Postoperative pain is an unpleasant consequence of the tissue injury and inflammatory responses that are incurred as a result of disease, trauma and surgery. Adequate alleviation of pain is a priority during the postoperative recovery period, not only to reduce patient discomfort but also to potentially improve patient outcomes [1-5]. Studies continue to show, however, that postoperative pain is under-managed worldwide. To address this problem, significant efforts have been made over the last several years to standardize and improve the treatment of pain through the establishment of pain management guidelines [6-10], although quantifiable progress in pain management has been limited.
Further efforts to improve the treatment of postoperative pain should focus on optimizing the implementation of care by healthcare providers and the techniques with which they perform their services. The safe and effective delivery of postoperative analgesics should be performed under the supervision of specialized personnel in a properly organized acute pain service (APS) . In addition, the development and implementation of novel analgesics and/or improved methodologies for the treatment of pain could directly address inadequacies in conventional pain management strategies.
The objectives of this article were to evaluate the current state of postoperative pain management in Europe, including a description of commonly used analgesic modalities for the treatment of acute postoperative pain, and to describe a needle-free alternative to currently available analgesic modalities for the treatment of moderate-to-severe postoperative pain: the fentanyl HCl iontophoretic transdermal system (fentanyl ITS). This novel analgesic delivery system has a potential role in improving postoperative pain management in Europe and elsewhere.
Current status and importance of postoperative pain management
Despite the international attention to improving postoperative pain management, large number of patients in Europe and the rest of the world continue to experience acute, moderate-to-severe pain after surgery [12-14]. Recent surveys from the United Kingdom, Spain, Italy, Switzerland, the United States, Asia and Africa [12-16] show that undertreatment of postoperative pain remains an international problem. The results of a 17-nation European survey of anaesthesiologists that was presented in 1998 showed that contributors to this phenomenon include the lack of an organized APS, lack of qualified ward personnel to carry out and monitor analgesic techniques, such as epidural procedures and patient-controlled analgesia (PCA), and lack of funds for PCA pumps . In fact, multiple factors may contribute to the inadequate management of postoperative pain.
Wide inter-patient variability in analgesic requirements and narrow therapeutic ranges result in the need for individualized titration of pain immediately following surgery. Since pain is a subjective experience of the patient, it may be routinely underestimated by the hospital staff because of variations in the methodologies used for pain assessments [17-19]. Stamer and colleagues reviewed the literature on methods of pain assessment and management by an APS and concluded that, in spite of published pain management guidelines, most APS worldwide did not meet basic quality criteria: regular (at least once daily) assessment and documentation of pain scores at rest, written protocols for pain management, assignment of personnel to postoperative pain management, and policies for postoperative pain management during nights and weekends . Healthcare providers may have misconceptions about the effective doses and side-effects of opioids that are delivered by various routes, resulting in an inadequate administration of pain medication . It is not uncommon for patients to be so apprehensive about the side-effects of opioids (especially nausea and vomiting) that they limit opioid consumption, despite the presence of pain.
Several practical and organizational barriers exist in hospitals that can also complicate the effective treatment of postoperative pain . Nurses often face high workloads amidst an insufficient number of personnel, preventing them from adequately monitoring a patient's level of pain and limiting their ability to expeditiously meet each patient request for pain medication . As a result, delays in dosing of nurse-administered analgesics can lead to gaps in effective pain relief. In addition, under existing regulations in many European countries and institutions, nurses are prohibited from injecting drugs into i.v. lines, epidural catheters and peripheral nerve block catheters; they are also required to call a physician for dose adjustments to i.v. PCA and epidural analgesia regimens . Furthermore, the prevalence of hospitals lacking a dedicated APS [16,24-27], high-dependency beds, a post-anaesthesia care unit (PACU) or expensive equipment, such as i.v. PCA pumps, can result in sub-optimal pain management practices [16,28].
Inadequate pain management may lead to negative clinical consequences to patient health that extend beyond acute discomfort. Pain can lead to sympatho-adrenal activation, and in turn may contribute to complications such as coronary ischaemia, myocardial infarction and poor wound healing [29,30]. Pain may also limit respiratory effort and impair mobilization, thereby increasing the risk of pneumonia, deep vein thrombosis and pulmonary embolism [29,30]. Conversely, effective management of postoperative pain can potentially improve patient outcomes . Benefits to patient health that can stem from the effective management of acute postoperative pain include better pulmonary function, reduced cardiovascular stress and reduced postoperative complications [1,4].
Use of a combination of effective therapeutic options and treatment strategies may serve to improve the efficiency and quality of postoperative pain management. The concept of fast-track surgery incorporates effective pain management into a multidisciplinary approach to enhance the postoperative outcomes of surgical patients. Fast-track surgery or accelerated rehabilitation programmes, may include several perioperative and postoperative interventions, such as minimally invasive surgical procedures, optimal fluid management, prevention of intraoperative hypothermia and hypoxia, multimodal analgesia, reduction of postoperative nausea and vomiting, early enteral nutrition and early patient mobilization [31,32]. Evaluations of outcomes from fast-track rehabilitation programmes have shown a reduction in general patient morbidity, healthcare costs and the duration of hospital convalescence compared with conventional care [33,34]. The potential influence of analgesic strategies on the incidence and severity of postoperative nausea, tolerance of an oral diet and early patient mobility highlight the importance of integrating optimal pain management practices into accelerated rehabilitation programmes.
Importance of an APS for optimal pain management
The optimal management of postoperative pain encompasses a number of important stages. Having administered a loading dose of opioid intraoperatively, any residual pain must be treated immediately following surgery by titration with bolus doses of opioids, until a tolerable level of pain is achieved and then maintained into the recovery period. Patients should be provided with a pain management plan prior to their discharge from the hospital to ensure that continuity of pain relief is achieved outside the hospital setting.
Recognition of the benefits resulting from the provision of postoperative analgesia by multidisciplinary pain management teams has led a number of hospitals throughout Europe and the rest of the world to resource and develop a formal APS [26,35]. It is believed that the introduction of an APS has led to an increase in the appropriate use of specialized analgesic techniques, such as i.v. PCA, epidural analgesia and perineural analgesia. The implementation of these techniques may represent a true advantage in improving analgesia and patient well-being and also in reducing postoperative morbidity [5,9]. In a recent literature review, Werner and colleagues evaluated the impact of an APS on postoperative outcome and concluded that the implementation of an APS was associated with a significant decrease in pain intensity .
The number of hospitals with an APS has increased across Europe and worldwide over the last several years [16,25,36,37], but room for improvement remains. For example, a lack of consensus exists regarding the proper organization and function of an APS . The development of standards against which the performance of an APS may be measured could aid in the evaluation of institutional practices and assist in clearly defining the specific role of APS in patient care. In addition, the continued development of effective postoperative pain management technologies that serve to simplify the process of postoperative patient care may contribute to efficient APS function and improved patient outcomes.
Current pain management practices in Europe
This article summarizes the findings of recent surveys of postoperative analgesic practices in Europe and discusses the merits of various opioid and multimodal therapies (Table 1). Although oral opioids are non-invasive and convenient to administer for the treatment of moderate-to-severe pain, they are often precluded in the immediate postoperative period, restricting analgesic delivery to a variety of parenteral routes. Once patients are capable of tolerating oral medication, the relative simplicity and convenience of oral administration makes this the preferred approach for the remainder of therapy up to and following discharge from the hospital. It is accepted, however, that oral opioids have a delayed onset of action and a less predictable duration of action relative to parenteral opioids, resulting from poor absorption in the gastrointestinal tract and significant enterohepatic metabolism (i.e. first-pass effect). Therefore, larger doses of opioids are required for oral delivery than for parenteral administration .
Intramuscular (i.m.) administration
The i.m. route avoids first-pass hepatic metabolism and results in a more rapid onset of analgesia than that observed with oral administration, although absorption can be affected by variable muscle perfusion immediately following surgery . The i.m. route has additional drawbacks: frequent (every 3-4 h), painful injections that may result in cycles of analgesic peaks and troughs, the latter exacerbated by the delay between patient requests for doses and the onset of analgesic action . An additional drawback to i.m. opioid therapy is the increased labour costs relative to PCA .
The i.m. analgesia was associated with more patients experiencing inadequate pain relief compared with i.v. PCA or epidural administration in a review of publications that analysed the severity of pain intensity . In addition, patient satisfaction with i.m. analgesia was shown to be much lower than with i.v. PCA . Nevertheless, recent European surveys indicate that i.m. analgesia is still routinely used in many hospitals. Results of a 2001 survey of the heads of anaesthesiology services in Spanish hospitals revealed that i.m. injections were ‘available/used' for analgesia in more than 55% of surgical wards and in more than 30% of PACUs in Spain, despite this method of administration being rated poorly in terms of analgesic outcome . A recent audit of drug prescription charts in a large UK hospital found that over 50% of the anaesthetic staff routinely prescribed i.m. analgesics for postoperative pain . Likewise, a study of analgesic administration practices in Italian ICUs found that the second and third most commonly used opioids, morphine and buprenorphine, were administered by i.m. injection to 13% and 38% of patients, respectively, in the first 2 postoperative days .
I.v. bolus administration
Administration of i.v. bolus doses of opioids provides rapid, effective analgesia resulting from the direct administration of analgesics into the systemic circulation. However, similar to i.m. analgesia and other intermittent dosing regimens, i.v. bolus administration is not well suited to providing continuous pain relief and can lead to fluctuations in serum concentrations. In addition, the requirement for administration of i.v. injections by certified hospital personnel introduces the potential for treatment delay and adds to the labour costs for this technique. Despite these limitations, however, i.v. bolus analgesia is routinely used in many hospitals. For example, analgesic administration by i.v. bolus injection was the most commonly used technique for opioid administration to patients during the first 2 postoperative days in Italian ICUs , and this method was recently shown to be ‘available/used' in more than 80% of PACUs and more than 65% of surgical wards in Spain .
Epidural analgesia generally utilizes small doses of opioids, most often in combination with local anaesthetics, to produce highly effective, long-lasting pain relief. The first-pass hepatic effect is avoided by this route, and the time to onset of analgesia is generally short. Epidural analgesia was found to provide pain relief superior to common parenteral procedures (i.m. analgesia and i.v. PCA) in large meta-analyses of published data [14,43].
Epidural analgesia was associated with a reduced risk of pulmonary complications in high-risk patients with poor preoperative pulmonary function . In addition, the administration of epidural analgesia for longer than 24 h after surgery was shown to reduce the incidence of postoperative myocardial infarction . However, conflicting evidence exists regarding the influence of epidural analgesia on reducing postoperative morbidity; therefore, further analyses are warranted [4,44,45].
Administration of epidural analgesia is an invasive technique that requires substantial staff training and is prone to improper catheter placement and complications; technical failures such as catheter dislodgement, migration and infiltration occur at a relatively high rate [14,46,47]. In addition, indwelling epidural catheters are associated with a small risk of superficial and deep infections . A recent Swedish study showed that the risks of severe neurologic complications associated with epidural blocks in elderly patients are far higher than previously presumed . Due to the rare but very serious risks such as late onset respiratory depression, hypotensive episodes and spinal haematoma (particularly in patients who have received anticoagulants), patients have to be monitored frequently. In many institutions, such patients cannot be properly cared for in surgical wards due to the lack of a trained staff, appropriate protocols and an APS.
Epidural administration of opioids is frequently performed throughout Europe. Nearly all hospitals in the United Kingdom offer epidural analgesia; however, its use is limited to less than one-third of surgical disciplines . A survey of epidural practice in Germany in 2000 showed that 58% of anaesthetic departments practised continuous epidural infusion and 57% administered bolus doses via the epidural route . The majority of German surgical departments combined ropivacaine or bupivacaine with an opioid for epidural administration; the most frequently used opioid was sufentanil, followed by morphine and then fentanyl . The majority of respondents to a recent survey of hospitals in the United Kingdom used a combination of bupivacaine and opioid for thoracic epidural procedures, with fentanyl (58%) or diamorphine (41%) being the most commonly used opioids, followed by alfentanil and morphine .
Peripheral regional analgesia
Peripheral regional analgesia (e.g. non-opioid nerve blocks and wound infiltration) can be very effective in the treatment of postoperative pain following specific surgical procedures. Local anaesthetics may be delivered via a catheter by on-demand, self-administered bolus doses or continuous infusion. An advantage to this approach is that excellent analgesia is targeted to the relevant affected area, thereby reducing systemic exposure to opioids and their associated side-effects. Patients with known sensitivities to opioids are therefore ideal candidates for this therapy. Nerve blocks may also enable vigorous postoperative physiotherapy as a result of the effective, targeted analgesia.
Nerve blocks are useful following orthopaedic surgery, but are not practical following cardiothoracic and major abdominal surgical procedures. In addition, nerve blocks can sometimes cause nerve damage from needle trauma, local anaesthetic toxicity, inadvertent intravascular injection and delayed effects from motor or autonomic blockade . Perineural techniques have the disadvantages of requiring exact needle placement and substantial time for administration. Furthermore, perineural catheter tip position may be unreliable in many patients. These procedures must be carried out by skilled anaesthesiologists, as the failure rate can be relatively high, even in experienced hands. Because of the limited number of anaesthesiologists whoare trained and skilled to perform these techniques, perineural analgesia is not as widely available as other analgesic therapies.
PCA is well established in the management of acute pain, particularly postoperative pain. PCA modalities are said to ‘empower' patients, giving them control of their analgesic regimen (within limits) and thereby avoiding the treatment delays associated with the administration of analgesics by staff members of the hospital. PCA administration requires programmable pumps or mechanical devices to deliver small incremental doses of i.v. opioid or epidural local anaesthetics upon patient demand. This approach enables patients to achieve a relatively uniform, titrated level of pain relief, while reducing the incidence of adverse events associated with larger bolus doses.
Patients have reported high satisfaction with PCA , and studies indicate that patients prefer i.v. PCA to intermittent i.m. and i.v. bolus dosing regimens [41,54]. Interestingly, in comparative studies, patients preferred i.v. PCA to patient-controlled epidural analgesia (PCEA), despite the former being associated with higher pain scores . Patients using i.v. PCA in these studies achieved more uniform pain relief and experienced fewer side effects than patients using PCEA.
A disadvantage to both i.v. PCA and PCEA is the necessity for a PCA pump. Purchasing or rental of PCA pumps requires substantial hospital resources, and reusable PCA pumps require routine maintenance. In addition, PCA pumps must be programmed by hospital personnel prior to each use. Incorrect entry of dosing parameters may lead to overmedication, and has resulted in patient death in some cases .
Intravenous PCA is the standard of care for acute postoperative pain management in many European countries. In Germany, the percentage of hospitals using i.v. PCA ‘often' or ‘occasionally' increased from 46.6% in 1997 to 64.5% in 2002 . Similarly, intravenous PCA was recently shown to be ‘available/used' in approximately 50% of surgical wards and more than 50% of PACUs in Spain . In contrast, results of a survey of epidural practice in Germany in 2000 showed that only 20% of anaesthetic departments used PCEA .
A multimodal approach (combined with opioid-based PCA) is one of the key elements of modern acute postoperative pain management. Multimodal therapy for postoperative pain control combines the administration of different classes of analgesics that act by complementary mechanisms to provide an additive or synergistic analgesic effect. Combining adjuvant analgesics (usually paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs) and local anaesthetics) with opioid therapy results in a lower opioid dose requirement, with consequent benefit of a reduced incidence of opioid-associated side-effects, such as nausea, vomiting, respiratory depression and pruritus [10,57]. It is becoming apparent that to optimize opioid sparing, the non-opioid adjuvants such as NSAIDs, paracetamol, ketamine and clonidine should be started early and continued on a regular ‘by the clock' basis. Pre- or intra-operative administration of the non-opioid analgesic in a ‘preventative therapy' strategy aims to have effective analgesia by the time of emergence from anaesthesia, so as to avoid the patient waking in severe pain and needing substantial opioid rescue boluses, with increased potential for associated opioid side-effects.
It has also been recognized that strategies not currently in widespread use may be invoked to reduce hyperalgesia of central origin using an N-methyl-d-aspartate receptor antagonist such as ketamine . Gabapentin, well established in the treatment of neuropathic pain, has also been assessed as an opioid-sparing adjuvant analgesic drug for postoperative pain . It has also been postulated that such strategies may reduce the progression from acute to chronic pain states post-surgery.
Nevertheless, while opioid-sparing strategies are highly desirable, opioids remain the essential analgesic ‘ingredient' for the systemic treatment of moderately severe to severe postoperative pain.
Fentanyl HCl iontophoretic transdermal system (fentanyl ITS)
The fentanyl ITS is a novel analgesic delivery system that has been approved by the European Medicines Evaluation Agency (EMEA) for the management of acute, moderate-to-severe postoperative pain (Fig. 1). The fentanyl ITS is a needle-free, patient-controlled system that administers a pre-programmed dose of fentanyl upon patient demand. It utilizes the process of iontophoresis to deliver ionized fentanyl molecules across intact skin and directly into the systemic circulation upon the application of an imperceptible electric current. Iontophoresis significantly enhances the penetration rate of fentanyl through the stratum corneum of the epidermis relative to passive diffusion [60,61].
The self-contained fentanyl ITS is compact and is applied to a patient's upper outer arm or chest via a self-adhesive backing. Drug delivery is initiated when the patient double-clicks the on-demand dosing button. A 40-μg dose of fentanyl is delivered over a 10-min period, time during which additional dosing is prevented. The patient can self-administer up to 6 doses h−1 for 24 h or a maximum of 80 doses per system, whichever occurs first. The system will no longer respond to dosing requests after this point, and may be replaced with a new system if continued analgesia is required. Approximately 41% of the nominal 40-μg dose of fentanyl is absorbed into the bloodstream in the first hour of treatment with fentanyl ITS, and absorption increases to nearly 100% after 10 h of treatment . The maximum serum fentanyl concentration (Cmax) with fentanyl ITS is 1.37 μg L−1 compared to 1.82 μg L−1 with i.v. fentanyl .
The efficacy of the fentanyl ITS is supported by data from one active-controlled study and three placebo-controlled studies of adult patients following major abdominal, orthopaedic or thoracic surgery (Table 2) [64-67]. Results of the placebo-controlled studies demonstrated that fentanyl ITS was superior to placebo in providing postoperative pain relief, as measured by the number of patient withdrawals from the study due to inadequate analgesia, and by patient ratings of pain intensity and the method of pain control [64-66]. Additional outcome measures were evaluated using patient questionnaires in the largest of the placebo-controlled studies . A larger percentage of patients (61.5%) in the fentanyl ITS group than in the placebo group (32.1%) were very satisfied with their method of pain management, and the majority of patients found the fentanyl ITS to be very convenient (79.8%) and very easy to use (87.0%).
The fentanyl ITS was shown to be an equivalent method of pain control compared to a standard regimen of morphine i.v. PCA in a large study of adult patients following major abdominal, orthopaedic or thoracic surgery (Table 2) . A similar percentage of patients in each treatment group (>73%) reported a rating of success (‘excellent' or ‘good') on the global assessment of the method of pain control in the first 24 h, and >80% of patients in each group reported a rating of success on this measure in the second and third 24-h periods of continued treatment.
The fentanyl ITS also has a favourable safety profile. A total of 1142 patients have been treated with the system in several clinical studies; none of these patients experienced clinically relevant respiratory depression (defined as <8 breaths min−1 and excessive sedation) . Most of the adverse events that occurred in patients treated with the fentanyl ITS in the four controlled phase III trials (n = 791) were of mild or moderate severity and were those that are commonly experienced during opioid therapy. In the active-controlled phase III trial, opioid-related adverse events occurred at a similar frequency between the fentanyl ITS and morphine i.v. PCA groups, the most common of which were nausea, headache, vomiting and pruritus, respectively .
Skin reactions may occur at the application site of the fentanyl ITS. The most common application-site reactions reported as adverse events in the four controlled phase III trials were erythema, itching and vesicles, which combinedly occurred in 13% of patients [64-67]. The majority of these application-site reactions were of mild-to-moderate severity. Skin assessments completed at 24 h after removal of the fentanyl ITS from patients (n = 789) in the four controlled studies revealed that most patients had no erythema (51.7%) or barely perceptible/noticeable redness (27.8%) at the application site.
The fentanyl ITS addresses several of the limitations to the currently available therapies for postoperative pain management. The pre-programmed circuitry of the fentanyl ITS eliminates medication errors resulting from improper programming. In addition, the system's non-invasive drug delivery technology avoids the risk of complications from catheter infiltrations or accidental needlestick injuries, which may occur when using existing analgesic techniques. The fentanyl ITS also does not require patients to be attached to infusion tubing or a PCA pump that may restrict movement and potentially interfere with physiotherapy sessions following surgery.
Although the pre-programmed electronic circuitry of the fentanyl ITS provides an inherent safety advantage by preventing improper manual programming, the inability to make dosing adjustments to the system may also be viewed as a limitation. For example, the size of a dose cannot be increased for patients with a high opioid demand, nor decreased for patients who are opioid sensitive. Although the system cannot be adjusted to add a continuous, basal infusion, the addition of a basal infusion to a standard regimen of morphine i.v. PCA was not shown to improve pain control, and may decrease the inherent safety of PCA . An i.v. PCA pump offers the ability to adjust the dosing regimen over a wide range. In practice, however, clinicians use a narrow range, and preferred dosing parameters reported in the literature are similar .
It is well known that hypothermia is common during the postoperative period . The reduction in skin perfusion that is associated with hypothermia has the potential to affect the rate of drug delivery from the fentanyl ITS. Hypothermia, however, does not appear to be of concern since the clinical studies have shown that fentanyl ITS is clearly effective in the postoperative setting. Another potential limitation of the fentanyl ITS is the risk of detachment from a patient's skin, although evidence from clinical studies indicates that this is a low probability event.
Until the fentanyl ITS becomes available for use in clinical practice, the financial cost of treating patients with the system remains undetermined. The likely sources of expenditure associated with its use, however, are expected to be fewer than for i.v. PCA. The cost of treatment using i.v. PCA includes expenses associated with the PCA pump (e.g. purchase or rental, maintenance and replacement of the pump) and materials consumed by treatment (e.g. analgesic, catheter and i.v. tubing). In addition, the administration of i.v. PCA incurs significant labour costs related to training the hospital personnel, loading the analgesic, setting up the i.v. PCA apparatus and programming the pump . Because the fentanyl ITS is self-contained and pre-programmed, no hospital resources would be required for its assembly or programming. Utilization of the fentanyl ITS also would not consume resources dedicated to maintenance or repair, since the system is discarded following each use. For these reasons, the purchase price of the fentanyl ITS would likely constitute most of the expenses associated with its use.
Inadequate management of postoperative pain continues to be a problem in hospitals across Europe and the rest of the world. An important step in making progress in the alleviation of postoperative pain is the development of analgesic modalities that improve upon existing therapies. For example, PCA modalities have resulted in improved pain relief and greater patient satisfaction compared with conventional techniques used to administer intermittent bolus doses of opioids [38,41,53,54]. However, existing PCA modalities are associated with a number of limitations that can lead to potentially dangerous sequelae. Modalities that utilize PCA pumps introduce a risk of manual programming errors that have led to over-medication and patient death in some cases . In addition, invasive techniques for the administration of analgesics increase the risks of infection to patients and the hospital staff and of needlestick injuries.
The fentanyl ITS can be expected to be a useful alternative to existing therapies for the management of moderate-to-severe postoperative pain. In addition to its favourable efficacy and safety profile, as well as its non-invasiveness and ease of use, this system may overcome a challenging regulatory hurdle to the management of postoperative pain in parts of Europe. Nurses are prohibited from administering i.v. or epidural opioids in many European countries and institutions. Analgesic techniques that do not require physicians for their administration represent one solution to this significant restriction. However, there is a need to further evaluate this novel method of PCA.
In addition to the development of improved analgesic techniques, further progress in the treatment of postoperative pain may be achieved through the proper organization and function of pain management teams that are responsible for postoperative patient care. The utilization of improved analgesic modalities under the guidance of an effective APS holds the potential to resolve current inadequacies in postoperative pain management.
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