologies including surgery, trauma, arthritis, and cancer. These drugs act primarilyby inhibiting the enzyme cyclooxygenase, namely COX-1 & COX-2 (except acetaminophen), preventingthe formation of prostaglandins that tend to sensitize peripheral nerves and central sensory neurons topainful stimuli. They do not promote tolerance or physical or psychological dependence. They have theadded effect of being antipyretic. Both aspirin and NSAIDS may cause gastric disturbances andhemorrhage that can limit their usefulness in certain patients, and can inhibit platelet activity, which can bedetrimental in the surgical patient.Acetaminophen has no antiplatelet activity, few anti-inflammatory effects, and does not damage the gastricmucosa. The recommended therapeutic dose is 325-1000 mg per dose in adults. Furthermore, themaximum recommended dose is 4 gm per day in adults. Acetaminophen poisoning is one of the mostcommon causes of medication-related poisoning and death. However, this toxic level may vary amongpatients depending on their baseline glutathione levels and other factors. Clinical studies show that evenat levels 7.5 to 10 gm per day, toxicity is unlikely. Acetaminophen poisoning may occur following a singleingestion or through repeated ingestion of supratherapeutic amounts. Excessive doses can cause hepaticnecrosis and must be kept in mind as many of the oral opioid preparations contain acetaminophen and thecumulative acetaminophen dose is frequently under recognized.NSAIDS inhibit platelet aggregation by reversibly inhibiting prostaglandin synthetase (unlike aspirin whosebinding is irreversible). Such agents must therefore be taken “around-the-clock” as opposed to “as needed”in order to be effective. Anticoagulation, coagulopathy, and the presence of thrombocytopenia are allrelative contraindications to the use of NSAIDS. NSAIDS are associated with dose-independentgastrointestinal complications such as ulceration, bleeding, and perforation. The risk of gastrointestinalcomplications increases with a history of gastrointestinal ulcers, high dose NSAID use, age 60 years,concurrent use of steroids and anticoagulants. NSAID therapy is commonly accompanied by administrationof either H2-blocker or proton pump inhibitor therapy in an attempt to avoid these complications. NSAIDScan also induce renal insufficiency, especially in the presence of dehydration. NSAID inhibition ofcyclooxygenase with subsequent reduction in PGE synthesis leads to renal ischemia and decreased GFRthereby causing acute kidney injury.A drug class that selectively inhibits the COX-2 isoform of cyclooxygenase (the isoenzyme associated withinflammation) is available. This class purportedly avoids inhibition of the COX-1 isoenzyme that isassociated with renal and gastric side effects. Prospective, randomized controlled studies comparing theCOX-2 inhibitors with standard NSAID therapy demonstrate equivalency of these medications, but with adecreased incidence of gastrointestinal side effects including perforation, bleeding, and ulceration (2,3).Despite the initial enthusiasm regarding the pharmacologic benefits of selective COX-2 inhibition, significantsafety concerns have emerged resulting in the removal of two such agents from the market. COX-2inhibitors, like standard NSAIDS, can cause renal failure (especially in patients with pre-existing dysfunctionor hypovolemia) and are associated with potentially life-threatening gastrointestinal bleeding. Additionally,they are associated with an increase in the potential for thrombotic cardiovascular events by creating animbalance between the prothrombotic properties of thromboxane A2 and the antithrombotic properties ofprostacyclin (PGI2). Finally, the use of COX-2 inhibitors for the treatment of acute pain following traumaticmusculoskeletal injury has become a controversial practice due to a growing body of literature suggestingthat NSAIDS interfere with fracture healing and may be associated with an increased incidence of nonunion. Although the mechanism of these adverse effects is not fully understood, it is postulated that3Approved 5/08/2001Revised 4/08/2003, 6/21/2005, 10/11/2009, 09/30/2015

decreased prostaglandin synthesis and inhibition of the initial inflammatory response are responsible.There may also be a direct effect on osteoblast proliferation, differentiation or maturation.TABLE I: SELECTED NON-OPIOID imalDaily DoseAnalgesicEfficacyCompared nol)500-1000 mg4-64000 mgComparable toaspirin2-3Rectal and sustainedrelease preparationavailable.Aspirin(ASA)500-1000 mg4-64000 mg0.25Not for use in children.Rectal and sustainedrelease preparationavailable.Ibuprofen(Motrin, Advil)200-400 mg4-62400 mg500 mg initial,250 mgsubsequent8-121250 mg30 mg equivalentto 6-12 mgmorphine6Limit treatment to 5 days.May precipitate renalfailure in dehydratedpatients.Less effectivethan ibuprofen11Avoid in sulfa allergies.Caution in liver and olac(Toradol)30-60 mg IM or30 mg IV initial,15-30 mg IM orIV subsequent6150 mg first day,120 mgsubsequentCelecoxib(Celebrex)100-200 mg12-24400 mg200 mg superiorto ASA 650 mg2-2.512-15* All doses are oral unless otherwise specified.Opioid Analgesics (1,4)Opioid analgesics relieve pain by interacting with a variety of central and peripheral opioid receptors. Theseagents are typically added to non-opioid analgesics when the patient’s pain does not respond to non-opioidsalone. A common mistake is substituting one class of agent for the other. Both classes work wellsynergistically through their differing mechanisms of action. For this reason, opioids are commonlymarketed in combination with a non-opioid analgesic such as aspirin or acetaminophen.Opioids may be administered by a variety of methods (orally, rectally, intramuscularly, intravenously,subcutaneously, transdermally). The onset of action, peak effect, and duration varies by method. For oral(PO) administration (with the exception of sustained-release formulations), peak drug effect occurs within90-120 minutes. Patients with inadequate pain control after an initial opioid dose may safely take a seconddose 2 hours after the first dose. Rectal (R) opioid formulations are useful in the patient who is unable totake PO medications. Intramuscular (IM) administration is marked by painful injection, variable absorption,delayed onset, and decreased duration of effect. Such injections should be avoided in the patient withinadequate perfusion and shock, as bolus opioid absorption may occur once perfusion is restored,potentially resulting in over sedation and respiratory depression.Intravenous (IV) administration has the most rapid onset of effect with the time to peak effect varyingaccording to the lipid solubility of the drug. Duration of action is shorter than for other methods, butadditional doses may be given earlier as a result. Continuous opioid infusions, or “patient controlledanalgesia” (PCA) provides for maintenance of steady blood drug levels and effective control of severe pain.Transdermal (TD) administration is slow in onset (12-24 hours) and long in duration making this methodespecially useful for control of chronic pain. This method is less effective in the patient with acute pain asrapid titration of drug to effect is not possible.The selection and administration of an individual opioid agent is dependent upon its pharmacology, potentialside effects, and indications for use. The most commonly utilized opioids are listed in Table II. Of theintravenous opioids, fentanyl has the most rapid onset and shortest duration of effect. It has minimal effects4Approved 5/08/2001Revised 4/08/2003, 6/21/2005, 10/11/2009, 09/30/2015

on systemic blood pressure making it particularly useful in the hemodynamically unstable patient. Repeatedadministration can lead to drug accumulation and prolonged side effects. Morphine, perhaps the mostcommonly used intravenous opioid, has a longer duration of action making intermittent dosing efficacious.Morphine, however, can cause hypotension in the hemodynamically unstable or hypovolemic patient as aresult of peripheral vasodilation and an active metabolite may accumulate in patients with renalinsufficiency. Hydromorphone has a similar duration of effect as morphine, but it lacks an active metaboliteand is not associated with histamine-mediated vasodilatation. Meperidine’s metabolite, normeperidine, isa central nervous system excitotoxin that causes anxiety, tremors, myoclonus, and generalized seizureswith accumulation. As meperidine and normeperidine are renally excreted, such side effects are a concernin patients with decreased renal function. Meperidine should also be used with caution in patients receivingmonoamine oxidase inhibitors as the combination of these two drugs can lead to a hyperpyrexic syndromewith delirium. Of note, the American Pain Society and International Society for the Management of Pain donot recommend meperidine’s use as an analgesic. If used in acute pain (in patients without renal or CNSdisease) cannot be avoided, treatment should be limited to 48 hours and doses should not exceed 600mg/24 hours. The oral route is not recommended for treatment of acute or chronic pain. If the intravenousroute is required, consider a reduced dose.Opioid therapy may be initiated using the recommended initial doses from Table II. Therapy should betitrated to achieve control of the patient’s acute pain using opioids with a relatively rapid onset of effects.Once a patient’s opioid requirement for a 24-hour period has been determined, longer acting opioidanalgesics can be administered on a scheduled around-the-clock basis achieving “smoother”, moreefficacious pain control with fewer side effects. Essential to this method is provision for a supplementary,rapid-acting opioid for “break-through” pain in addition to the scheduled sustained release formulations. Ingeneral, approximately two-thirds of the patient’s estimated opioid dose should be administered as asustained-release formulation with the remaining one-third prescribed as an immediate-release formulationto be administered every 2 hours as needed. As with any drug therapy, the efficacy of the medicationregimen must be constantly assessed and altered as needed to achieve the intended effect.The most common side effects encountered with the use of opioids include sedation, constipation, nausea,vomiting, itching, and respiratory depression. These potentially detrimental effects of therapy areassociated with high peak serum levels that are avoided through the use of sustained-release preparationsor continuous intravenous infusions. Patients with impaired renal and hepatic function are at particular riskfor developing side effects as the opioids are commonly metabolized and excreted by these two organs. Insome patients, switching to a different opioid may also decrease the incidence of side effects. All patientson narcotics should be placed on a bowel regimen to prevent opioid induced constipation. Opioids decreasegastrointestinal motility though activity on opioid receptors in the GI tract as well as the brain. Therapeuticoptions include, increasing fiber & fluid intake, increasing activity, or initiating a stool softener, stimulant orcombination. Most recently in the literature, Alvimopan or “Entereg” a new and promising GI motility agentwas introduced. Alvimopan is a drug which behaves as a peripherally acting mu-opioid antagonist. It haslimited ability to cross the blood-brain barrier and therefore combats constipation without affecting thepatient’s analgesia or precipitating withdrawal. It is approved for short term, inpatient use only. The cost ofthis medication is significant and the data supporting its efficacy is limited as yet.5Approved 5/08/2001Revised 4/08/2003, 6/21/2005, 10/11/2009, 09/30/2015

TABLE II: EQUIANALGESIC OPIOID DOSE CHARTMedicationMorphine(MSO4,Oramorph SR,MS done(Vicodin, Lortab)Hydromorphone(Dilaudid)Meperidine(Demerol) **Oxycodone(Percocet, Tylox,Oxycontin, in)Duration(hr)Half-life(hr)10 mg30 mg30-60 (PO)30-60 (CR)230-60 (R)5-10 (IV)10-20 (SC)10-20 (IM)60-90 (PO)90-180 (CR)260-90 (R)15-30 (IV)30-60 (SC)30-60 (IM)3-6 (PO)8-12 (CR)24-5 (R)3-4 (IV)1,33-4 (SC)3-4 (IM)2-4100 mcg/hr IV orTD 4 mg/hrmorphine IV;1 mcg/hr TD morphine 2mg/24 hr PO---5 (OT)1-5 (IV)7-15 (IM)12-16 hr (TD)15 (OT)3-5 (IV)10-20 (IM)24 hr (TD)2-5 (OT)0.5-4 (IV)1,30.5-4 (IM)48-72 (TD)130 mg200 mg30-60 (PO)10-20 (SC)10-20 (IM)60-90 (PO)unknown (SC)30-60 (IM)3-4 (PO)3-4 (SC)3-4 (IM)2-4---30 mg5NR30-60 (PO)60-90 (PO)4-6 (PO)41.5 mg7.5 mg15-30 (PO)15-30 (R)5 (IV)10-20 (SC)10-20 (IM)30-90 (PO)30-90 (R)10-20 (IV)30-90 (SC)30-90 (IM)3-4 (PO)3-4 (R)3-4 (IV)1,33-4 (SC)3-4 (IM)2-375 mg300 mgNR30-60 (PO)5-10 (IV)10-20 (SC)10-20 (IM)60-90 (PO)10-15 (IV)15-30 (SC)15-30 (IM)2-4 (PO)2-4 (IV)1,32-4 (SC)2-4 (IM)2-3---20 mg30-60 (PO)30-60 (CR)730-60 (R)60-90 (PO)90-180 (CR)730-60 (R)3-4 (PO)8-12 (CR)73-6 (R)2-34.5 (CR)63-4413-24 (TD)From McCaffery M, Pasero C: Pain: Clinical Manual, pp.241-243. Copyright ÆÉ 1999, Mosby, Inc.CR – oral controlled-release; IM – intramuscular; IV – intravenous; OT – oral transmucosal; PO – oral; R – rectal; SC –subcutaneous; TD – transdermal; NR – not recommended; hr – hours; min - minutes1Duration of analgesia is dose dependent; the higher the dose, usually the longer the duration.2As in, e.g., MS Contin.3IV boluses may be used to produce analgesia that lasts approximately as long as IM or SC doses. However, of all routes ofadministration, IV produces the highest peak concentration of the drug, and the peak concentration is associated with thehighest level of toxicity (e.g. sedation). To decrease the peak effect and lower the level of toxicity, IV boluses may beadministered more slowly (e.g., 10 mg of morphine over a 15 minute period) or smaller doses may be administered more often(e.g., 5 mg morphine every 1-1.5 hours).4At steady state, slow release of fentanyl from storage in tissues can result in a prolonged half-life of up to 12 hr.5Equianalgesic data not available.6The recommendation that 1.5 mg of parenteral hydromorphone is approximately equal to 10 mg of parenteral morphine isbased on single dose studies. With repeated dosing of hydromorphone (e.g., PCA), it is more likely that 2-3 mg of parenteralhydromorphone is equal to 10 mg of parenteral morphine.7As in, e.g., OxyContin**Not recommended for use as an adjunct to acute or chronic pain“Tolerance” refers to the need for increasing doses of opioid analgesic to maintain the original effect. Thisis a common finding in virtually all patients on chronic opioid analgesics. The first sign of tolerance may bea decrease in the duration of effective analgesia. “Withdrawal” refers to the development of anxiety,6Approved 5/08/2001Revised 4/08/2003, 6/21/2005, 10/11/2009, 09/30/2015

tachycardia, sweating, and other autonomic symptoms occurring with the abrupt discontinuation of anopioid drug. Such symptoms can be avoided by slowly tapering the dose downward prior to discontinuingtherapy altogether. Symptoms may also be lessened by administration of a transdermal clonidine patchdelivering 0.1-0.2 mg/day.Local Anesthetics (5)Peripheral use of local anesthetics for prophylaxis against postoperative pain and as an adjunct to nonopioid and opioid analgesics is becoming increasingly popular. With the trend towards performing manysurgical procedures on an outpatient basis, local anesthetic infiltration either during or at the conclusion ofthe procedure has been proposed as one method by which to improve postoperative pain control. A largemeta-analysis of randomized trials found statistically significant decreases in analgesic consumption andincreased time to first rescue analgesic request, but no difference in postoperative pain scores in patientswho had preincisional local anesthetic infiltration. In laparoscopic surgery, a multitude of trials have beenperformed evaluating the use of local anesthetics. Unfortunately, the methodology behind these trials hasbeen quite variable making comparisons and systematic analysis difficult. Overall, there is insufficientagreement in these trials to make clear recommendations regarding intraperitoneal, port-site, orsubcutaneous infiltration using local anesthetic agents.Analgesic Adjuvants (4)A variety of medications can be utilized to either enhance the effects of opioid analgesics or counteracttheir side effects. Occasionally, these agents may actually have pain-relieving properties of their own.These medications are discussed below.TABLE III: ANALGESIC ADJUVANTSMedicationTricyclic antidepressants(amitriptyline, imipramine, ne)Benzodiazepines(diazepam, lorazepam)SteroidsPhenothiazines(chlorperazine, prochlorperazine)Anticonvulsants(gabapentin, phenytoin, carbamazepine,clonazepam)ClonidineTherapeutic EffectUsed to treat neuropathic pain.May potentiate opioids.No data to support use in acute pain.Contraindications / SideEffectsPatients with coronary artery disease,conduction abnormalities. Amitriptylinecan cause sedation, anticholinergiceffects. Nortriptyline and desipraminecan cause insomnia.Has mild analgesic (IM), antiemetic, andsedative activity.Effective for acute anxiety or musclespasm associated with acute pain.Can ameliorate painful nerve or spinalcord compression by reducing edema.Useful in treating anxiety / agitationMay relieve brief lancinating pains arisingfrom peripheral nerve syndromes suchas trigeminal neuralgia, diabeticneuropathy, postherpetic neuralgia,glossopharyngeal neuralgia, andposttraumatic neuralgia.Useful as an epidural infusion forneuropathic painCan cause sedation and respiratorydepressionCan increase the risk of GI bleeding,especially when used in combination withNSAIDS.Rapid withdrawal may exacerbate pain.Prolonged use may lead to tardivedyskinesiaRarely may cause hypotension andbradycardiaLITERATURE REVIEWProspective, randomized comparative trials or evidence-based medicine guidelines of opioid therapy in themanagement of postoperative pain are lacking. The existing evidence for this therapy is based upon smallclinical trials, consensus statements, widespread clinical practice, and expert opinion. As a result, no Level1 recommendations can be made at this time. Further, an attempt to review the numerous analgesic studiesand clinical trials that have been performed over the years is beyond the intent of these guidelines. Thefollowing are literature reviews of two areas of current controversy in the management of acutepostoperative / posttraumatic pain. The evidence-based medicine algorithm that follows addresses thevarious analgesic medication classes and their appropriate use in pain management for the surgical patient.7Approved 5/08/2001Revised 4/08/2003, 6/21/2005, 10/11/2009, 09/30/2015

Non-selective NSAIDS and Bone HealingGiannoudis et al. performed a retrospective study evaluating factors affecting bone union in patients withfemoral shaft fractures (6). Non-union occurred in 32/377 (9%) patients. Sixty-seven patients with fractureunion served as a control group. There was more NSAID use in the nonunion group (63%) compared withthe union group (13%). The odds ratio for nonunion was 10.7 (95% CI 3.55-33.23). The reliability of theseresults has been questioned due to inaccuracy of the outcome measures used to define union and failureto include detail regarding NSAID administration. Additionally, baseline characteristics were variablebetween groups making it difficult to attribute non- or delayed union to NSAIDS alone (Class III).COX-2 Inhibitors and Bone HealingLong et al. investigated the effect of COX-2 specific inhibitors on spinal fusion in 66 New Zealand Whiterabbits (7). A single level posterolateral intertransverse process arthrodesis was performed bilaterally atthe level of the fifth and sixth lumbar segment with bone from both iliac crests. Seventy-two rabbits wererandomized to receive either celecoxib (10 mg/kg), indomethacin (10 mg/kg), or placebo daily for eightweeks. Following the 8-week treatment course, the lumbar spines were harvested and evaluated with grosspalpation, radiographs, and histological analysis. All analyses were blinded. Results of gross examinationrevealed that fusion rates in the control and celecoxib groups were significantly better than in theindomethacin group. Radiographic assessment demonstrated a significantly lower fusion rate in theindomethacin group compared with the control group. Finally, the histologic scores were significantly betterin the control group than in the indomethacin group. No significant difference was found between the controland celecoxib groups. The authors concluded that celecoxib does not significantly inhibit the rate of spinalfusion in rabbits and that impaired of bone healing is likely mediated by inhibition of COX-1.In contrast to the previous trial, the results of a smaller study demonstrate that bone growth is impaired byCOX-2 inhibition (8). Goodman and colleagues examined the effects of a non-specific COX inhibitor versusa COX-2 inhibitor on bone ingrowth and tissue differentiation in eight rabbits. Subjects receiving eithernaproxen or rofecoxib had significantly less bone ingrowth when compared to placebo. There was nosignificant difference between naproxen and rofecoxib. Simon et al. conducted a study assessing theeffects of COX-2 inhibition on femur fracture healing in a rat model (9). The four treatment arms includedplacebo, indomethacin, celecoxib, or rofecoxib. Drug administration began two days prior to fracture.Radiographic analysis demonstrated that healing was delayed with indomethacin and inhibited withcelecoxib and rofecoxib. Mechanical testing data revealed that healing was delayed with both indomethacinand rofecoxib. There were no significant differences between the celecoxib and placebo treated rats.Histologic evaluation revealed that both indomethacin and the COX-2 inhibitors resulted in abnormalcartilage formation. The authors concluded that COX-2 function is essential for fracture healing.COX-2 Inhibitors and Adverse Cardiovascular EventsMukherjee et al. analyzed the randomized trials that have evaluated whether COX-2 inhibitors areassociated with an increased risk of cardiovascular events (10). These include the Vioxx GastrointestinalOutcomes Research Study (VIGOR), Celecoxib Arthritis Safety Study (C

A patient's pain medication regimen should be constantly evaluated and adjusted as needed to achieve appropriate pain control while avoiding oversedation. For enteral opioid therapy, a combination of a sustained-release formulation for long-acting pain control and an immediate-release formulation for breakthrough pain is preferred.