Pain

Managing Pain in Trauma Surgery Patients

ABSTRACT: Major advances have been made in caring for trauma surgery patients, including in managing their pain. It is well-known that effective pain management is crucial for optimizing patient outcomes and quality of life. This review focuses on the management of perioperative pain resulting from acute or chronic injuries in the trauma setting, with particular emphasis on pharmacologic options and special considerations for pediatric and geriatric populations. 

KEYWORDS: Trauma, surgery, pain management, acute pain, chronic pain, pharmacologic interventions, invasive techniques, noninvasive techniques, pediatrics, geriatrics
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Trauma accounts for more than 41 million emergency department visits and 2.3 million hospital admissions in the United States annually.1 In 2014, traumatic injuries accounted for 30% of all US life-years lost.2 Because trauma affects people of all ages, its impact on life-years lost is equal to the life-years lost from cancer, heart disease, and HIV combined.1 The number of trauma patients requiring surgery is significant. The CDC estimates that approximately 15% of trauma patients require emergency surgery.1 In the trauma setting, common surgical emergencies include orthopedic, vascular, and skin injuries; burns; massive upper GI hemorrhage; perforated abdominal viscus; and rectal bleeding.3

In recent years, major advances have been made in treating trauma surgery patients, leading to a significant reduction in morbidity and mortality.4 One major advance has been in the area of postoperative pain management. This article provides an overview of the management of perioperative pain following an acute or chronic traumatic injury. Particular emphasis is placed on pharmacologic options, but pain management considerations in special patient populations, including geriatric and pediatric patients, are also discussed.

ANALGESICS

Analgesics are often the first line of defense against pain. These agents stop pain signals from reaching the brain or alter how the brain interprets these signals. The 2 primary types of analgesics are nonopioids and opioids. Milder pain typically can be managed with nonopioids, whereas severe pain often requires opioids or a combination of pain medicines (Table).

steps to treat pain

Nonopiods

Numerous nonopioid medications can be used to treat perioperative pain in trauma patients. Among the most useful are acetaminophen and NSAIDs. 

Acetaminophen is typically used to treat mild postoperative pain. Its mechanism of action is not yet entirely understood; however, it has been shown to selectively inhibit cyclooxygenase-2 (COX-2), an enzyme that speeds up the production of prostaglandins, which play a key role in promoting inflammation, fever, and pain.5 Acetaminophen crosses the blood–brain barrier intact and is unique among analgesics because it has both pain-relieving and antipyretic effects, making it ideal for managing postoperative pain and fever.6 Acetaminophen also has a neutral pH and a low affinity for plasma proteins, leading to low accumulation in the bloodstream and collecting ducts of the kidneys.7 The drug is available in regular-strength (325 mg) and extra-strength (500 mg) tablets. Current recommendations advise administering no more than 4000 mg of acetaminophen daily.8 Intravenous (IV) acetaminophen can be given every 4 to 6 hours as needed to relieve pain or reduce fever, and its dosage is based on age, weight, and response to treatment.9 Cost is an important consideration when administering IV acetaminophen. On average, each IV dose costs more than 10 times as much as an oral dose.10 A major benefit of IV acetaminophen, however, is that it may be administered before or during surgery.7 When given during surgery, it can serve as an effective analgesic in the early phase of the postoperative period. A major drawback of acetaminophen is that it is typically not sufficient to manage postoperative pain in trauma patients, and adjuvant medications are generally required.

Although NSAIDs are not technically a part of the analgesic family because of their anti-inflammatory effects, they are often treated as analgesics in clinical practice. NSAIDs are potent inhibitors of both COX-1 and COX-2 enzymes, both of which contribute to prostaglandin production.11 Prostaglandins sensitize nerves to pain and enhance pain perception.12 Research has shown that lowering prostaglandin levels can provide effective pain management, reduce the need for opioid medications, and improve postoperative pain relief after major surgeries.13 

NSAIDs are not risk-free. COX-1 receptors are present throughout the body but are found primarily on platelets, in the kidneys, and in the gastric mucosa,14 increasing the risks of bleeding, acute kidney injury, and gastric ulceration, respectively. To mitigate such risks, additional medications might be needed. Administration of proton-pump inhibitors (eg, lansoprazole) can decrease the erosive effects of NSAIDs on the gastric mucosa.14 Adequate IV hydration decreases the risks of acute renal failure and bleeding risks in trauma patients throughout the perioperative period. Another way to reduce the risk of NSAID-related adverse effects is to use a subclass of NSAIDs known as selective COX-2 inhibitors. One such agent is celecoxib, which has been associated with a lower rate of upper gastrointestinal complications compared with traditional NSAIDs.15 

Opioids

Opioids are the gold standard for treating severe pain and are often the only medications capable of relieving intense and unrelenting pain in trauma patients. These drugs exert their effects by interacting with mu, delta, or kappa opioid receptors, which are coupled to G1 proteins.16,17 They close N-type voltage-operated calcium channels and open calcium-dependent inwardly rectifying potassium channels, resulting in hyperpolarization and reduced neuron excitability.17 They also stimulate the release of nociceptive neurotransmitters.17,18 Opioids have no effect on motor or other sensory modalities.19 They occasionally produce euphoria or dysphoria, which are more common with short-acting opioids.7 Although analgesia is achieved without loss of consciousness, drowsiness is common, and overdose can lead to unconsciousness and respiratory depression.7 

Common opioids used in trauma surgery patients include morphine, hydromorphone, fentanyl, and oxycodone.20 Surgeons often rely on IV opioids to relieve pain immediately after surgery, but patients are switched to tablets once they are able to tolerate oral medications.20 Most hospitals also offer patient-controlled analgesia (PCA), enabling patients to self-administer certain dosages of opioids using a computerized pump. PCA is indicated to control pain associated with surgery, trauma, burns, and sickle cell crisis.21 Advantages of PCA include empowerment of the patient; immediate pain control; control of incident pain (eg, pain during dressing changes or physiotherapy); improved recovery and quality of care; decreased bed occupancy time, resulting in economic benefits; and patients viewing their hospital stay more favorably.21,22

 

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ANESTHETICS

Lidocaine is a commonly used local anesthetic and a class-IB antiarrhythmic drug that has many applications in trauma surgery. Due to its pain-relieving properties, quick onset of action (45-90 s), and relatively short duration (10-20 min), it is a mainstay of treatment for a number of minor surgical procedures.23 The elimination half-life of lidocaine is biphasic and approximately 90 to 120 minutes in most patients. Longer-acting agents such as bupivacaine have a half-life of approximately 160 minutes.24

The use of lidocaine during trauma surgery is hindered by fear of toxicity.7 Rare cases of systemic toxicity have been reported upon topical application to mucosal membranes and with lidocaine gel applied to burns in children.25,26 Despite these rare complications, lidocaine remains a mainstay in managing pain from traumatic injuries, such as burns and lacerations, and as a peripheral nerve block for minor procedures.7 Topical analgesics are also available for blunt trauma in the form of a patch.7 Adding epinephrine to lidocaine solutions for peripheral nerve block potentiates and prolongs the duration of subcutaneous infiltration by causing vasoconstriction and increases duration of analgesia by approximately 100% at concentrations of 1:50,000.27

Research performed at Northwestern University School of Medicine advocates the use of IV lidocaine to improve the quality of postoperative recovery after ambulatory laparoscopic surgery.28 Research has also shown that IV lidocaine reduces postoperative pain and opioid consumption in the postanesthesia care unit and decreases the length of hospital stay.29 IV lidocaine is also useful for ambulatory surgery patients.30

Ketamine is another anesthetic that can be considered for some patients. Unlike lidocaine, a local anesthetic, it is a dissociative anesthetic that controls pain by distorting pain perceptions and producing feelings of detachment (or dissociation) from oneself and the environment. It is an N-methyl-D-aspartate receptor (NMDA) antagonist that has generated great interest in pain research because of its lipid solubility, enabling it to rapidly cross the blood–brain barrier and provide quick onset of action.31 Studies have suggested that ketamine might be useful in reducing acute postoperative pain.32 Low doses of ketamine have also been shown to reduce opioid use and nausea and vomiting after surgery.32 Notable adverse effects include the production of a dissociative state within 1 minute of administration and concomitant amnesia and profound analgesia.33 While few studies have produced quality evidence for its use in an acute pain setting, a double-blind trial of 40 adult patients in India with acute pain from musculoskeletal trauma found that low-dose, subcutaneous infusion of ketamine provided better analgesia, less sedation, and less nausea and vomiting than intermittent morphine.34 Another prospective randomized trial that compared morphine and ketamine with morphine and placebo for severe acute pain in 73 trauma patients in France found the addition of ketamine to morphine significantly reduced morphine consumption.35 Further research on the use of ketamine to treat acute pain is warranted.

Regional anesthesia can serve as another effective strategy for reducing pain in trauma surgery patients. It entails injecting anesthetic medication near a collection of nerves to provide analgesia to only the region of the body requiring surgery. It is a particularly attractive option for patients who have sustained crush injuries, fractures, or burns.7 For upper extremity injuries, interscalene, supraclavicular, infraclavicular, and axillary nerve blocks provide excellent pain relief to specific areas of the shoulder, arms, hand, and forearm, respectively.7 For injuries involving the lower extremities, the lumbar and sciatic nerve plexuses are targeted.7 A lumbar plexus nerve block provides excellent analgesia to the entire anterior surface of the lower extremity, while a sciatic nerve block targets the posterior thigh and leg.7 Regional anesthesia can be given as an epidural or spinal block. In an epidural block, anesthetic medication is injected through a catheter into the epidural space, whereas in spinal anesthesia, the anesthetic medication is injected directly into the subarachnoid space. The onset of action for an epidural is approximately 25 to 30 minutes compared with 5 minutes for a spinal block.36 An epidural may be given anywhere along the spinal column, whereas a spinal block must be given below the level of the L2 vertebra to avoid piercing the spinal cord.37 Commonly used anesthetic medications include local anesthetics like lidocaine; however, opioids (eg, morphine or fentanyl) are also added to provide additional pain relief.38 Epidural and spinal anesthesia, alone or in combination with sedation or general anesthesia, enable physicians to perform a plethora of invasive surgical procedures.

ADJUVANTS

Adjuvants are medications that are generally not used to control pain but that can help alleviate pain in some patients. Commonly used adjuvants for managing pain in acute trauma patients include antidepressants, anticonvulsants, benzodiazepines, and corticosteroids.

Antidepressants

Selective serotonin reuptake inhibitors (SSRIs) are a class of antidepressants that may reduce chronic pain after surgery by alleviating depression and sleep deprivation in patients with traumatic injuries.39 A randomized controlled trial showed SSRI use to reduce postoperative neuropathic pain40; however, the effects of these drugs on patients undergoing surgery are unclear. One study showed surgery patients who had been previously taking SSRIs to be at increased risk of postoperative complications.41 The study analyzed the medical records of more than 530,000 patients at 375 US hospitals who took SSRIs and underwent surgery between 2006 and 2008.41 The study findings suggested an approximately 10% increased risk of surgical complications, such as bleeding.41 However, the study also stated that the patients being treated with SSRIs were more likely to be obese, have chronic pulmonary disease, and have depression, which are independent risk factors for postoperative complications.41 Nevertheless, SSRIs have been linked to platelet dysfunction, which could also explain their increased bleeding risk.42 Further research is needed to better determine the impact of SSRIs on surgical risk.

Anticonvulsants

Traumatic injuries that impact the peripheral or CNS can cause neuropathic pain that does not respond well to traditional pain therapies.43 Similarities between the pathophysiologic phenomena observed in some epilepsy models and in neuropathic pain models has led some physicians to use anticonvulsant drugs to manage the symptoms associated with neuropathic pain disorders.43 Anticonvulsants have also shown benefits in alleviating postoperative pain by modulating the postoperative neural changes that can contribute to pain.44 Drugs such as fosphenytoin, carbamazepine, and phenobarbital are older anticonvulsants that suppress spontaneous neuronal firing in the brain. They are typically used to prevent seizures in brain trauma patients requiring neurosurgery.45 Newer agents include gabapentin, topiramate, lamotrigine, tiagabine, and oxcarbazepine. A study that assessed gabapentin for controlling posttraumatic and postoperative pain in thoracic surgery patients in Hong Kong found that most achieved pain relief with gabapentin and that the drug was particularly useful in alleviating severe refractory chest wall pain.46 There is also some indication that anticonvulsant drugs may alleviate postoperative anxiety, accelerate postoperative functional recovery, and reduce chronic postsurgical pain.44 However, there are currently no formal guidelines on using anticonvulsants in the postoperative period.

Benzodiazepines

Benzodiazepines are a class of psychoactive drugs that have sedative, anticonvulsant, muscle relaxant, and amnesic actions. These effects are produced by the allosteric modification of GABA receptors, which increases the overall conductance of these inhibitory channels.47 In the surgery setting, the usefulness of benzodiazepines lies in their ability to alleviate psychological distress rather than reduce physical pain. When administered via IV, whether alone or in combination with pain medications, benzodiazepines can be a safe and effective regimen for many surgical procedures.48 These agents may also be given before an anesthetic to produce muscle relaxation and reduce patient anxiety during surgery preparation.49

Benzodiazepines may be especially useful in traumatic injuries resulting from the use of alcohol. In ICUs, alcohol withdrawal during the postoperative period is a common and serious condition that can be life threatening. Short-acting and longer-acting benzodiazepines, such as lorazepam and diazepam, respectively, provide effective prophylaxis for seizures and alcohol withdrawal symptoms.50 This is because alcohol and benzodiazepines have similar physiologic mechanisms in the body, with both agents potentiating the effects of the inhibitory neurotransmitter GABA.51

Corticosteroids

Corticosteroids (eg, prednisone, methylprednisolone, hydrocortisone, and dexamethasone) can be helpful in select groups of trauma surgery patients.7 These agents are useful in managing postoperative pain associated with spinal cord injuries, increased intracranial pressure, visceral distention, nerve compression, bone metastasis, soft tissue damage, and peripheral nerve injuries.7 Administration of stress doses of corticosteroids has become a common practice, such as the administration of 300 mg daily of hydrocortisone before surgery and for several days postoperatively.52 However, use of chronic corticosteroid therapy should be avoided preoperatively because it has been associated with several risks, including adrenal insufficiency during surgery.52

 

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RECENT ADVANCES IN POSTOPERATIVE PAIN MANAGEMENT

Within the last decade, major technologic breakthroughs have been made to advance the field of postoperative analgesia, including in molecular mechanisms, pharmaceutical products, routes and modes of delivery, alternative modes of analgesia, and organizational and procedural techniques.53 Molecular advances include the understanding that NMDA receptors play a key role in central sensitization, which has a transcription-independent and a transcription-dependent phase, both of which contribute to the long-term potentiation of pain.53 Since postoperative pain is mostly nociceptive, these measures aim to improve pain perception following surgical procedures.

Multimodal analgesia, first proposed 20 years ago, is another innovation that is now well established in clinical practice.54 The concept involves the coadministration of 2 or more analgesic medications intravenously, such as an NSAID combined with morphine, to provide additive and synergistic analgesia.54 Analgesic adjuvants sometimes have undesirable adverse effects but, when combined with opioids, enable lower narcotic dosing. Novel adjuvant medications include capsaicin, gabapentin, pregabalin, and dexmedetomidine.53 All have recently gained FDA approval and are widely used to manage postoperative pain.

Many mainstay analgesic medications that have been used for decades, such as morphine, are now available in extended-release (ER) formulations. ER formulations enable pain medications to be administered less frequently compared with immediate-release formulations of the same drug.55 Advancements have also aimed at overcoming the limitations of IV administration. The fentanyl iontophoretic transdermal system, a novel PCA system, was designed to enable analgesia to be administered through the skin by creating a low-intensity electrical field.55 The system has been approved by the FDA and is widely available. Studies have shown the transdermal system to be safe, effective, and well-tolerated by patients.55 Other advances in perioperative pharmacotherapy include improved local anesthetics and the creation of combination analgesics such as tapentadol.53

One of the most significant changes in surgical practice in the last 25 years has been the growth of ambulatory surgery.56 Sending these patients home with perineural, incisional, and intra-articular catheters to provide analgesia is a new and evolving area of postoperative pain management. Evidence suggests that these techniques are feasible and safe in the home environment if appropriate patients are selected and routine follow-up care is scheduled.56 

Trauma can exert an enormous amount of damage on the human body and is a significant cause of morbidity and mortality. Many trauma patients require surgery, either corrective or exploratory, which can exacerbate their pain. Effective pain management is a critical component of trauma care and has been associated with reduced morbidity and mortality, improved quality of life, and shorter hospital stays. Many advances in pain management over the past few decades have put a plethora of pain management options at the disposal of physicians and surgeons; thus, even the frailest patients should be able to achieve adequate pain control. However, the hope is that as research continues, pain management will eventually become genetically informed, enabling a truly personalized approach.

Pain management  is a critical component of surgical care. When pain is managed effectively, trauma patients are more comfortable, there is less morbidity and mortality, and long-tem outcomes are improved.7 In contrast, untreated or inadequately treated pain in the perioperative period intensifies the effect of trauma on nearly every system of the body, including the respiratory, cardiac, renal, GI, and neurological systems.7 Poorly treated pain significantly increases patient suffering and the risk of complications, including chronic pain syndrome (CPS).7,57

CPS is a neurologic sequela that can result when the body is exposed to repeated painful stimuli.57 It is a complex and poorly understood condition that can make it difficult for healthcare providers to provide effective pain management. To reduce the risk of this complication, pain should be aggressively managed in trauma surgery patients.

Nevertheless, several studies have shown disparities in pain management among this patient population. One study revealed that approximately 15% of emergency admissions either did not receive adequate pharmacologic pain management or did not receive it in less than 1 hour.58 Another study found a disparity between adequate pain control and patient age.59 In the study, elderly patients consistently received fewer analgesics than younger patients despite identical levels of pain.59 A prospective cohort study that included 450 trauma patients in the Netherlands indicated a possible disparity between physicians’ and patients’ perception of appropriate pain control.60 In the study, nearly two-thirds of trauma patients reported having moderate to severe pain upon hospital discharge.60

A variety of patient- and healthcare-related factors can account for inadequate pain control in surgical patients, including fear of addiction to narcotic medications, poor pain reporting, hemodynamic instability, and respiratory depression.7 Despite these concerns, inadequate pain management can be deleterious to the patient and have extreme ramifications. To optimize patient outcomes, surgical pain must be treated aggressively. Many options are available to control pain, including nonopioid and opioid analgesics, anesthetics, and adjuvants (eg, antidepressants and anticonvulsants).

Pain management can be especially challenging in certain trauma patients, but those at highest risk of suboptimal pain management are the very young and the very old. This is due to a variety of factors, including toxicity concerns, frailty, decreased physiologic reserves, and communication challenges. However, proper pain management in these patients, as with all patients, is essential for optimizing outcomes. What follows is a brief review of special considerations in these patients.

PEDIATRIC PATIENTS

Trauma surgery pediatric patients are consistently undertreated for their pain, a practice that often stems from a fear of overdose and toxicity to pain medications.61,62 Although the evidence continues to show that treating pain in children is safe, and guidelines are available to aid physicians in administering analgesics to pediatric patients, fear of toxicity remains in clinical practice.61-63

The primary cause of trauma requiring surgery in children is motor vehicle accidents. Ambulatory pain management should include parenteral analgesics as well as intramuscular morphine at a dosage of 0.1 mg/kg.64 Emergency personnel can use femoral nerve blocks on the scene in a child as young as 2 years before placing the child on a stretcher, operating table, or imaging table.64 Low-dose opioids should be used preoperatively or when transporting the patient.64 Ketamine and benzodiazepines are effective adjuncts to opioids and provide additional pain relief, anxiolysis, and anterograde amnesia for invasive procedures.49,65

Assessing pain in children can often be difficult. A number of scales have been devised to aid physicians in evaluating pain in pediatric patients. Such scales include the visual analogue scale, the FACES pain scale, and physiologic and behavior scales.66 The Neonatal Facial Coding System is considered to be the most reliable.67 After the patient’s pain has been approximated, medications may be given. In preoperative patients, nerve blocks are useful for chest or limb trauma.7 Patients with poor mental function must be closely watched for subtle signs of pain and should be examined routinely.7 In these patients, pain medication dosing should be gauged by close monitoring of signs of pain, such as abnormal vital signs.7 Morphine is considered a first-line treatment, whereas fentanyl is given if the patient is hemodynamically unstable. If the patient is uncooperative, epidural or spinal analgesia should be avoided. If the patient is cooperative, PCA is a viable option postoperatively.7 NSAIDs can be used in conjunction with opioids. As with all medications, pain medication dosages should be adjusted for body weight, age, and renal function.

GERIATRIC PATIENTS

The percentage of persons older than 65 years is increasing annually in the United States.68 The number of geriatric patients being treated in trauma centers is increasing accordingly.69 In 2007, 35% of surgical procedures were performed on patients 65 years or older, and approximately 42% of hospitalized geriatric patients required at least 1 invasive procedure during their hospital stay.70 As the population of geriatric persons continues to grow, it is reasonable to assume that these numbers will increase. 

The prevailing causes of traumatic injuries in geriatric patients include falls, motor vehicle accidents, burns, assault, domestic abuse, and penetrating trauma.71 Complications in geriatric patients are often multifactorial. Physiologic changes in the elderly include reduced immunity, decreased organ function, and metabolic changes.72 Due to decreased renal and liver function, the dosage of many medications must be reduced to prevent longer-lasting effects, delirium, decreased mobility, and longer hospital stays. Placing as little stress as possible on the body of geriatric patients is key when contemplating surgical intervention.

In recent years, there has been a growth in laparoscopic surgery, or keyhole surgery.73 Laparoscopy is far less invasive than open procedures, and patients experience shorter hospital stays, fewer complications, and less postoperative pain, but a laparoscopic approach might not always be possible. Regardless of which approach is taken, proper postoperative pain management is essential. Postoperative pneumonia is a leading cause of mortality in elderly patients undergoing thoracic or upper abdominal surgery due to decreased respiratory function from painful incisions.7 Effective treatment of such pain enables these patients to take deeper breaths, reduces the risk of atelectasis, and improves respiratory function.7 Conversely, overtreating pain with opioids reduces respiratory drive and level of consciousness, significantly increasing the risk of delirium, hypoxia, and aspiration.7 During surgery, catecholamines are released into the bloodstream as a natural response to pain and stress. Many of the drugs used to treat postoperative pain decrease epinephrine and norepinephrine. This is of particular importance to patients with coronary artery disease, as it lessens cardiovascular demand and can exacerbate postoperative myocardial ischemia and infarction.74 Adequate pain management also improves the rehabilitation process by enabling patients to become ambulatory much sooner in the course of the healing process.74

Stephen Winfield is a medical student at Saba University School of Medicine in the Caribbean.

John Folland is a medical student at Saba University School of Medicine in the Carribean.

Andrew Rosenthal, MD, is associate director of the division of trauma services at Memorial Regional Hospital in Hollywood, FL.

References:

  1. Injury prevention & control: data & statistics (WISQARS). CDC. www.cdc.gov/injury/wisqars/. Updated July 13, 2015. Accessed October 6, 2015.  
  2. Years of potential life lost (YPLL). CDC. www.cdc.gov/injury/wisqars/years_potential.html. Updated January 22, 2015. Accessed October 6, 2015. 
  3. Lamberti J. Common surgical emergencies. Arch Surg. 1974;108(6):882.
  4. Haynes AB, Weiser TG, Berry WR, et al; Safe Surgery Saves Lives Study Group. A surgical safety checklist to reduce morbidity and mortality in a global population. N Engl J Med. 2009;360(5):491-499. 
  5. Hinz B, Cheremina O, Brune K. Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man. FASEB J. 2008;22(2):383-390.
  6. Botting RM. Mechanisms of action of acetaminophen: is there a cyclooxygenase 3? Clin Infect Dis. 2000;31(suppl 5):S202-S210.
  7. Cohen SP, Christo PJ, Moroz L. Pain management in trauma patients. Am J Physical Med Rehabil. 2004;83(2):142-161.
  8. Krenzelok EP, Royal MA. Confusion: acetaminophen dosing changes based on NO evidence in adults. Drugs R D. 2012;12(2):45-48.
  9. Candiotti KA, Bergese SD, Viscusi ER, Singla SK, Royal MA, Singla NK. Safety of multiple-dose intravenous acetaminophen in adult inpatients. Pain Med. 2010;11(12):1841-1848.
  10. Ammar M. Intravenous acetaminophen—is it worth the cost? Cleveland Clinic Clinical Rx Forum. 2013;1(2):1,5-8.
  11. Brzozowski T, Konturek PC, Konturek SJ, et al. Classic NSAID and selective cyclooxygenase (COX)-1 and COX-2 inhibitors in healing of chronic gastric ulcers. Microsc Res Tech. 2001;53(5):343-353.
  12. Harvey RJ, Depner UB, Wässle H, et al. GlyR α3: an essential target for spinal PGE2-mediated inflammatory pain sensitization. Science. 2004;304(5672):884-887.
  13. Vadivelu N, Mitra S, Narayan D. Recent advances in postoperative pain management. Yale J Biol Med. 2010;83(1):11-25.
  14. Scheiman J. The use of proton pump inhibitors in treating and preventing NSAID-induced mucosal damage. Arthritis Res Ther. 2013;15 suppl 3:S5.
  15. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. JAMA. 2000;284(10):1247-1255.
  16. Al-Hasani R, Bruchas MR. Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology. 2011;115(6):1363-1381.
  17. Bovill JG. Mechanisms of actions of opioids and non-steroidal anti-inflammatory drugs. Eur J Anaesthesiol Suppl. 1997;15:9-15.
  18. Altier C, Zamponi GW. Signaling complexes of voltage-gated calcium channels and G protein-coupled receptors. J Recept Signal Transduct Res. 2008;28(1-2):71-81.
  19. Holzer P. Pharmacology of opioids and their effects on gastrointestinal function. Am J Gastroenterol Suppl. 2014;2(1):9-16.
  20. Garimella V, Cellini C. Postoperative pain control. Clin Colon Rectal Surg. 2013;26(3):191-196.
  21. Smythe M. Patient-controlled analgesia: a review. Pharmacotherapy. 1992;12(2):132-143.
  22. Cepeda MS, Farrar JT, Baumgarten M, Boston R, Carr DB, Strom BL. Side effects of opioids during short-term administration: effect of age, gender, and race. Clin Pharmacol Ther. 2003;74(2):102-112.
  23. Thomson PD, Melmon KL, Richardson JA, et al. Lidocaine pharmacokinetics in advanced heart failure, liver disease, and renal failure in humans. Ann Intern Med. 1973;78(4):499-508.
  24. Veering BT, Burm AGL, van Kleef JW, Hennis PJ, Spierdijk J. Epidural anesthesia with bupivacaine: effects of age on neural blockade and pharmacokinetics. Anesth Analg. 1987;66(7):589-593.
  25. Sharma SC, Rama PR, Miller GL, Coccio EB, Coulter LJ. Systemic absorption and toxicity from topically administered lidocaine during transesophageal echocardiography. J Am Soc Echocardiogr. 1996;9(5):710-711.
  26. Read JM, Bach PH. Sterile topical lignocaine jelly in plastic surgery: an assessment of its systemic toxicity. S Afr Med J. 1980;57(17):704-706.
  27. Sinnott CJ, Cogswell LP III, Johnson A, Strichartz GR. On the mechanism by which epinephrine potentiates lidocaine’s peripheral nerve block. Anesthesiology. 2003;98(1):181-188.
  28. De Oliveira GS Jr, Fitzgerald P, Streicher LF, Marcus R-J, McCarthy RJ. Systemic lidocaine to improve postoperative quality of recovery after ambulatory laparoscopic surgery. Anesth Analg. 2012;115(2):262-267.
  29. Farag E, Ghobrial M, Sessler DI, et al. Effect of perioperative intravenous lidocaine administration on pain, opioid consumption, and quality of life after complex spine surgery. Anesthesiology. 2013;119(4):932-940.
  30. McKay A, Gottschalk A, Ploppa A, Durieux ME, Groves DS. Systemic lidocaine decreased the perioperative opioid analgesic requirements but failed to reduce discharge time after ambulatory surgery. Anesth Analg. 2009;109(6):1805-1808.
  31. Kohrs R, Durieux ME. Ketamine: teaching an old drug new tricks. Anesth Analg. 1998;87(5):1186-1193.
  32. Loftus RW, Yeager MP, Clark JA, et al. Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery. Anesthesiology. 2010;113(3):639-646.
  33. Curran HV, Morgan C. Cognitive, dissociative and psychotogenic effects of ketamine in recreational users on the night of drug use and 3 days later. Addiction. 2000;95(4):575-590.
  34. Gurnani A, Sharma PK, Rautela RS, Bhattacharya A. Analgesia for acute musculoskeletal trauma: low-dose subcutaneous infusion of ketamine. Anesth Intensive Care. 1996;24(1):32-36.
  35. Galinski M, Dolveck F, Combes X, et al. Management of severe acute pain in emergency settings: ketamine reduces morphine consumption. Am J Emerg Med. 2007;25(4):385-390.
  36. Burm A. Clinical pharmacokinetics of epidural and spinal anaesthesia. Clin Pharmacokinet. 1989;16(5):283-311.
  37. Kopacz DJ, Neal JM, Pollock JE. The regional anesthesia “learning curve”. What is the minimum number of epidural and spinal blocks to reach consistency? Reg Anesth. 1996;21(3):182-190.
  38. Aslan B, Izdeş S, Kesimci E, Gümüş T, Kanbak O. Comparison of the effects of lidocaine, lidocaine plus tramadol and lidocaine plus morphine for intravenous regional anesthesia [in Turkish]. Agri. 2009;21(1):22-28.
  39. Lynch ME. Antidepressants as analgesics: a review of randomized controlled trials. J Psychiatry Neurosci. 2001;26(1):30-36.
  40. Dworkin RH, O’Connor AB, Audette J. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clinic Proc. 2010;85(3 suppl):S3-S14.
  41. Auerbach AD, Vittinghoff E, Maselli J, Pekow PS, Young JQ, Lindenauer PK. Perioperative use of selective serotonin reuptake inhibitors and risks for adverse outcomes of surgery. JAMA Intern Med. 2013;173(12):1075-1081.
  42. Hergovich N, Aigner M, Eichler HG, Entlicher J, Drucker C, Jilma B. Paroxetine decreases platelet serotonin storage and platelet function in human beings. Clin Pharmacol Ther. 2000;68(4):435-442.
  43. Tremont-Lukats IW, Megeff C, Backonja MM. Anticonvulsants for neuropathic pain syndromes: mechanisms of action and place in therapy. Drugs. 2000;60(5):1029-1052.
  44. Gilron I. Review article: the role of anticonvulsant drugs in postoperative pain management: a bench-to-bedside perspective. Can J Anaesth. 2006;53(6):562-571.
  45. Temkin NR. Prophylactic anticonvulsants after neurosurgery. Epilepsy Curr. 2002;2(4):105-107.
  46. Sihoe AD, Lee T-W, Wan IY, Thung K-H, Yim APC. The use of gabapentin for post-operative and post-traumatic pain in thoracic surgery patients. Eur J Cardiothorac Surg. 2006;29(5):795-799.
  47. Olsen RW, Betz H. GABA and glycine. In: Siegel GJ, Albers RW, Brady ST, Price DL, eds. Basic Neurochemistry: Molecular, Cellular, and Medical Aspects. 7th ed. New York, NY: Elsevier Academic Press; 2006:291-302.
  48. Loeffler PM. Oral benzodiazepines and conscious sedation: a review. J Oral Maxillofac Surg. 1992;50(9):989-997.
  49. Duggan M, Dowd N, O’Mara D, Harmon D, Tormey W, Cunningham AJ. Benzodiazepine premedication may attenuate the stress response in daycase anesthesia: a pilot study. Can J Anaesth. 2002;49(9):932-935.
  50. Spies CD, Rommelspacher H. Alcohol withdrawal in the surgical patient: prevention and treatment. Anesth Analg. 1999;88(4):946-954.
  51. Ticku MK. Alcohol and GABA-benzodiazepine receptor function. Ann Med. 1990;22(4):241-246.
  52. Garcia JEL, Hill GE, Joshi GP. Perioperative stress dose steroids: is it really necessary? ASA Monitor. 2013;77(11):32-35.
  53. Vadivelu N, Mitra S, Narayan D. Recent advances in postoperative pain management. Yale J Biol Med. 2010;83(1):11-25. 
  54. Buvanendran A, Kroin JS. Multimodal analgesia for controlling acute postoperative pain. Curr Opin Anaesthesiol. 2009;22(5):588-593.
  55. Katz N, Sun S, Johnson F, Stauffer J. ALO-01 (morphine sulfate and naltrexone hydrochloride) extended-release capsules in the treatment of chronic pain of osteoarthritis of the hip or knee: pharmacokinetics, efficacy, and safety. J Pain. 2010;11(4):303-311.
  56. Marshall SI, Chung F. Discharge criteria and complications after ambulatory surgery. Anesth Analg. 1999;88(3)508-517.
  57. Jepma M, Jones M, Wager TD. The dynamics of pain: evidence for simultaneous site-specific habituation and site-nonspecific sensitization in thermal pain. J Pain. 2014;15(7):734-746.
  58. Curtis LA, Morrell TD. Pain management in the emergency department. Emerg Med Pract. 2006;8(7):1-28.
  59. Thomas SH. Management of pain in the emergency department. ISRN Emerg Med. 2013;2013:1-19. doi:10.1155/2013/583132.
  60. Berben SAA, Meijs THJM, van Dongen RTM, et al. Pain prevalence and pain relief in trauma patients in the accident & emergency department. Injury. 2008;39(5):578-585.
  61. Jacob E, Puntillo KA. Variability of analgesic practices for hospitalized children on different pediatric specialty units. J Pain Symptom Manage. 2000;20(1):59-67.
  62. Zeltzer LK, Barr RG, McGrath PA, Schechter NL. Pediatric pain: interacting behavioral and physical factors. Pediatrics. 1992;90(5 pt 2):816-821.
  63. Krauss B, Green SM. Procedural sedation and analgesia in children. Lancet. 2006;367(9512):766-780.
  64. Behrman RE, Kliegman RM, Jenson HB, eds. Nelson’s Textbook of Pediatrics. 16th ed. Philadelphia, PA: WB Saunders Co; 2000:231-237.
  65. Beaudoin FL, Lin C, Guan W, Merchant RC. Low-dose ketamine improves pain relief in patients receiving intravenous opioids for acute pain in the emergency department: results of a randomized, double-blind, clinical trial. Acad Emerg Med. 2014;21(11):1193-1202.
  66. Wong DL, Baker CM. Pain in children: comparison of assessment scales. Pediatric Nurs. 1988;14(1):9-17.
  67. Peters JWB, Koot HM, Grunau RE, et al. Neonatal Facial Coding System for assessing postoperative pain in infants: item reduction is valid and feasible. Clin J Pain. 2003;19(6):353-363.
  68. State & County QuickFacts. US Census Bureau Web site. Updated September 30, 2015. Accessed October 6, 2015.
  69. Adams SD, Cotton BA, McGuire MF, et al. Unique pattern of complications in elderly trauma patients at a level 1 trauma center. J Trauma Acute Care Surg. 2012;72(1):112-118.
  70. Lagoo-Deenadayalan SA, Newell MA, Pofahl WE. Common perioperative complications in older patients.” In: Rosenthal RA, Zenilman ME, Katlic MR, eds. Principles and Practice of Geriatric Surgery. 2nd ed. New York, NY: Springer; 2011:361-376.
  71. Gowing R, Jain MK. Injury patterns and outcomes associated with elderly trauma victims in Kingston, Ontario. Can J Surg. 2007;50(6):437-444.
  72. Boss GR, Seegmiller JE. Age-related physiological changes and their clinical significance. West J Med. 1981;135(6):434-440.
  73. Singla A, Li Y, Ng SC, Csikesz NG, Tseng JF, Shah SA. Is the growth in laparoscopic surgery reproducible with more complex procedures? Surgery. 2009;146(2):367-374.
  74. Landesberg G, Beattie WS, Mosseri M, Jaffe AS, Alpert JS. Perioperative myocardial infarction. Circulation. 2009;119(22):2936-2944.