Technical Measures to Prolong Analgesia: Comparison
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Please note this is a comparison between Version 2 by Jessie Wu and Version 1 by Lukas Gasteiger.

With the development of extended-release formulations and enhanced selectivity for nociceptive sensory neurons, a very promising contribution to the development of pain medications has been achieved. At present, liposomal bupivacaine is the most popular, non-opioid, controlled drug delivery system, but its duration of action, which is still controversially discussed, and its expensiveness have decreased initial enthusiasm. Continuous techniques can be seen as an elegant alternative for providing a prolonged duration of analgesia, but for logistic or anatomical reasons, they are not always the best choice. Therefore, focus has been directed towards the perineural and/or intravenous addition of old and established substances. 

  • anesthesia
  • continuous techniques
  • regimen

1. Introduction

With more than 80% of patients experiencing acute pain following surgical procedures, and half of them reporting inadequate pain therapy, the control and management of post-surgical pain remains one of the most challenging aims of modern anesthesia [1]. Post-surgical pain and immobilization reinforce each other and lead to low patient satisfaction, delayed recovery and discharge from hospital. Thus, both reflect main targets for Enhanced Recovery after Surgery (ERAS) pathways [2,3,4][2][3][4]. For decades, opioids, with their potent analgesic effectiveness, have been the mainstay of postoperative pain management. However, opioids may also lead to adverse events, e.g., prolonged length of hospital stay (LOS) due to dose-related side effects such as respiratory depression, sedation, postoperative nausea and vomiting (PONV), tolerance and hyperalgesia, urinary retention or the development of bowel dysfunction [5,6,7][5][6][7]. Additionally, when considering the current opioid crisis, effective pain control considerably reduces the need for opioids after surgical procedures.
Therefore, modern concepts of multimodal pain therapy, including minimal-invasive approaches in surgery, regional anesthesia (RA) and non-opioid pain medication, aim at facilitating different pathways in order to provide effective pain control, early mobilization and minimize opioid demand, leading to faster patient recovery following major surgery.
RA techniques have shown their benefit by reducing opioid use and shortening the stay on postoperative care units [2,8][2][8]. However, a single injection of local anesthetics (LA) hardly lasts longer than 24 h. A common alternative is the use of catheter-based anesthesia techniques, for which prolonged analgesia and shorter LOS have been described [9]. Unfortunately, these techniques have some disadvantages, amongst others: catheter tip dislocation, infection and the need for more complex in-hospital logistics [2].
Several pharmacological and application strategies have therefore been assessed, with the primary goal to achieve a safe, reliable and long-lasting analgesic effect with minimal motoric restrictions, enabling the patient to be as autonomous as possible. Promising solutions incorporate LAs and/or analgesics into biodegradable structures that provide extended release of the drug at the target location with low systemic side effects. In addition, progress has been made in the field of selectively blocking sodium channels, which play a central role in the genesis and conduction of nociceptive stimuli.

2. Clinical Concepts

Mixture of LAs

The practice of mixing LAs to combine the characteristics of two substances has a long tradition and goes back to the 1950s [69][10]. The combination of short- and long-acting drugs should accelerate block onset to rapidly obtain surgical anesthesia on the one hand, and prolong block duration to achieve postoperative analgesia on the other hand. The two components are mixed in one syringe or injected sequentially. Both methods show similar results regarding block characteristics [70,71][11][12]. Basically, the driving force of an LA to penetrate neural tissue is its concentration gradient. The combination of two substances results in the dilution of each component, lowering its concentration and thus limiting its transfer across the cell membrane [72][13]. Moreover, mixing solutions of varying physicochemical properties (e.g., pH) results in changes to their ionized and non-ionized fractions [72,73][13][14]. LAs can cross lipid layers only in their non-ionized form. Thus, lowering the pH as a result of mixing two LAs (e.g., lidocaine and bupivacaine) decreases the efficacy of each or both components [72][13]. Some examples of investigated compounds in currently available LAs are as follows: lidocaine/bupivacaine, lidocaine/ropivacaine, mepivacaine/bupivacaine, mepivacaine/ropivacaine, chloroprocaine/bupivacaine, prilocaine/bupivacaine and prilocaine/ropivacaine. Such mixtures are used for several regional techniques, such as epidural and caudal anesthesia, as well as peripheral nerve blocks (PNB). Clinical and experimental studies from the last century obtained conflicting results. In common, they all showed an accelerated block-onset when a short-acting drug was added to a long-acting drug, but at the expense of block duration [69,74,75][10][15][16]. These findings have been reproduced in recent studies [76,77][17][18]. Since peripheral RA has changed significantly with the implementation of ultrasound-guided peripheral nerve block (US-PNB) techniques, block onset is of limited clinical relevance. US-PNB is known to reduce the time to onset of sensory block. In contrast to traditional nerve localization techniques, high-resolution ultrasound imaging has led to the precise injection and monitoring of LA spread around nerves [78,79][19][20]. Thus, even long-acting drugs show acceptable onset times. Accordingly, US-PNB allows for the reduction in dosage of LA and a reduced potential for direct local LA toxicity [80][21]. Thus, the initial idea of combining the advantages of two drugs (rapid block onset and long-lasting analgesia) cannot be supported in the light of modern regional anesthetic techniques. Furthermore, the systemic toxicity of two injected LAs is regarded to be additive [81][22]. This issue is often neglected in clinical practice. Additionally, mixing LAs might increase their neurotoxic potential [82][23].

3. Continuous Techniques

The use of continuous techniques by means of perineural catheters has been described for all regional anesthetic techniques (epidural and spinal anesthesia, PNB). In modern perioperative care, epidural and peripheral catheters are used to prolong postoperative analgesia by the continuous infusion of low-concentrated LAs (e.g., ropivacaine 0.2%). Electronic delivery systems allow for additional boluses on demand (patient-controlled analgesia). Although recently developed nerve block techniques (e.g., fascial plane blocks) have been introduced into clinical practice as safe alternatives to epidural analgesia, the latter remains an effective alternative for postoperative pain management after major upper abdominal and thoracic surgery [107][24]. Nevertheless, careful patient selection based on a risk-benefit discussion is mandatory [108][25].
The epidural administration of LAs and opioids provides efficacious analgesia during labor [109][26]. Likewise, peripheral catheters have been frequently used to provide optimal analgesia for various indications [110][27]. In terms of toxicity, continuous infusions of LAs are regarded as safe, since common infusion rates do not result in toxic LA plasma concentrations [111][28].
Nevertheless, their use has decreased for several reasons. Multiple pharmacologic interventions as part of a multimodal analgesic regimen seem to be equally effective when combined with single-shot nerve blocks. Moreover, catheters have a high incidence of dislocation, and their insertion can be challenging [112][29]. Other technical problems and side effects are leakage, pump malfunction, undesired motor block and local infection. All continuous techniques have in common a requirement of additional nursing to check for their effectiveness and side effects. Thus, staff shortages have further limited the use of these techniques.

4. Continuous Wound Infusion

Continuous wound infusion (CWI) has been established as a safe and effective alternative to traditional regional anesthesia techniques. CWI is mediated through specially designed multi-hole catheters, which are inserted into the wound mostly at the end of surgery. The underlying mechanism of action is a blockade of afferent nociceptive fibers around the surgical wound. A recent meta-analysis showed a favorable analgesic profile without severe complications for different types of abdominal surgeries [113][30]. CWI has gained an important role in perioperative pain management in several types of surgeries as part of a multimodal regimen [114][31].

5. Infusion Systems

Many devices are marketed to deliver LAs via catheters. Electronic systems offer a variety of settings, whereas disposable elastomeric pumps provide continuous infusion and fixed bolus rates, depending on pump model (e.g., 2 mL every 15 min). In general, several modes of drug administration are being used: continuous infusion, programmed intermittent bolus (PIB) and bolus on demand, and a combination of all of those (e.g., continuous infusion and bolus on demand). The optimal result would be complete analgesia without any or less motor weakness. Since LAs are non-selective for Nav channels, differential effects for sensory and motor blockades are difficult to achieve. Various infusion regimes have been studied. So far, a specific setting for the peripheral infusion of LAs cannot be recommended, since current data are extremely heterogeneous [115][32]. Nevertheless, the intermittent application of large boluses is preferred when extended spread is warranted [116][33]. In contrast, PIB has proven to be beneficial for labor analgesia, resulting in a higher patient satisfaction, less motor block and a lower incidence of instrumental vaginal delivery [117,118,119][34][35][36]. Thus, many institutions consider PIB as a standard mode for epidural analgesia during labor.

References

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