Recent Advances in Postoperative Pain Management

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REVIEW

Nalini Vadivelu, MD a* ; Sukanya Mitra, MD b; and Deepak Narayan, MD c

Departments of aAnesthesiology and cSurgery, Yale University School of Medicine, New Haven, Connecticut, and bDepartment of Anaesthesia & Intensive Care, Government Medical College & Hospital, Chandigarh, India

Good pain control after surgery is important to prevent negative outcomes such as tachy - cardia, hypertension, myocardial ischemia, decrease in alveolar ventilation, and poor wound healing. Exacerbations of acute pain can lead to neural sensitization and release of medi - ators both peripherally and centrally. Clinical wind up occurs from the processes of N-Methyl D-Aspartate (NMDA†) activation, wind up central sensitization, long-term potentiation of pain (LTP), and transcription-dependent sensitization. Advances in the knowledge of molec - ular mechanisms have led to the development of multimodal analgesia and new pharmaceu - tical products to treat postoperative pain. The new pharmacological products to treat postoperative pain include extended-release epidural morphine and analgesic adjuvants such as capsaicin, ketamine, gabapentin, pregabalin dexmetomidine, and tapentadol. Newer postoperative patient-controlled analgesia (PCA) in modes such as intranasal, regional, transdermal, and pulmonary presents another interesting avenue of development.

Proper pain relief is a major concern concerns of the surgeon because of its close and area of focus in the United States today. ties with clinical outcome and acute post - Pre-operatively, one of the most common operative patient well-being. Studies have questions asked by patients pertains to the indicated such negative clinical outcomes amount of pain they will experience after to include decreases in vital capacity and the surgery. Pain is also one of the primary alveolar ventilation, pneumonia, tachycar -

*To whom all correspondence should be addressed: Dr Nalini Vadivelu, Department of Anesthesiology and Surgery, Yale University School of Medicine, New Haven, CT 06511; E-mail: [email protected].

†Abbreviations: NMDA, N-Methyl D-Aspartate; LTP, long-term potentiation; PCA, patient- controlled analgesia; BK, bradykinin; 5HT, 5 hydroxytryptamin; CGRP, calcitonin gene-re - lated protein; AMPA, amino-3-hydroxyl-5-methyl-4-proprionic acid; KAR, Kainate; EPSP, excitatory postsynaptic potentials; NO, nitric oxide; SO, superoxides; NK1, neurokinin re - ceptor; COX-2, cycloxygenase 2; EREM, extended-release epidural morphine; fentanyl ITS, fentanyl hydrochloride iontophoretic transdermal system; FDA, U.S. Food and Drug Administration; IV, intravenous; MAOI, monoamine oxidase inhibitors; PCRA, patient-con - trolled regional analgesia; RM, ropivacaine/morphine; RMK, ropivacaine/morphine/ketoro - lac; IN, intranasal; PCINA, patient-controlled intranasal analgesia; NNT, number-needed-to-treat; IA, intraarticular.

Keywords: opioids, acute pain, pain mechanisms, postoperative, patient-controlled anal - gesia 11 12 Vadivelu: Advances in postoperative pain management

dia, hypertension, myocardial ischemia, my - MOLECULAR MECHANISMS ocardial infarction, transition to chronic pain, poor wound healing, and insomnia It is important to know about the recent [1,2,3]. advances in central sensitization since it Pain has been found to be one of the plays an important role in post surgical and three most common medical causes of de - post traumatic pain [5,6]. Postoperative pain layed discharge after ambulatory surgery, is mostly nociceptive, which is pain percep - the other two being drowsiness and nau - tion following surgical insult. sea/vomiting. Despite this overwhelming However, there can be exacerbation of rationale for effective postoperative pain acute nociceptive pain leading to neural sen - control, the clinical reality is, unfortu - sitization when sensations that are not nor - nately, still far from satisfactory. As a re - mally painful are perceived as painful, as in cent editorial title suggests, we have a long hyperalgesia and allodynia. Mechanical al - way to go to achieve satisfactory postop - lodynia occurs due to the release of several erative pain control [3]. In an often-cited primary and secondary noxious sensitizers study [4] that assessed patients’ postoper - such as PGEs, leukotrienes [7], bradykinin ative pain experience and the status of (BK), histamine, and 5 hydroxytryptamine acute pain management in a random sam - (5HT). These conditions are commonly seen ple, approximately 80 percent of patients in those patients developing neuropathic said they experienced acute pain after sur - pain. Primary hyperalgesia occurs when gery. The authors concluded that despite an there is sensitization of peripheral nocicep - increased focus on pain management pro - tors, while secondary hyperalgesia is asso - grams and the development of new stan - ciated with the sensitization of the spinal dards for pain management, many patients cord and the central nervous system. continue to experience intense pain after In peripheral sensitization, there is a re - surgery. lease of primary mediators such as During the last couple of decades and prostaglandins, 5 hydroxytryptamine, especially the last few years, major techno - leukotrienes, and bradykinins. These pri - logical breakthroughs that have the potential mary mediators stimulate the release of pep - to significantly advance the field of postop - tides such as calcitonin gene-related protein erative analgesia have occurred and are still (CGRP) [8], substance P [9], and cholecy - underway. This article discusses some of the tokinin [10] at the site of injury. Histamine- more important of these recent advances. We induced vasodilatation, nerve growth factor focus on the developments particularly over release, and reflex sympathetic efferent re - the last five years. lease of norepinephrine are other processes There are several strands of develop - related with peripheral sensitization. ment that overlap, and it is difficult to do Impulses from the peripheral nocicep - justice to this burgeoning area within the tors travel via A delta and C fibers to scope and limits of this article. This review synapse in the lamina II and lamina V of the will outline the main directions of this de - spinal cord. C fibers also synapse in the lam - velopment and dwell upon a few selected re - ina I of the spinal cord. cent ones in some detail. The second order neurons of the spinal The recent advances in postoperative cord are of two types: the first, in lamina I, re - pain management can be loosely grouped in sponds to impulses from the C fibers; the sec - the following areas: ond is the wide dynamic range neuron located in lamina V that responds to both noxious and • Molecular Mechanisms non noxious stimuli. Neurotransmitters such • Pharmaceutical products as glutamate and aspartate present in lamina V • Routes and modes of delivery produce fast synaptic transmission. They do so • Other modes of analgesia by binding and activating amino-3-hydroxyl- • Organizational and procedural aspects 5-methyl-4-proprionic acid (AMPA) and Vadivelu: Advances in postoperative pain management 13

Kainate (KAR) receptors that regulate Na+ scription independent in the induction phase. and K+ ion influx. AMPA and KAR are almost Long-term potentiation of pain increases the impervious to Ca++ ions. Once the AMPA and excitatory postsynaptic potentials (EPSP) in - KAR receptors are activated, they start the volved in chronic pain. priming of NMDA, which is voltage mediated [11]. Transcription-independent and transcription-dependent central NMDA receptor and central sensitization sensitization NMDA is a membrane protein that reg - Central sensitization can be transcrip - ulates the flow of Na+ and Ca++ into the tion dependent and transcription independ - cell and the outflow of K+ outside the cell ent. Both activation of NMDA wind up and by an ion channel present intrinsically. The early LTP of pain are transcription-indepen - NMDA receptor is made up of four subunits: dent processes. There is increasing pain with two NR1, one NR2A, and one NR2B. Each each repetitive stimulation [15]. The tran - of these has a cytoplasmic portion outside scription-independent process is heterosy - the cytoplasm that can be allosterically mod - naptic central sensitization, in which low ified by zinc ions. threshold A Beta input elicit responses after NMDA receptors require ligand binding C fiber conditioning. Wind up and early LTP with glutamate and aspartate and AMPA-in - are reversible processes. duced membrane depolarization and a posi - Transcription-dependent sensitization tive change in the voltage inside the cell. occurs in prolonged noxious facilitation This makes NMDA receptors ligand de - leading to the activation of genes, mRNA pendent and voltage gated. Activated AMPA transcription, and subsequent translation receptors produce a depolarization that dis - into modified proteins. Excitotoxicity occurs lodges a magnesium plug from the ion chan - from increased influx of Ca++ with resultant nel of the NMDA receptor. The removal of increase in prostaglandins PGE, nitric oxide the magnesium plug initiates the entry of (NO), and superoxides (SO). Transcription- calcium ions into the neuronal. Direct action dependent sensitization affects the spinal of glutamate at the glutamate binding site cord and other areas within the central nerv - further sensitizes the channel [12]. ous system. It is now thought that transcrip - As intracellular calcium accumulates, a tion-dependent sensitization is mediated by chain of neurochemical and neurophysio - inflammation and related alterations in the logic changes leads to the rapid and inde - dorsal root ganglion, the dorsal horn, and ir - pendent firing of spinal neurons without reversible structural modifications in the stimulation. This process is termed as “ wind central nervous system [16]. Transcription- up ,” which is the excitation of the dorsal dependent sensitization can take two forms: horn neurons not dependent on transcription activity independent localized form, which of specific genes. includes the late phase of LTP, and the ac - tivity independent widespread form. Late Long-term potentiation of pain phase LTP has been studied mainly in the Clinical hyperalgesia occurs from the hippocampus and other cortical areas [11]. processes of NMDA activation, wind up, and central sensitization [13]. Central sensi - Common mechanisms of pain and memory tization can occur in the spinal cord as well as in the supraspinal regions of the central It has been seen that the neurokinin re - nervous system, such as anterior cingulate ceptor (NK1) and cycloxygenase 2 (COX- gyrus, amygdale, and rostroventral medulla. 2) are involved in central sensitization. The Activation of the NMDA in the spinal cord genes for Dynorphin and NK1 have been and the supraspinal areas and increased neu - seen to be upregulated in the spinal cord, ronal calcium ion (Ca++) influx lead to wind and widespread COX-2 has been seen to be up and early LTP [14] of pain that is tran - upregulated in many areas of the central 14 Vadivelu: Advances in postoperative pain management

nervous system by pain facilitation [11]. (notably gabapentin). There is also a re - However, NK1 and COX2, which are in - newed interest in judicious use of cyclooxy - volved in central sensitization, are not in - genase inhibitors (coxibs). Long-acting volved in hippocampal LTP. It is also known preparations of local anesthetics constitute that NMDA receptors, essential for activity another area of ongoing research. dependent central sensitization, also are nec - Newer PCA in modes such as in - essary for the initiation of LTP, which has a tranasal, regional, transdermal, and pul - role in the consolidation of memory. The monary presents an interesting avenue of common mechanisms in hippocampal early development. phase LTP and central sensitization are phosphorylation of synaptic receptors and Multimodal analgesia the insertion of AMPA receptors into the The concept of multimodal analgesia post-synaptic membrane. There is only first proposed about 15 years ago is now synaptic strengthening in hippocampal LTP, quite well established in clinical practice. For while central sensitization also can cause example, non-steroidal anti-inflammatory neuronal network changes and other cellular medications combined with intravenous pa - mechanisms. It is necessary then to avoid tient-controlled morphine administration the interruption of memory formation and may decrease nausea and sedation in patients cortical function while treating central sen - when compared with those using patient- sitization since the process of LTP is present controlled morphine alone [17]. Different in central sensitization as well as in memory classes of analgesics using different routes of mechanisms in the cortex [11]. administration such as intravenous and Advances in knowledge of the molecu - epidural are used to produce fewer side ef - lar mechanisms of pain have led to develop - fects of sedation, nausea, vomiting pruritis, ment of multimodal analgesia and new constipation, and improved pain relief. Mul - pharmaceutical products to treat pain. We timodal analgesia also can produce opioid will highlight the important recent advances sparing. Other studies have shown, however, in pharmaceutical products and the routes that multimodal analgesia may not improve through which they can be given, as well as postoperative outcome significantly. Faster important non-pharmacological advances in recovery, reduced hospital stay, and de - pain control that are useful for health care creased length of convalescence can occur if personnel treating postoperative pain. Non- multimodal analgesia is combined with a re - pharmacological advances in analgesia are habilitation program that is multidisciplinary exemplified by application of acupuncture, and multimodal [18]. The development of and related therapies for postoperative pain newer agents available for postoperative pain control will be discussed. In addition, drug control opens up possibilities for newer com - tolerance in patients with illicit drug use or a binations in multimodal analgesia. history of taking high doses of pain prescrip - tion medications prior to admission are mak - Extended-release epidural morphine ing postoperative pain management a The goal of current postoperative pain re - challenge and warrants discussion as well. search and development is to find a medication that can work locally to give long-lasting pain relief at the site of surgical focus. The new drug, ADVANCES IN PHARMACEUTICAL a single-dose, extended-release epidural mor - PRODUCTS phine (EREM) called DepoDur™, may be a The two most important new products step toward this analgesic goal. When clinically are extended-action epidural morphine and applicable, the use of DepoDur™ has been iontophoretic transdermal fentanyl. Others found to have a duration of action up to 48 include the use of various non-analgesic hours [19,20] with long-lasting analgesia in the substances as adjuvants, major examples absence of large systemic concentrations of being ketamine and some anticonvulsants opioids as well as better patient activity levels. Vadivelu: Advances in postoperative pain management 15

EREM is formulated for a one-time demonstrated to have efficacy and safety dose, given epidurally at the lumbar level. equivalent to morphine IV-PCA in four ran - DepoDur™ has been evaluated in such sur - domized controlled trials [28,18], a sub - geries as knee arthroplasty and cesarean sec - group analysis [29], and a meta-analysis tion. Several studies have shown that EREM [30]. It is thought that 40 percent of the ad - produces long-term pain relief [8-10]. ministered dose is absorbed in the first hour Side effects of EREM have been of treatment and the system reaches 100 per - treated with opioid antagonists. Twelve to cent efficacy in 100 hours. 12.5 percent of patients who received Panchal et al. [31] evaluated the inci - EREM required opioid antagonists [19,20]. dence of analgesic gaps resulting from sys - It has been stated that pruritis [19] and res - tem-related events (SREs) for patients using piratory depression [20] were the primary the fentanyl ITS vs. morphine IV PCA for causes for antagonist administration. The postoperative pain management. Fentanyl elderly are particularly sensitive to the ef - ITS was associated with a significantly fects of EREM and require close perioper - lower incidence of analgesic gaps than mor - ative monitoring. It was shown that the phine IV PCA. elderly treated with 15 mg of EREM had equivalent fentanyl usage as younger pa - Safety and tolerability of fentanyl ITS tients treated with 20 mg of EREM [21]. At - The safety and tolerability of fentanyl tentive perioperative monitoring is needed ITS have been found to be acceptable by for elderly patients. several studies and pooled data analysis [32]. Adverse events associated with fen - Fentanyl iontophoretic transdermal tanyl ITS are similar to those reported with system IV opioid administration, including nausea, Although PCA has demonstrated effi - vomiting, pruritis, headache, and mild-to- cacy and patient satisfaction, current tech - moderate dizziness. Nausea was the most niques using intravenous (IV) administration common adverse event, with the incidence present limitations, including the risk of pro - ranging between 26.6 percent and 67.5 per - gramming errors and the potential to limit pa - cent [27,28,33]. tient mobility due to pumps, lines, and tubing. The patient-controlled fentanyl hydrochloride Disadvantages iontophoretic transdermal system (fentanyl As with all transdermal systems, skin ITS) was designed to address these concerns hypersensitivity, skin redness, and hyperpig - [22]. Fentanyl ITS is an innovative, needle- mentation are potential problems. The sys - free, self-contained, pre-programmed drug- tem has not been adequately studied in delivery system that uses iontophoretic children. It should be used with extreme technology to deliver fentanyl through the caution for in-patients with severe hepatic skin by application of a low-intensity electri - dysfunction, head injuries, sleep apnea, and cal field [23,24,25]. It has not been approved impending respiratory failure and in patients by the U.S. Food and Drug Administration with increased intracranial pressure of any (FDA) for current clinical use; however, clin - etiology. ical studies have been conducted on human The system lacks programmability and subjects to evaluate it for efficacy, safety, and a basal infusion rate that may be important tolerability. in opioid-dependent and opioid-tolerant pa - tients. The number and timing of attempts Efficacy of fentanyl ITS by the patient also cannot be determined. The efficacy of fentanyl ITS in treating The system has to be disposed only after dis - acute postoperative pain was first estab - assembly by the pharmacist. The most im - lished in three phase 3 double-blind placebo- portant disadvantage at the current time is controlled clinical trials [26,27]. More the availability of fentanyl ITS, since it is importantly, fentanyl ITS now has been not currently being produced due to techni - 16 Vadivelu: Advances in postoperative pain management

cal problems. Perhaps technological modi - pains, and strains and sprains. Capsaicin fications, including recording the number cream is also used in higher concentrations and timing of the attempts and the addition for the treatment of the neuropathic pain of of a basal rate, may make it more advanta - post herpetic neuralgia. It can be used in the geous in the future. elderly as an adjuvant, as it is thought to have opioid sparing effects. This can be par - ticularly beneficial for the elderly who are ANALGESIC ADJUVANTS sensitive to respiratory depression that can Adjuvants are compounds, which by occur with opioids. themselves have undesirable side effects or Injectable capsaicin is used for the con - low potency but in combination with opi - trol of post operative pain, such as after total oids allow a reduction of narcotic dosing knee replacement, total hip replacement, for postoperative pain control. Adjuvants hernia repair [36], shoulder arthroscopy, and are needed for postoperative pain manage - bunionectomy. It also has uses in more long- ment due to side effects of opioid anal - term pain such as that due to intedigital neu - gesics, which hinder recovery, especially in romas, osteoarthritis of the knee, and the increasingly utilized ambulatory surgi - neuropathic pain occurring after surgery or cal procedures [34]. Multiple adjuvanta re - trauma. Pre-administration of neural block - cently have been developed for the control ade before injection of capsaicin may greatly of pain. decrease the burning discomfort. Capsaicin appears to be a relatively safe Capsaicin drug with the only absolute contraindication Capsaicin (8-methyl-N-vanillyl-6- being patient hypersensitivity. Relative con - nonenamide) is a non narcotic and acts pe - traindications include age less than 2 years, ripherally. It acts as a TRPV-1 agonist [35]. patients with elevated liver enzymes, patients TRPV1 is a receptor that is markedly re - on ACE inhibitors, and patients showing duced in inflammatory conditions and is signs of septic arthritis and joint infections. present on unmyelinated C fiber endings in the periphery. The activation of the TRPV Ketamine receptors releases high intensity impulses NMDA receptor antagonists, and and releases substance P, which results in the specifically ketamine commonly used in initial phase of burning. Continued release clinical practice, have been used in perioper - of substance P in the presence of capsaicin ative pain management. Routes of adminis - leads to the depletion of capsaicin and a sub - tration include intravenous, subcutaneous, sequent decrease in C fiber activation. It is epidural, transdermal, and intra-articular. At important to remember that capsaicin does low sub anesthetic doses (0.15–1 mg/kg), not produce significant effects on the A delta ketamine exerts a specific NMDA blockade and A alpha fibers and does not affect the and, hence, modulates central sensitization temperature and touch sensations. induced both by the incision and tissue dam - It can be used as a cream and also as an age and by perioperative analgesics such as injectable analgesic. It is not an FDA ap - opioids. proved product but is currently in Phase 3 There has been a renewed interest in the trials for postoperative pain control, arthritis, use of sub-anesthetic doses of ketamine as an musculoskeletal pain, and chronic neuro - adjunct to provide postoperative pain relief in pathic pain. Capsaicin is present in high con - opioid-dependent patients [37]. There is a def - centration in the seeds and stem of chili inite role of ketamine in preventing opioid-in - peppers. It is an alkaloid. duced hyperalgesia in patients receiving high Capsaicin cream contains capsaicin that doses of opioid for their postoperative pain re - is usually combined with narcotic analgesics lief [38]. However, clinical use of ketamine and NSAIDS to relieve a variety of painful can be limited due to psychotomimetic adverse ailments such as back pain, arthritic joint effects such as hallucinations and bad dreams. Vadivelu: Advances in postoperative pain management 17

Other common adverse effects are dizziness, nificant analgesic effect in the acute, includ - blurred vision, and nausea and vomiting [39]. ing postoperative, pain scenario [43], other studies suggest pregabalin to have effective Gabapentin and pregabalin sedative [44] and opioid-sparing effects Gabapentin is an anti-epileptic drug that [45,46], useful characteristics for the control has demonstrated analgesic effect in diabetic of acute pain. Research on its established role neuropathy, post-herpetic neuralgia, and as an analgesic adjuvant as a part of multi - neuropathic pain. Gabapentin does not bind modal analgesia for acute pain control is on - to GABA A or GABA B receptor but to the going. Opioid sparing effects and improved alpha-2 delta subunit of the presynaptic volt - pain scores have been seen after abdominal age gated-calcium channels responsible for and pelvic surgery. Its many potential actions the inhibition of the calcium influx. The in - such as reducing opioid requirements, pre - hibition of calcium release then prevents the vention and reduction of opioid tolerance, release of excitatory neurotransmitters in - improvement of the quality of opioid analge - volved in the pain pathways. Most of the sia, decreased respiratory depression, relief studies of gabapentin (and occasionally its of anxiety, and gastric sparing make it an at - structural analog pregabalin) in the perioper - tractive drug to consider for control of pain ative setting have been published in the last in the post operative period [47]. three to four years, and several systematic reviews on the subject are available [31,39]. Dexmedetomidine Most of the reviews and meta-analyses Dexmedetomidine is a relatively new, concur that perioperative gabapentin helps to highly selective central alpha2 agonist. Its seda - produce a significant opioid-sparing effect tive, pro-anesthetic, and pro-analgesic effects and probably also improves postoperative at 0.5-2 micrograms/kg given intravenously pain score relative to the control group [40]. stem mainly from its ability to blunt the central Tiippana et al. [41] found that the opioid- sympathetic response by as yet unknown sparing effect during the first 24 hours after mechanism(s). It also minimizes opioid-in - a single 300 to 1,200 mg dose of gabapentin, duced muscle rigidity, lessens postoperative administered one to two hours preopera - shivering, causes minimal respiratory depres - tively, ranged from 20 percent to 62 percent. sion, and has hemodynamic stabilizing effects. Gabapentin and similar drugs seem to have a Dexmedetomidine, when used as an adjunct, strong potential for perioperative use as an can reduce postoperative morphine consump - analgesic adjuvant and anti-hyperalgesic tion in various surgical settings using various agent when used in conjunction with opioids. routes such as intravenous [48,49]. A recent study has shown the analgesic efficacy of Pregablain dexmedetomidine in postoperative pain relief. Recent years also have witnessed a The authors of this study found that the addition heightened research interest in the analgesic, of dexmedetomidine to IV PCA morphine re - sedative, anxiolytic, and opioid-sparing ef - sulted in superior analgesia, significant mor - fects of pregabalin (S+ 3-isobutyl GABA), a phine sparing, and less morphine-induced structural analog of GABA and a derivative nausea, while it was devoid of additional seda - of gabapentin, in various pain settings, in - tion and untoward hemodynamic changes [49]. cluding postoperative pain. Its mechanism of action is thought to be probably similar to that of gabapentin but has a superior pharma - OTHER RECENT ADVANCES IN cokinetic profile [42]. Pregabalin has an es - PERIOPERATIVE PHARMACOTHERAPY tablished efficacy of varying degree in neuropathic pain conditions such as posther - Local anesthetics petic neuralgia, painful diabetic neuropathy, central neuropathic pain, and fibromyalgia. To effectively respond to the issue of While some studies do not demonstrate a sig - sending the ambulatory patient home in a pain- 18 Vadivelu: Advances in postoperative pain management

free state, one has to have methods to provide Although nonspecific NSAIDs provide anal - several days of effective and safe relief of gesic efficacy similar to coxibs, their use has moderate to severe pain for the unmonitored been limited in the perioperative setting be - patients at home. It is clear that local anesthetic cause of platelet dysfunction and gastroin - techniques, particularly peripheral nerve testinal toxicity. Coxibs may be a safer blockade, will be one of the cornerstones of alternative in that setting. Both coxibs and postoperative pain management [50]. traditional NSAIDs may contribute to a There are basically two overarching dose-dependent increase in cardiovascular approaches for prolongation of local anes - toxicity and impaired osteogenesis. When thetic action. One is the use of novel deliv - used short term at the lowest effective dose, ery techniques for existing drugs. In an however, NSAIDs may provide for anal - endeavor to “make old drugs new” [51], li - gesic benefit without significant toxicity. posome or polymer encapsulation of local The potential benefits of coxibs include anesthetics are being formulated. The sec - [18] improved quality of analgesia; reduced ond approach is the development of novel, incidence of GI side effects vs. conventional extremely long-acting local anesthetics. NSAIDs; and no platelet inhibition. Aceta - Liposomes are microscopic phospho - minophen is antipyretic and analgesic but has lipid-bilayered vesicles that are biocompati - little, if any, anti-inflammatory action. Its ble, biodegradable, and non-immumnogenic. analgesic efficacy is not more than that of Recently, substantial interest has been shown traditional analgesics; however, it has fewer in developing drug delivery systems utilizing side effects. The mechanism of action has nanoparticles, micro-particles composed of been debated. In animal models, it has been biodegradable polymers. They have some seen to inhibit COX-3. At the spinal cord advantages over liposomes in terms of sta - level, it has been shown to antagonize neuro - bility both during storage and in vivo . transmission by NMDA, substance P, and ni - To date, many local anesthetics (most tric oxide pathways. Preparation of commonly bupivacaine, but also mepiva - intravenous (IV) acetaminophen recently has caine, ropivacaine, lidocaine, prilocaine, been released in the United Kingdom and etc.) have been loaded in liposomes or Europe (Perfalgan®, Bristol Meyers Squibb, polymer microspheres [52,36]. It is hoped New York). It is dissolved in mannitol and that in the near future, some of these for - pH-buffered by disodium phosphate, with mulations will become a part of the pain cysteine added as an anti-oxidant. A 100 ml clinician’s armamentarium. However, the solution is presented as 10 mg/ml for admin - road toward achieving this goal may be istration over a period of 15 minutes. The long and winding, due to problems of these onset of action is within five to 10 minutes, drug delivery systems, such as shelf life, with the peak at one to two hours. Optimal aggregation, leakage, and toxicity [53]. analgesia for moderate to severe postopera - tive pain cannot be achieved using a single Renewed interest in NSAIDs and coxibs agent alone, but a balanced approach in com - and acetaminophen bination with non-steroidal agents can result A recent review highlights current ad - in up to a 40 to 50 percent reduction in opioid vances in our understanding of the role peri - requirements. IV propacetamol (1 g), a pro - operative NSAIDs have on modulating drug of acetaminophen, has been shown to nociception, their benefits when utilized as be as efficacious as intramuscular morphine components of a multimodal analgesic reg - (10 mg) following dental extractions [54] imen, and potential deleterious cardiovascu - and as effective as intramuscular ketorolac lar and estrogenic effects. Recent research (30 mg) following lower limb arthroplasty indicates that, in addition to peripheral [55]. With its inherent safety and demon - blockade of prostaglandin synthesis, central strated efficacy, IV acetaminophen can prove inhibition of cyclooxygenase-2 may play an to be an asset in managing perioperative important role in modulating nociception. pain, especially of mild to moderate severity. Vadivelu: Advances in postoperative pain management 19

Other agents Tapentadol’s two mechanisms of ac - Other non-opioid analgesic adjuvants tions also may lend it opioid-sparing effects include clonidine, neostigmine, tapentadol, while maintaining adequate analgesia. and, recently, adenosine [56], though further Tapentadol is considered to have a potency research is necessary to establish their clin - between tramadol and morphine, with ical efficacy. Of these, the use of low doses equivalent potency to that of opioids such as of clonidine proved to be a useful adjunct hydrocodone and oxycodone. The role of an analgesic when given neuraxially and in oral preparation has inherent limitations in combination with peripheral nerve blocks. the acute postoperative period, but some re - Data about the systemic administration of cent data have shown its efficacy in dental clonidine could support the usefulness of surgery [62] and bunionectomy. low-dose IV administration [57]. Tapentadol is contraindicated in patients with severe bronchial asthma, paralytic ileus, Tapentadol and in patients taking monoamine oxidase Combination analgesics that have mod - inhibitors (MAOI). Serotonin syndrome can erate opioid efficacy and central adrenergic develop with the use of tapentadol, and it analgesic effects (e.g., tapentadol) have been should not be combined with serotonergic found to provide analgesic effects similar to drugs such as selective serotonin reuptake in - more potent opioids but with a lower ad - hibitor, selective norepinephrine reuptake in - verse event profile. Recently, tapentadol has hibitor, tryptans, or tricyclic antidepressants, been approved in the United States as imme - which can cause serotonin syndrome. Sero - diate release oral preparations of 50 mg, 75 tonin syndrome can include mental status mg, and 100 mg (Nucynta®, Johnson & changes such as hallucinations, coma, auto - Johnson) to be used every four to six hours, nomic instability such as tachycardia, hyper - depending on pain intensity, with a maxi - thermia, and neuromuscular abnormalities mum daily dose of 600 to 700 mg. Tapenta - such as hyperreflexia and incoordination. dol was approved by the FDA in November 2008 for the treatment of moderate to severe pain in patients 18 years or older. Tapentadol ACUPUNCTURE FOR is a centrally acting analgesic with a unique POSTOPERATIVE ANALGESIA dual mode of action as an agonist at the µ- The term acupuncture describes a family opioid receptor and as a norepinephrine re - of procedures involving the stimulation of uptake inhibitor [58,59]. anatomical points on the body using a variety Tapentadol has an 18-fold affinity for of techniques. Acupuncture theory is based on the µ opioid receptor in humans as compared two conditions: “yin,” which is considered to morphine but is about two- to three-fold feminine, passive, dark, and cold, and “yang,” less potent than morphine, most likely be - which is masculine, aggressive, bright, and cause it is a norepinephrine reuptake in - hot, as well as “qi,” which is considered the hibitor. It has improved gastrointestinal vital energy that flows and cycles throughout tolerability when compared to classical opi - the body. The acupuncture theory is to harmo - oids. The dose of tapentadol does not have to nize any imbalance in yin-yang and qi in a be adjusted in the presence of renal impair - human body to restore the body to a healthy ment. Hepatoxicity has not been reported. condition. Acupuncture is thought to unblock The incidence of nausea and vomiting any obstruction to the flow of qi and, thereby, has been seen to be lower in patients taking relieves pain. The acupuncture technique that tapentadol as compared to patients taking has been most often studied scientifically in - oxycodone immediate release [44,60]. volves penetrating the skin with thin, solid, Tapentadol has been useful for postoperative metallic needles that are manipulated by the pain after bunionectomy. Significant pain re - hands or electrical stimulation. lief was obtained 32 to 46 minutes after sur - Acupuncture has been used to treat a gery [61]. variety of conditions such as chronic lower 20 Vadivelu: Advances in postoperative pain management

back pain, chronic neck and shoulder pain, new and evolving area of postoperative pain osteoarthritis of the knee, migraine management. Current evidence suggests that headache, dysmenorrhea, labor pains, and these techniques are effective, feasible, and acute post operative pain. safe in the home environment if appropriate Sun et al. [63] conducted a systematic patient selection routines and organization review to quantitatively evaluate the effi - for follow-up are in place [25,66]. cacy of acupuncture and related techniques Patient-controlled regional analgesia as adjunct analgesics for acute postoperative (PCRA) encompasses a variety of tech - pain management. The authors concluded niques that provide effective postoperative that perioperative acupuncture might be a pain relief without systemic exposure to opi - useful adjunct for acute postoperative pain oids [25]. Using PCRA, patients control the management. However, there are issues with application of pre-programmed doses of applicability and generalizability of the pro - local anesthetics, most frequently ropiva - cedure [64]. caine or bupivacaine (occasionally in combi - Further, acupuncture is an umbrella nation with an opioid), via an indwelling term that encompasses several often dis - catheter, which can be placed in different re - parate procedures. This can create confusion gions of the body depending upon the type in scientific studies and their interpretation. of surgery. Infusions are controlled either by To reduce this confusion, Usichenko et al. a staff-programmed electronic pump (simi - [65] focused on randomized controlled trials lar to that used for IV PCA) or a disposable of only auricular acupuncture (a popular elastomeric pump. An elastomeric pump is a method in which needles are placed in vari - device that has a distensible bulb inside a ous parts of the earlobe) for postoperative protective bulb with a built-in filling port, pain control. They identified nine studies of delivery tube, and bacterial filter [56]. Anal - acceptable quality (though none of the best gesia can be delivered directly into a surgi - quality), of which eight upheld the superior - cal incision (incisional PCRA), ity of auricular acupuncture over the control intra-articular (IA) tissue (IA PCRA), or per - conditions. The mechanism of pain relief by ineural site (perineural PCRA). auricular acupuncture is not known. The au - thors concluded that the evidence that auric - Incisional PCRA ular acupuncture controls postoperative pain Placebo-controlled trials have estab - is promising but not compelling. More re - lished the efficacy and safety of incisional search of methodologically rigorous design PCRA [67]. In an active-comparator trial (especially ensuring therapist blindness, [68], incisional PCRA with ropivacaine 0.5 which none of the published studies ad - percent via an elastomeric PCRA pump pro - dressed) on larger samples from different vided superior analgesia without major side centers are needed to reach a definitive con - effects compared with bolus infusion in pa - clusion in this regard. tients recovering from arthroscopic subacro - mial decompression.

NEWER PATIENT-CONTROLLED Intraarticular (IA) PCRA ANALGESIC ROUTES Although IA administration of opioids with or without local anesthetics is estab - Patient-controlled regional analgesia lished practice for joint anesthesia, studies One of the most significant changes in evaluating IA PCRA are limited, as pub - surgical practice during the last two decades lished data focus primarily on single-dose has been the growth of ambulatory surgery and continuous modes of IA administration. [66]. Adequate postoperative analgesia is a Vintar et al. [69] conducted a randomized, prerequisite for successful ambulatory sur - placebo-controlled trial evaluating the effi - gery. Sending patients home with perineural, cacy of ropivacaine/morphine (RM), ropiva - incisional, and intra-articular catheters is a caine/morphine/ketorolac (RMK), and saline Vadivelu: Advances in postoperative pain management 21

for postoperative pain management follow - continuous infusion in various settings and ing anterior cruciate ligament construction. operations [72]. Patients self-initiated bolus doses of the anal - gesic mixture or saline solution via Microject Patient-controlled intranasal analgesia (PCINA) PCA pump. While no significant differences in pain scores, side effects, and patient satis - Intranasal (IN) opioids, either in the faction were noted among the study groups, form of a dry powder or water or saline so - patients receiving RMK consumed signifi - lution, are delivered using a syringe, nasal cantly less rescue morphine per day com - spray or dropper, or nebulized inhaler. In ad - pared with those receiving RM and placebo dition to needle-free administration, patient- (RMK, 8 ± 8 mg; RM, 23 ± 20 mg; placebo, controlled IN opioid administration 46 ± 21 mg; p < 0.001). (especially fentanyl) bypasses the hepatic first-pass effect and because of the excellent Perineural PCRA perfusion of the nasal mucosa, displays Perineural PCRA allows patients to rapid absorption and rise in plasma concen - self-titrate local anesthetic peripheral nerve tration [73,74,75]. blocks to achieve comfort. In a randomized, While evidence suggests that PCINA is double-blind, placebo-controlled study (Il - efficacious, safe, noninvasive, and easy to feld et al. [70]), perineural PCRA with ropi - administer, there have been only a limited vacaine 0.2 percent in the interscalene number of small-sampled, randomized, brachial plexus was shown to provide pain placebo-controlled trials evaluating this control superior to placebo in outpatients route of analgesic administration in the post - after moderately painful orthopedic surgery operative period [75]. An acceptability study of the shoulder. On the first postoperative reported that 79 percent of patients receiving day, patients receiving perineural PCRA PCINA would want to use it again [76]. with ropivacaine reported significantly re - duced pain (P < 0.001), less oral opioid use Patient-controlled transpulmonary analgesia (P < 0.001), and lower sleep disturbance scores (P = 0.13) compared with patients re - AeroLEF™ (aerosolized liposome-encap - ceiving placebo infusions. sulated Fentanyl; YM BioSciences Inc., On - Rawal et al. [71] studied ambulatory pa - tario, Canada) is a novel, proprietary inhalation tients receiving perineural PCRA into the formulation of free and liposome-encapsulated brachial plexus at home. They have demon - fentanyl intended to provide rapid, extended, strated that treatment with either ropivacaine and personalized analgesia for patients experi - 0.125 percent or bupivacaine 125 percent encing acute pain episodes. AeroLEF™ is in provides effective analgesia without signs development for the treatment of moderate to and symptoms of local anesthetic toxicity. severe pain, including cancer pain. The incidence of side effects and technical In contrast to fixed-dose approaches to problems was generally low with the most opioid delivery, in which a significant titra - common complaint being numbness of the tion period is often required to determine the fingers (6.9 percent of ropivacaine patients suitable dose for the patient, AeroLEF™ is and 29.0 percent of bupivacaine patients). being developed to offer a simple and non- On the day after surgery, the percentage of invasive route of administration, rapid onset patients who were “satisfied or “very satis - of action, sustained effect, and self-titratable fied” was similar in the two groups (79 per - dosing for the treatment of acute and break - cent for ropivacaine and 83 percent for through pain. Using AeroLEF™, patients bupivacaine, respectively). can identify and select a personalized dose A number of studies have demonstrated for each pain episode, achieving both rapid that perineural PCRA results in equivalent onset and extended duration of analgesia. or superior analgesic efficacy with lower However, it is still a long way from being total anesthetic consumption compared with used in clinical practice. 22 Vadivelu: Advances in postoperative pain management

ADVANCES IN ORGANIZATIONAL available evidence from that particular sur - ASPECTS OF POSTOPERATIVE gical procedure. Such procedure specific PAIN CONTROL guidelines are available from two sources: 1) the U.S. Veteran’s Health Administration, Procedure-specific analgesia in collaboration with the U.S. Department of There is a need for the development of Defense and the University of Iowa an evidence-based approach to reliable, (www.oqp.med.va.gov/cpg/cpg.htm) [78], comprehensive, individualized analgesic and 2) the PROSPECT Working Group plans for specific surgical procedures. Al - (www.postoppain.org), a group of European though number-needed-to-treat (NNT) of a anesthesiologists and surgeons [79]. particular analgesic can give a valuable overview of efficacy, this concept is not nec - essarily applicable to all types of surgery. CONCLUSION They proposed that procedure-specific acute With the many advances in pain man - pain management guidelines may be helpful agement for the surgical patient, surgeons because the pain intensity and its conse - and pain care providers have myriad choices quences may be procedure-related. Although of analgesic pharmacotherapy and analgesic the intensity of the acute pain state is ex - techniques to choose from to provide ade - pected to be related to the magnitude of the quate postoperative pain control for the sur - operation, this may not necessarily be so. gical patient in the 21st century. However, When the size of the injury is considered, many factors must be considered before de - dental pain with a smaller injury may be rel - ciding on the type of pain therapy to be pro - atively more painful compared with the pain vided to the surgical patient. These include observed in relation to the magnitude of tis - the patients’ co-morbid conditions, psycho - sue injury after hip replacement. However, logical status, exposure to analgesic thera - the consequences of the injury and pain may pies, and the type of surgical procedure. be entirely different between these proce - In the future, genetically informed “per - dures because stress responses and organ sonalized medicine” may become a reality dysfunctions resulting from the injury are even for acute pain management. With the different. The risk-benefit ratio of different recent advent of studies documenting ge - analgesics also may vary according to the netic polymorphisms with respect to pain re - surgical procedure. Thus, the clinical effects sponse to morphine [80] and pressure pain of opioid sparing (which are variable be - sensitivity [81], this exciting possibility tween analgesics) also may depend on the looks promising in the near future. effects of the surgical injury. Similarly, the REFERENCES risk and clinical implications of postopera - tive bleeding associated with certain anal - 1. Breivik H. Postoperative pain management: why is it difficult to show that it improves out - gesics are also procedure-specific. For come? Eur J Anaesthesiol. 1998;15(6):748- example, the inhibition of platelet aggrega - 51. tion and, therefore, the risk of bleeding asso - 2. Carr D, Goudas L. Acute pain. Lancet. 1999;353(9169):2051-8. ciated with NSAIDs are more relevant in 3. Breivik H, Stubhaug A. Management of acute operations that pose a risk of bleeding (e.g., postoperative pain: still a long way to go! a tonsillectomy). Therefore, analgesics with Pain. 2008;137(2):233-4. no effects on platelet function (e.g., aceta - 4. Apfelbaum J, Chen C, Mehta S, Gan T. Post - operative pain experience: results from a na - minophen and COX-2 specific inhibitors) tional survey suggest postoperative pain may be preferable in these but not in other continues to be undermanaged. Anesth operations. Analg. 2003;97(2):534-40, table of contents. Kehlet et al. [77] argued that clinicians 5. Eliav E, Teich S, Benoliel R, Nahlieli O, Lewkowicz A, Baruchin A, et al. Large need information in which the choice of myelinated nerve fiber hypersensitivity in analgesic technique includes the considera - oral malignancy. Oral Surg Oral Med Oral tion of the operation and is based on the Pathol Oral Radiol Endod. 2002;94(1):45-50. Vadivelu: Advances in postoperative pain management 23

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