After plantar incision, peripheral C- and Aδ-fibers are sensitized contributing to nonevoked pain and heat and mechanical hyperalgesia in the early days after incision.8,62,133 Some of the underlying mechanisms were investigated within the last 10 years. Combined behavioral and neurophysiological experiments revealed that muscle nociceptors play a central role in the genesis of nonevoked guarding behavior after incision; the mechanism seems to be the spontaneous activity of C-fibers sensitized after incision.18,187,188 In contrast, a skin incision without a muscle tissue injury seems to be responsible for inducing mechanical hyperalgesia after incision; muscle injury seems to be not required.18,187,188 A series of studies revealed mechanisms inherent in (muscle) fiber sensitization after incision. They basically found a decrease in pH (pH ∼6.8) and an increase in lactate concentration (6 mM) that correlated well with a peak in pain behaviors at 1 to 2 days after incision.83,184 Similarly, a decrease of oxygen tension in both skeletal muscle and skin was detected immediately after incision for several days74; together with an increased lactate and decrease pH (see above), these ischemic-like conditions in the incisional wound are likely to contribute to peripheral sensitization (eg, muscle C-fibers, see81) and pain behavior (eg, nonevoked pain) after incision.74 Furthermore, a response of muscle C-fibers to antagonists to acid-sensing ion channels (ASICs) in cultured dorsal root ganglion (DRG) neurons points towards the role of tissue acidity in nonevoked pain behavior after incision.81 Interestingly, the ASIC3 channel is upregulated early after incision in muscle tissue innervating DRG neurons and seems to be important for nonevoked incisional pain, weight-bearing, and also partially for heat hyperalgesia. The role of ASIC3 for heat hyperalgesia is being controversially discussed in the literature with regard to different pain models. Whereas in vivo knockdown or specific inhibition via toxin APETx2a leads to complete remission of heat hyperalgesia after Complete Freund's Adjuvant (CFA) injection,41 mechanical but not heat hyperalgesia after carrageenan injection into the muscle seems to be ASIC3 mediated.161 Together, the role of ASIC (eg, ASIC3) channel blocker for pain in general and specifically for incisional pain needs further investigation.
The role of specific peripheral mechanisms contributing to hyperalgesia after the incision has been investigated as well. There are 2 important aspects, which will be highlighted here: Firstly there are different nociceptors that seem to be responsible for heat vs mechanical hyperalgesia after incision. Secondly, the molecular mechanisms of the fiber sensitization process responsible for mechanical and heat hyperalgesia after incision differ in many ways to other pain entities. Hints for the first aspect came from early studies using pretreatment of the incision site with a low dose of capsaicin (transient receptor potential vanilloid 1 receptor agonist); this reduced the heat hyperalgesia (and nonevoked pain) but not mechanical hyperalgesia after incision.61 Consistent with other pain models, there is an upregulation of peripheral (and spinal) transient receptor potential vanilloid 1, which contributes to the development of heat (but not mechanical) hyperalgesia after incision.10,138,174 There are many other examples differentiating mechanical and heat hyperalgesia after incision, which we will not address in detail but which are represented in Table 1.
One example for the second aspect, a differential sensitization process relevant for hyperalgesia after incision compared to inflammation or neuropathic pain, is the important role of calcitonin gene-related peptide in inflammation-related pain (CFA), which is not involved in spontaneous pain or mechanical and heat hyperalgesia after incision in mice.67 Further confirmation for an unique peripheral sensitization process after incision came from a study investigating 84 mRNAs from the neurotrophins and inflammatory cytokines families in skin, muscle, and DRG after plantar incision.164 As demonstrated, most alterations in the mRNA expression are present in incised skin and muscle, less in the DRG. They occur within the first 48 hours after incision when the mechanical and heat hyperalgesia, as well as guarding pain, is most obvious. In particular, genes for wound healing, re-innervation, and the immune response are differently expressed in comparison to other pain models.164 More examples supporting this are shown in Table 1.
Only recently peripheral inflammatory cell responses were investigated after incision injury in animals. For instance, migration of neutrophilic granulocytes (NGs) into tissue traumatized by incision occurs shortly after surgery, reaching a maximum at 24 hours and declining rapidly to baseline within 3 days.27,45,153 Neutrophilic granulocytess release many well-known proinflammatory mediators and contain endogenous opioid peptides (met-enkephalin and β-endorphin).146 Sahbaie and colleagues demonstrated that the systemic depletion of NGs (with Gr-1 antibody) reduced the paw edema and the interleukin-1β (IL-1β) concentration, but increased significantly the heat hyperalgesia for 24 hours and did not alter the mechanical hyperalgesia after plantar incision in mice.153 This suggests a role of endogenous opioids (released by NGs) for incisional pain similar to that shown in inflammatory pain models.147 However, another study from Carreira et al.27 used the same method to deplete NGs but showed attenuation of mechanical hyperalgesia after incision; they suggested the role of CXCL-1-CXCR1/2 recruitment of NGs after incision. Presumably, proinflammatory mediators from NGs (IL-1β and C5a) may play a role for hyperalgesia after incision.69,99,153 Thus, as the local concentration of C5a after the incision is increased, this complement factor may provide a novel target for analgesic drug development.69,99 However, the exact role of NGs in postoperative pain is currently unclear because of the contradictory results of both NG-depletion studies.27,153
The prevention of mast cell degranulation (mast cell membrane stabilization with Cromoglycate) or depletion of mast cell mediators (with Compound 48/80 prior to incision), thus inhibiting the effect of histamine, 5-HT, and tryptase (a serine protease localized exclusively in mast cells) reduce the mechanical hyperalgesia and nonevoked pain in mice.127,192 Similar effects are observed by administration of tryptase-binding receptor antagonist (protease-activated receptor 2, PAR2).127 These results suggest a role of mast cells contributing to hypersensitization after incision. However, it should be noted that the mast cell degranulation alone seems insufficient to promote pain (eg, allergies, some drug administration).
Our understanding of the processing of pain in the human brain has improved significantly105; however, activity and neuroplasticity in the pain matrix after incision contributing to pain-related behavior remains poorly understood. A recent study in animals indicates directly how the brain reacts to an incision compared to inflammation by using functional magnetic resonance imaging to assess oxygenation levels of the blood as an indirect measure of neural activity and functional magnetic resonance spectroscopy.5 Mechanical stimulation of the incised hind paw showed blood oxygen level dependent (BOLD) signals, which differed significantly in quantity and quality to BOLD signals related to mechanical stimulation of the hind paw after CFA inflammation. Similarly, BOLD signals after electrical stimulation in both animal models differed to mechanical stimulation.5 However, GABA levels (measured with functional magnetic resonance spectroscopy) increased in both pain models within the thalamus, during rest and during mechanical stimulation.5 Thus, the thalamus might play a central role for hyperalgesia regardless of the pain entity and GABA neurotransmission might be involved. Further imaging studies investigated central neuroplastic changes relevant for the development of more chronic pain after incision. Human functional magnetic resonance imaging studies confirmed the role the thalamus139 and indicated a lack of descending inhibition in enhanced pain responses of patients with chronic pain after incision.22,23 By using the positron emission tomography-method, Romero et al.148 demonstrated long-lasting changes in glucose metabolism in central pain-related areas and opioid-related pathways up to 21 days after incision. The metabolic changes in the pain matrix were positively correlated with hypersensitivity caused by naloxone injection in rats which received remifentanil anesthesia earlier.148 This suggests long-lasting neuroplastic adaptations in central opioid circuits possibly contributing to chronic pain after incision.
Systemic administration of gabapentin, or inhibition of ERK within the anterior cingulate cortex (ACC) early after surgery, but not systemic morphine, reduced incision-induced anxiety.36,86,97 Interestingly, ERK-inhibition reduced anxiety-like behavior and mechanical hyperalgesia early after surgery (1 hour), but (different to inflammatory and neuropathic pain) in the later phase (6 hour), it exclusively reduced anxiety.
A recent study showed that presurgical or postsurgical exposure to stress factors like immobilization and force swimming test does not change the basal pain perception to different stimuli, such as mechanical, hot and cold, but prolongs the duration of incision-induced hyperalgesia after incision.26 By blocking spinal glucocorticoid receptors or removing the adrenal glands, stress-induced prolongation of incision-induced hyperalgesia was abrogated. These results indicate a direct connection between the activation of the hypothalamic-pituitary-adrenal axis through presurgery and postsurgery stress and duration of incision-induced hypersensitivities. Maternal adversity in the form of perinatal stress and depression may also activate the hypothalamic-pituitary-adrenal system and increased incisional pain in adult rats.85 Thus, acute stress might be—similar to other psychological factors—relevant for the transformation of acute into chronic pain after surgery.26
In recent years, a growing body of publications has examined the potential of the epigenetic modulation, such as DNA methylation, histone acetylation and noncoding RNA, for chronic pain conditions.90,131 Some epigenetic results are now available for acute postoperative incisional pain in animals.154,169,170 An incision seems to induce changes in global DNA methylation, which leads to increased incision-induced hyperalgesia. Peripheral and spinal inhibition of a DNA methyltransferase via 5-Aza-2`-deoxycytidine led to attenuation of the mechanical and heat hyperalgesia and reduced hind paw swelling.170 Furthermore, epigenetic modulation of spinal Bdnf− (brain-derived neurotropic factor) and Pdyn− (prodynorphin) genes via acetylated Histone H3K9 in mice under chronic opioid exposure seems to be involved in opioid tolerance after incision.154 Notably, different histone deacetylase inhibitors, such as suberoylanilide hydroxamic acid or trichostatin A, attenuated heat hyperalgesia7 or mechanical hyperalgesia159 in an inflammatory (CFA) and in a neuropathic pain model, but exacerbated mechanical hyperalgesia after incision in mice.169 Taken together, these first epigenetic results suggest that peripheral and spinal epigenetic modulation are involved in increased postoperative nociceptive sensitization (Fig. 2). The additional influence of epigenetic regulation by drugs (eg, opioids) or environmental input could induce long-lasting changes in the pain system, one possible cause for a transformation from acute to chronic conditions.
In recent years, nonclassical active pharmaceutical ingredients from venoms of spiders128,163 or from other sources66,82,84,100,106,122,155,180,200,201 have been tested for their potential to reduce mechanical/heat hyperalgesia and/or nonevoked pain or gait abnormalities after incision. Some substances act directly at receptors, such as the vitexin, a C-glycosylated flavone present in several medicinal herbs, which binds to GABAA and opioid receptors.200 Some more recent studies report that curcumin (diferuloylmethane), a phenolic constituent of turmeric, reduces incisional inflammation, nociceptive hypersensitivity,201 spontaneous pain, and functional gait abnormalities by increasing the level of TGF-β in incisional skin.155 Other substances block spinal N-type voltage-sensitive Ca2+ channels and reduce mechanical hyperalgesia after incision without altering the normal nociceptive sensitivity, eg, venom of the Brazilian armed spider Phoneutria nigriventer.128 These nonclassical active pharmaceutical substances have characteristics making them suitable as potential candidates for the development of new analgesics for postoperative pain.
The translation of findings from animals to patients (and back) is one of the greatest challenges in modern (pain) research. Previous studies have shown that the direct translation of results from rodent experiments is difficult and should be performed and interpreted with caution.111 One major disadvantage of many animal pain models is that they are not representing the pain etiology or pain entity they are translated to.111,112 The development of more sophisticated animal models, mimicking human pain conditions to improve bench-to-bedside translation, is part of the current discussion.24,34,111 The same, in fact, relates to human experimental pain models and their translation to patients and needs attention as well.103 Furthermore, the portfolio of behavioral pain measurements in animals does not represent well clinically relevant pain aspects in humans. For several years, we and others assess spontaneous pain behavior in rats after incision representative of pain at rest in patients.19,133,143,144 Hyperalgesia to pinprick stimuli are assessed in rats frequently; interestingly, the same stimuli are used to assess hyperalgesia around a surgical wound in patients,37,167 the mechanisms behind this might be relevant for central sensitization and prolongation of pain after surgery and are therefore useful to study.44,93 More recently, movement-evoked pain and pain-related anxiety and depression are explored in animals after incision; presumably, these might be other translatable pain-related behaviors and should be focused on in the future.111,112,176 Together, adequate animal pain models (eg, incisions for surgical pain,18,19) and relevant pain behavior assessed in these models combined with experimental human studies139 will pave the way for a refined and more applicable bench-to-bedside translation in postoperative pain.
The preceding part of this article has outlined quite clearly that postoperative pain as a manifestation of acute pain is markedly more complex than originally thought. The complexity of postoperative pain requires, therefore, considerably more than simply applying opioids as required. It is, therefore, not surprising that there is now a large scientific evidence basis for the management of postoperative pain. This has been summarized recently in the fourth edition of the document “Acute Pain Management: Scientific Evidence”, published by the Australian and New Zealand College of Anaesthetists and its Faculty of Pain Medicine.157 The sheer size of this document reflects the complexity quite well; the document has nearly 650 pages, assesses over 8500 references, and condenses the evidence-based information in 669 key messages. It is obvious that it would be impossible to summarize that entire document in this article. The article will, therefore, concentrate on overarching key strategies and specific treatment options as far as they are of more general importance.
The concept of multimodal (“balanced”) analgesia has been introduced into the management of postoperative pain more than 20 years now.79 The concept suggests that it is superior to combine analgesics with different modes or sites of action, as such combinations will improve analgesia, reduce opioid requirements (so-called “opioid-sparing” effect), and thereby reduce the adverse effects of opioids.194 This concept is in line with the observations in basic science models that combinations of, for example, peripherally and centrally acting analgesic compounds are of value here. In addition, such multimodal approaches show further benefits with regard to other postoperative outcomes. Just to mention a few examples here, after total knee joint replacement, multimodal analgesia increases patient satisfaction scores and permits earlier achievement of milestones of physical therapy.87 Similarly, after spinal surgery, use of multimodal analgesia improves postoperative mobilization.108 In view of data showing that increased opioid use, with resulting opioid adverse effects (in particular nausea, vomiting, and constipation), delays recovery after surgery and thereby leads to extended hospital stay with increased costs,124 multimodal analgesia would reduce such complications, speed up recovery, and possibly even reduce hospital costs. This is nicely reflected in the fact that more or less all approaches using enhanced recovery after surgery protocols include multimodal analgesia concepts as one component.78 However, it has to be acknowledged that multimodal analgesia by itself does not result in early rehabilitation or enhanced recovery after surgery. To achieve these goals, multimodal analgesia needs to be integrated into a holistic and multidisciplinary approach to the postoperative period.119 In particular, again the importance seems to be the opioid-sparing effect, as avoidance of oral opioids in the postoperative period after colorectal surgery reduces the length of stay.2 This is confirmed by other data that show that opioid-sparing analgesic techniques reduce postoperative ileus.11
In this context, it is interesting to look in more detail at which compounds are actually useful components of multimodal analgesia and should thereby be combined with opioids.
As outlined before, peripheral sensitisation of nociceptors leading to primary hyperalgesia is an important contributor to postoperative pain. It is, therefore, not surprising that in clinical reality drugs which are reducing peripheral prostaglandin concentration and thereby leading to reduced peripheral sensitisation are a useful component of multimodal analgesia. In randomized controlled trials52 and their meta-analyses, these drugs fulfill all 3 requirements on multimodal analgesia, ie, improved analgesia, reduced opioid requirements, and reduced adverse effects of opioids.109 A reduction of postoperative nausea and vomiting, one of the most disturbing adverse effects of opioids in the early postoperative period, is reported. COX-2 selective nonsteroidal anti-inflammatory drugs (NSAIDs) (coxibs) have similar efficacy to nonselective NSAIDs.113 However, they are superior in the postoperative setting because of reduced adverse events.
The effect of NSAIDs may be enhanced by the addition of paracetamol as the combination of paracetamol and NSAIDs is more effective than either compound alone.129
Dexamethasone as an anti-inflammatory corticosteroid is widely used in anesthetic practice to prevent nausea and vomiting.38 Other effects include an improvement of the quality of recovery and reduced fatigue.117 In addition, dexamethasone in therapeutic doses reduces postoperative pain scores and opioid consumption.179 However, these effects are small and only statistically significant and might not be of clinical relevance. In addition, there is still an ongoing debate about potential risks of perioperative steroid administration with regard to induction of hyperglycemia, increasing risk of infection and bleeding and possibly malignancy recurrence.173 A large randomized controlled trial currently underway will try to address these unresolved questions (https://www.paddi.org.au).
As outlined in detail in the preceding part of the article, it is obvious that central sensitisation plays a much more relevant role in the development of postoperative pain than previously thought. Findings in this setting illustrate that contrary to common beliefs, central sensitisation can occur within a very short time span and can significantly contribute to the overall picture of a postoperative pain state. It is therefore not surprising that there is increasing interest in the use of medications, which are attenuating such states of secondary hyperalgesia due to central sensitisation. A number of these compounds have become components of clinically useful multimodal analgesia. These include the NMDA receptor ketamine, the alpha-2-delta ligands pregabalin and gabapentin and the alpha-2-adrenergic agonist's clonidine and dexmedetomidine.
Ketamine is a noncompetitive antagonist of the NMDA receptor when used in subanaesthetic doses. Meta-analyses support the use of perioperative IV infusions of low-dose ketamine (in the range of around 0.1 mg·kg−1·h−1) with resulting improved analgesia, an opioid-sparing effect and reduction of opioid side effects such as postoperative nausea and vomiting.89 The benefits of ketamine are, in particular, seen in patients after major surgeries that are suffering severe pain (VAS >7/10). This explains why these benefits have been shown after thoracic and upper abdominal and major orthopedic surgery. In addition, not only in laboratory settings but also in the clinical settings, NMDA receptor antagonists such as ketamine are reducing the development of opioid-induced hyperalgesia, for example after remifentanil use.185 It is, therefore, not surprising that ketamine is also a useful analgesic in the settings of patients with established opioid tolerance13,175 and preoperative high opioid use.102 Similar findings with regard to opioid-sparing and improvement of analgesia have also been found with a perioperative infusion of magnesium which has to be regarded as another NMDA-receptor antagonist.118 Last, not least, there are data supporting the effect of perioperative ketamine in reducing the incidence of chronic postsurgical pain (see preventive analgesia).29
The alpha-2-delta ligands pregabalin and gabapentin, which were developed for the treatment of neuropathic pain where they find their most relevant indication, have also been shown to have an effect on central sensitisation and are, therefore, for example, indicated in the treatment of fibromyalgia with FDA approval. In this context, it is, therefore, not surprising that for both compounds there is evidence from meta-analyses supporting their role as a component of multimodal analgesia.110,172 Data show reduced pain scores as well as reduced opioid consumption and thereby reduced adverse effects of opioids. This beneficial effect can be achieved with a single preoperative dose. In addition, the anxiolytic effect of these drugs should be taken into consideration and might be an additional beneficial factor,130 again in analogy to the basic science findings.
Perioperative systemic use of alpha-2 agonists such as clonidine and dexmedetomidine also fulfills the criteria for successful multimodal analgesia resulting in reduced pain intensity, opioid consumption, and nausea.15 However, with their use, potential adverse effects such as hypotension and bradycardia and possibly dose-dependent sedation need to be considered.
In conclusion, the concept of multimodal analgesia is supported by a large clinical data set, which shows that addressing both peripheral and central sensitisation after surgical incision leads to improved analgesia with reduced opioid requirements and thereby opioid side effects. Current data do not permit a decision on which combinations of how many components may comprise multimodal analgesia after what kind of surgical incision. However, from a practical point of view it seems to become increasingly routine in the setting of acute pain services to use an NSAID (best seems to be a COX-2 selective one) routinely, paracetamol and (eg, before major procedures, in healthy patients) an alpha-2-delta ligand as standard components of multimodal analgesia with rescue opioid being available on top of this. Other components such as ketamine and alpha-2 agonists are used in specific indications. The role of corticosteroids is not yet fully established in this setting and requires further investigation.
The basic science data presented above suggest that depending on the type and location of the incisional model, different pain states result. Again this is confirmed by clinical data which show that analgesics may have different efficacies in different surgical settings.57 This is true even for a simple analgesic like paracetamol, which is significantly less effective after orthopedic surgery (relative risk reduction 1.87) than after dental extraction (relative risk reduction 3.77). Current large meta-analyses used to calculate the number needed to treat of analgesic agents might pool data from different postoperative pain states and thereby ignore the specific effects of a specific analgesic in a specific postoperative pain state.57 In addition, it has to be acknowledged that different surgical procedures do not only cause different pain states but also pain states of different severities in different locations. These observations and the support by basic science have led to the development of the concept of procedure-specific postoperative pain management. Treatment pathways for the management of postoperative pain after different surgical procedures can be developed in an evidence-based fashion by analyzing the literature specific to the respective procedure.72 Guidelines for a number of surgical procedures of different types have been developed by the PROSPECT initiative with the consideration of primarily procedure-specific evidence (www.postoppain.org). The guidelines can be found at the website of this initiative, and most of the guidelines have been accompanied by publications in the peer-reviewed literature with regard to these specific procedures.
Neuropathic pain is still widely considered a chronic pain state. However, clinical experience and clinical data, as well as the animal data provided above, are showing that neuropathic pain can occur acutely and can be a component of postoperative pain. The literature shows that for example following sternotomy 50% of patients presented with dysaesthesia in the early postoperative period as a manifestation of acute neuropathic pain.4 As in other chronic neuropathic pain states, a manifestation of neuropathic pain is accompanied by increased pain severity. Similarly, after cancer surgery, use of a screening tool in a prospective setting found acute neuropathic pain in the first week postoperatively in around 10% of the cases.68 A case series in a general surgical population identified an incidence in the range of 3% to 4%.151 It is, therefore, relevant for clinicians looking after postoperative patients (and even more so after post-traumatic patients) to identify a neuropathic pain component, which might then require appropriate treatment, for example, with alpha-2-delta ligands or ketamine on top of commonly used opioids.
Nerve injury leading to acute neuropathic pain is one of the major risk factors for the progression of acute to chronic pain.1 Chronic postsurgical pain is much more common than usually thought and the estimated incidence of chronic severe pain with an intensity of more than 5/10 occurs in 2% to 10% of patients after surgery.157 Besides nerve injury as a risk factor, other risk factors include preexisting preoperative pain, preoperative anxiety, catastrophizing as well as genetic predisposition. Postoperative factors are again severe acute postoperative pain and psychosocial risk factors similar to those in the preoperative setting. This is in line with some of the observations with regard to behavioral changes observed in animal studies. In view of nerve injury as a risk factor, it is not surprising that a large percentage of chronic postsurgical pain has features of neuropathic pain.71
With regard to the prevention of such pain states, there has been a significant change in concepts away from the previously supported pre-emptive analgesia approach to a preventive analgesia approach.91 Pre-emptive analgesia is defined as a preoperative treatment, which is more effective than the identical treatment administered after the incision. The key difference is the timing of the administration. It has become increasingly obvious that preventive analgesia, ie, an analgesic effect beyond its expected duration is a more useful approach. For practical terms, this has been defined as analgesia which persists beyond 5.5 half-lives of a medicine.76 In the context of prevention of chronic surgical pain, it is also important to maximize the benefits of any analgesic strategy by continuing the treatment into the postoperative period as long as the sensitising stimulus persists. With regard to the preventive effect on chronic postsurgical pain, best data are available for the use of regional or neuraxial analgesia. A meta-analysis supports the use of epidural analgesia after thoracotomy and the use of paravertebral blocks after breast cancer surgery.6 Data at lower levels of evidence support the use of spinal anesthesia over general anesthesia for Caesarean section121 and hysterectomy,17 as well as the use of epidural analgesia after major abdominal surgery92 and for amputations with regard to the reduction of phantom limb pain.54 Interesting specifically for phantom limb pain is the idea of decreasing the already existing preoperative pain to reduce phantom limb pain after surgery; here, both epidural analgesia and systemic opioids seem to be effective.75 Other data support the use of perioperative local anesthetics for wound infiltration.14,16 However, it is important in this context to realize that intravenous lignocaine also has preventive effects on acute postoperative pain12 and in one small study reduced chronic postsurgical pain.58
Further evidence supports the use of ketamine as a preventive treatment for chronic postsurgical pain. A meta-analysis of 14 rather small randomized controlled trials shows a reduction of chronic postsurgical pain at 3 and 6 months, in particular if ketamine is administered for more than 24 hours perioperatively.29 With regard to the alpha-2-delta ligands gabapentin and pregabalin, there may be an effect on preventing chronic postsurgical pain; however, the data are currently rather contradictory and looking at only a few usually small studies with a large degree of heterogeneity so that uncertainty continues here.29,33
In conclusion, the current evidence base for the management of acute postoperative pain is significant. Much of the clinical data, which support certain approaches are in line with findings in the experimental setting. However, there are a number of discrepancies here and it will be interesting to see if the development of new compounds based on basic science studies will further help to improve the management of acute postoperative pain. It remains important to realize that postoperative pain management is not only a humanitarian task to reduce patient suffering and improve patient satisfaction but that treatment of acute postoperative pain has the potential to reduce morbidity possibly even mortality after surgery and in parallel enhance recovery, improve rehabilitation, reduce hospital stay and thereby overall hospital cost.
Stephan Schug: The Anesthesiology Unit of the University of Western Australia, but not Stephan Schug personally, has received research, travel funding, and speaking and consulting honoraria from bioCSL/Seqirus/Grunenthal, iXBiopharma, Mundipharma, and Pfizer within the last 2 years. Esther Pogatzki-Zahn received travel funding, and speaking and consulting honoraria from Grünenthal, Mundipharma, MSD, Fresenius Kabi, Janssen Cilag, The Medicine Company and ArcelRx and research support from Mundipharma (paid to the hospital).
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