that holds a picture, illustration, etc. Object name is ms110_p0074f1.jpg" />Acute pain is a complex process involving activation of nociceptors, chemical mediators and inflammation. Medications can be used to target each of the key elements within the pain pathway and eliminate or reduce the sensation of pain. Pain management begins, when possible, prior to the tissue trauma and continues throughout the perioperative period. When acute pain is appropriately managed, patient’s clinical outcomes and satisfaction are improved.
Beginning in 1999, TJC (The Joint Commission) initiated a new focus mandating improvement in the treatment and evaluation of pain for patients. As a result, physicians of all specialties and hospitals began to implement processes to improve pain management through a variety of modalities. Key junctures of the pain cycle were targeted with the ultimate goal to interrupt or minimize factors within the pain pathway. Many advocated preemptive anesthesia, with the goal of preventing the pain message before it enters the central nervous system. 1 Despite numerous studies, there is no consensus regarding a single treatment protocol for acute or chronic pain. This article provides a broad basic background for understanding options regarding acute pain management for physicians outside of anesthesiology.
Pain is initiated when specialized nerves, called nociceptors, are activated in response to adverse chemical, thermal or mechanical stimulus. 2 Activation can be direct due to trauma or indirect via biochemical mediators released from damaged tissues and circulation. These mediators can further augment the pain process by up-regulating pain receptors 3 and recruiting additional surrounding nociceptors into activity. Mediators include, but are not limited to, prostaglandins, bradykinins, histamine, serotonin and arachidonic acid. The severity of the pain sensed is dependent on the number of receptors stimulated, the duration of the stimulus and the amount of mediators released locally. 2 Once the nociceptor is depolarized, a signal is sent from the periphery into the dorsal horn of the spinal cord, where pain signals are integrated to elicit spinal reflexes such as withdrawal of the affected area, muscle spasms, and to release additional mediators within adjacent spinal segments and relay information to higher cortical areas. 2 , 3 Nociceptors are divided into two major nerve groups based on presence or absence of myelination. Myelinated A-delta fibers transmit the signal rapidly and are responsible for the initial sharp pain changing later to burning or soreness. Unmyelinated C fibers are relatively slower in speed and are associated with deep aching or throbbing types of pain that follows the initial sharp pain. Both types of pain fibers then cross the midline and stimulate the ascending pain fibers in the spinothalamic tract. Substance P is one of the key neurotranmitters relaying the pain signal from the periphery and the spinothalamic tract. Fibers in the spinothalamic tract terminate in the thalamus, limbus and brain stem. 2 Further information is transmitted to multiple cortical areas of the brain responsible for localization and pain perception. Descending pain fibers are in turn activated from the cerebral cortex via efferent pathway to the spinal cord and periphery 4 and act to decrease the intensity of the pain signal via encephalin, serotonin and gamma aminobutyric acid (GABA) neurotransmitters. 3
In addition to pain perception, activation of the pain pathway causes the release of hormones and vasoactive substances such as cortisol, vasopressin, and catecholamines. 2 The release of these factors, referred to as the surgical stress response, peaks in the initial hours of the post-operative period. The stress response can cause hyperglycemia and impairment of immunological functions, as well as breakdown of fat and muscle. 2 Tissue trauma also causes release of vasoactive mediators which play a role in pain. Mast cells, platelets and plasma components contribute histamine, leukotrienes, and bradykinins. 5 Independently, the mediators further sensitize nociceptors, and activate additional cytokines that augment inflammation already present.
The autonomic nervous system can also be activated by pain. This occurs in large measure in the dorsal horn, and is responsible for the associated symptoms seen with pain such as nausea, sweating, alteration of heart rate and blood pressure. 6 An excellent example of autonomic activation associated with pain is angina, where myocardial pain is expressed with symptoms of nausea, sweating, in addition to chest pressure.
Pain can be classified as acute or chronic, or in broad categories based on the origin of the injury or pain fibers (See Figure 1 ). Somatic pain has nociceptors that originate in the peripheral tissues such as skin and muscle and allow more specific ability to localize the source. 7 Visceral pain originates in internal organs. These nociceptors are activated by actual tissue damage, or in the absence of damage, pressure and stretch of the organ. Visceral pain is not well localized and frequently the pain is referred to another area of the body. 4 This is due to somatic fibers in a separate anatomic location intermingling with visceral fibers within the dorsal column and stimulating the somatic fibers, thus causing pain to be felt in the undamaged somatic region. Neuropathic pain occurs with damage to a peripheral nerve, dorsal root, or anywhere in the central nervous system. 8 If pain is present it is described as a sharp or shooting pain found along the distribution of that nerve. Because the nerve itself is injured, it can continue to be abnormally activated, creating a hyper-excitable state within the central nervous system. Patients may have persistent or paroxysmal pain even in the absence of a painful stimulus. 8
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Pain can be classified as acute or chronic, or in broad categories based on the origin of the injury or pain fibers.
Management of pain has been linked to improved patient satisfaction, improved clinical outcomes, reduced number of clinical complications and an overall reduction in costs. 8 The acute pain process can be targeted at several critical junctures with different modalities. Traditionally, pain modification has been viewed mostly as a post-operative function in which opioids played the major role. The paradigm is shifting to an emphasis of pre-emptive pain control where the goal is to minimize or eliminate pain even before it begins and aggressive intervention after the initiation of pain. Pre-operative administration of anti-inflammatory medications, nerve blocks, and opioids are blended together to help reduce the perceived pain, degree of surgical stress, and decrease the release of biochemical mediators. By decreasing the overall intensity of pain perceived by the patient, less overall pain medications are used 11 resulting in an overall reduction in undesirable side effects and length of stay. Quality of care and patient outcomes are directly tied the ability to effectively treat pain. 12
Stemming from an unclear origin in ancient times, opioids have long been the gold standard for acute pain control. They act by binding presynaptic opioid receptors, which prevents release of substance P via membrane hyperpolarization, thereby preventing impulse propagation. The majority of opioid receptors are located in the central nervous system including the spinal cord; some are found peripherally. 3
Three subtypes of opioid receptors are found in varying locations: μ,κ and δ. Stimulation of differing receptors accounts for the varying clinical effects of opioids. Opioids useful in the treatment of acute pain are almost exclusively μ receptor agonists. There are two subspecies, μ1 and μ2. Stimulation of the μ1 receptor produces spinal and supraspinal analgesia, euphoria, miosis, bradycardia, hypothermia and urinary retention. Stimulation of μ2 produces spinal analgesia, respiratory depression, physical dependence and constipation. Mu receptors are also the primary receptors for the endogenous opioid agonists, endorphins. The κ and δ receptors also cause both spinal and supraspinal analgesia and a mixture of the unwanted effects listed above, plus dysphoria, sedation and diuresis. They are also stimulated by endogenous dynorphins and enkephalins, respectively. The vast majority of opioid receptors are located in the CNS and agonists must therefore cross the blood brain barrier. Generally speaking, greater lipid solubility hastens onset and enhances potency. Opioids do not have a ceiling effect like acetaminophen and NSAIDS. 3 Thus, if enough agonist is administered, analgesia will occur, though untoward effects may occur first and prevent further administration. The individual response to any given dose is highly variable and must be carefully tailored, particularly in the elderly and opioid naïve. Through receptor up-regulation, tolerance to opioids develops after repeated doses. This occurs for both analgesic properties as well as most adverse effects save two: miosis and constipation.
In the postoperative period, opioids are administered commonly through intravenous patient controlled analgesia, or PCA. Although initially thought to reduce the overall opioid delivered in the immediate postoperative period, patients have been found to require equal amounts whether administered by a nurse or by PCA. The major advantages have been overall patient satisfaction, decreased sedation scores and a lesser impact on the nursing staff. 13 Successful use of PCA requires diligence in patient monitoring and pain assessment and a willingness of the house staff to tailor the settings to each patient’s needs through the postoperative course.
Although opioid analgesia is well established and effective, there are significant advantages to achieving analgesia without sedation and respiratory depression. Termination of nociception at the level of the spinal cord is one such technique. This may be achieved in either the subarachnoid or epidural spaces. Though continuous spinal catheters have a role in some obstetrical and surgical cases, the use of epidural analgesia is far more common in the United States. 19
Continuous epidural infusion of local anesthetic and opioid provides superior analgesia when compared to most other techniques. Since opioid receptors are found in the substantia gelatinosa in the posterior spinal cord and these areas are anesthetized by an epidural infusion, far smaller anesthetic doses are required than when administered systemically thereby limiting unwanted effects. The solution infused into the epidural space spreads both rostrally and caudally, allowing exposure to spinal nerve roots at multiple spinal levels simultaneously. Most institutions offer a continuous infusion pump with the added function of a patient controlled bolus, which can limit the basal infusion rate.
In addition to blocking sensory fibers of the dorsal spinal nerve roots, the paraspinal sympathetic chain is inevitably blocked. With loss of sympathetic tone to the vascular smooth muscle of the corresponding spinal levels blocked, hypotension may occur. This effect will be more pronounced with the degree of sympathectomy as well as with concomitant hypovolemia or cardiovascular disease.
Although some early studies showed decreases in major morbidity and even mortality with neuraxial techniques, more recent data do not support such advantages. 18 An epidural should still be considered for patients specifically at risk of respiratory depression or prolonged ventilation, or for surgical incisions that may prevent deep breathing such as sub-xiphoid and thoracotomy, or blunt trauma such as rib fractures. This approach may facilitate incentive spirometry thereby limiting respiratory complications.
Risks of placing an epidural catheter range from minor perturbation to devastating. 14 From most common to least common, they are hypotension, inadequate analgesia, post dural puncture headache, unintentional subarachnoid injection (total spinal), epidural hematoma and epidural abscess. Fortunately, severe complications are rare. To minimize risk, scrupulous sterile technique must be used, as well as attention to coagulopathy whether pathologic or iatrogenic. The abundance of anticoagulants presents an added challenge. The American Society of Regional Anesthesia has published guidelines with regard to the use of epidural procedures in the setting of anticoagulants (www.asra.com).
Since inflammation plays an important role in the nociceptive pathway, non-steroidal anti-inflammatory drugs (NSAIDS) are an important part of the multimodal approach to analgesia. In addition, non-pharmaceutical therapies such as heat and ice can also be effective. Pain itself can also reciprocally fuel the inflammatory state, so-called neurogenic inflammation. 17 Neurogenic inflammation can itself produce the same physiologic effects as direct tissue injury. When tissues are disrupted, some of the phospholipid bilayer of the membrane is converted to arachadonic acid. The cyclooxygenase enzyme then converts arachadonic acid into prostaglandin, necessary for transduction of noxious stimuli to the nociceptor as well as neurosensitization of painful stimuli and subsequent hyperalgesia. 3
The cyclooxygenase enzyme has two isoforms, COX-1 and COX-2, with very different physiologic effects. Products of COX-1 sustain both platelet function and the gastric mucosal barrier whereas COX-2 affects the inflammatory cascade and pain. 15 Aspirin and most NSAIDS nonselectively blocks both isoforms, producing analgesia as well as potential adverse effects including coagulopathy, gastric ulceration and nephropathy. The hope that selective COX-2 inhibitors would produce analgesia alone has not been supported by clinical data, and several of these compounds have been removed from use due to increased incidence of myocardial infarcts and cerebrovascular accidents. However, NSAIDS remain a valuable adjunct to opioids and local anesthetics in the treatment of acute pain and can reduce perioperative opioid requirements by up to 50%. 16
Ketamine is a powerful analgesic with established opioid-sparing properties. 20 Its mechanism of action is complex but acts mainly as an antagonist of the N-methyl-D-aspartic acid (NMDA) receptor. Since it has no action at opioid receptors, it is devoid of respiratory depression at analgesic doses. There is also markedly less nausea and vomiting when compared to opioids. It’s initial use as a general anesthetic was limited by psychotropic side effects such as hallucinations. Fortunately, these are rare at analgesic doses. Nystagmus is more likely but may not be bothersome to a patient in pain.
One modality for the intervention of acute pain occurs in the periphery, at the level of the nociceptor. Local anesthetics can be used to prevent the depolarization of the nerve by blocking the sodium channel, thus preventing the pain signal’s propagation from the periphery into the CNS 21 (See Figure 2 ). While all local anesthetics act via similar mechanisms, they vary in onset time, duration of action and potency. These medications have the benefit of completely eliminating or greatly reducing the amount of acute pain experienced. In experienced hands, these medications can be safely and reliably placed to maximize their benefits. Toxic side effects, while uncommon, are possible and depend mainly on location of injection and total dose of local anesthetic entering the circulatory system. Local anesthetics enter the circulation either via inadvertent intravascular injection or via absorption of local anesthetic injected into surrounding tissue. Intravascular complications affecting the central nervous and/or cardiovascular systems include life-threatening seizures and cardiovascular collapse with complete electrical conduction blockade of the heart. 22 The rate of absorption is site specific and may be decreased by adding vasoconstrictive agents such as epinephrine. Needle trauma, causing mechanical disruption or ischemia of the nerve resulting in temporary or permanent nerve damage, is theorized to expose the nerve to high concentrations of local anesthetic resulting in nerve damage due to ischemia or chemical exposure. 23
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Spinal anestesia epidural being administered.
Past and current surgical practice included blocking initial pain signals by infiltration with local anesthetics. Infiltrated local anesthetic has both anti-inflammatory effect as well as ability to block nerve transmission. 23 To achieve sensory blockade, nerves innervating an area proximal to the trauma site are targeted to interrupt the pain pathway prior to the central nervous system. Nerve blocks have become more common, including “single-shot” and catheter techniques. Both involve injecting local anesthetic adjacent to the nerve. In the latter, a small catheter is placed through which additional local anesthetic can be delivered over an extended period of time. Nerve blocks can be performed proximal and adjacent to the spinal cord in nerve plexus or extend out to the distal terminal nerve. While specific blocks are beyond the scope of this review, each nerve block has unique risks and benefits, and even appropriately performed nerve blocks will have effects beyond blocking pain fibers. For instance, brachial plexus blocks can affect the nearby phrenic nerve, leading to a temporary elevated hemi-diaphragm and subjective shortness of breath until the local anesthetic affects resolve. Local anesthetics can also spread, causing deficits in motor, proprioception or temperature fibers, thus complicating early physical therapy.
Although orthopedic surgery is often associated with nerve blocks, general surgery and obstetrics utilize more nerve blocks for pain management. In some institutions, paravertebral blocks are being used in breast cancer surgery for post-operative pain control, with opioid use reduced by up to 40% when paravertebral blocks were utilized. 10 One study has shown pre-operative use of nerve blocks decreased the chances of developing chronic pain at the surgical site. 11 A randomized, controlled, double blinded study of patients undergoing major abdominal surgery who had transversus adbdominus plane blocks demonstrated improved recovery times, facilitated rehabilitation, decreased opioid requirements, and reduced overall postoperative morbidity. 12
Ultrasound has facilitated the increased number and types of nerve blocks. With appropriate training, ultrasound allows rapid recognition of and placement of a needle adjacent to nerve tissues. Equally important is the visualization of the local anesthetic as it is injected to ensure it is being deposited in the appropriate location. While many practitioners can have success without utilizing the ultrasound for nerve blocks, its use is becoming commonplace. A meta-analysis of randomized controlled studies comparing the use of ultrasound to traditional methods demonstrated that ultrasound guidance reduces the time performing the block, shortens block onset time, and decreases the amount of time in performing the block. 24 Ultrasound blocks are less painful for patients because a nerve stimulator is not needed to confirm position in most instances 25 , and fewer needle passes are needed when using ultrasound. However, most studies show no difference in complication rates when using ultrasound to perform blocks. Barriers most frequently cited against using the ultrasound include the cost of the equipment and the lack of training in using the technology. 25
Acute pain derives from combined effects of stimulated nociceptors, local inflammation, systemic stress response mediators, and psychological factors. No one single treatment will intervene to treat each factor; rather, a combination of modalities should be utilized to reduce pain perception. Because of individual variation, acute pain management plans should be tailored for the needs of each patient. Follow-up and adaptation of the plan is necessary as different etiological factors will dominate at different stages of the acute pain process. The use of temporary interventions such as nerve blocks will need to be continued with other modalities that were initiated at the same time (opioids) or added later (anti-inflammatory agents) in order to optimize pain relief. Ultimately, the patient with improved acute pain management yields increased satisfaction, reduced costs, decreased risk of chronic pain, and decreased overall morbidity.
Joseph L. Reeves-Veits, MD, MBA, is Professor and Chairman, and the Russell D. And Mary B. Shelden, Missouri Chair of Anesthesiology. Quinn Johnson, MD, is Interim Chairman, Department of Anesthesiology and Perioperative Medicine and Director of the Missouri Orthopedic Institute. Robert R. Borsheski, DO, is an Assistant Professor of Clinical Anesthesiology. All are at the University of Missouri School of Medicine.
