Transdermal Fentanyl as a Form of Rebound Pain Reduction in Fast Track Programme in Primary Knee Arthroplasty.

Total knee arthroplasty (TKA from now on) is a frequent surgery in routine clinical practice in constant evolution and improvement, with the objective being the earliest possible functional recovery of these patients, the role of the anaesthesiologist being fundamental in this sense throughout the perioperative period since, as we know, it is a surgery that improves the mobility and quality of life of the patient, but causes intense postoperative pain during the first 24 to 72 hours, it is a surgery that improves the patient's mobility and quality of life, but causes intense postoperative pain during the first 24 to 72 hours, a very important factor to take into account in these patients since it is known that adequate postoperative pain control promotes ambulation and the possibility of physiotherapy for the patient, This leads to an early recovery, a lower rate of complications (such as deep vein thrombosis or nosocomial infection) and a shorter hospital stay, allowing the strategy known as "fast-track" to be carried out, which would consist of achieving functional recovery and discharge as early as possible, this being the current trend in management by most trauma teams dedicated to this field, since it results in a decrease in morbidity and greater patient satisfaction. In relation to this approach, as has been mentioned, multiple studies have shown that one of the main causes of delayed hospital discharge is poor pain control and mobilisation problems.

Therefore, adequate postoperative pain control will be important in this surgery. This control could be achieved with a combination of locoregional techniques such as peripheral nerve blocks of the adductor canal (BCA) and the so-called "Infiltration between the Popliteal Artery and the Capsule of the Knee" (IPACK) together with conventional analgesia such as NSAIDs, paracetamol, metamizole and, if this is not sufficient, opioids.

The locoregional techniques mentioned (BCA + IPACK) have demonstrated their efficacy in controlling immediate postoperative pain in this type of surgery in multiple studies. The first of these, BCA, provides analgesia in the anteromedial area of the knee, avoiding the femoral nerve block with the consequent weakness of the quadriceps. The second of these, IPACK, is a relatively novel technique described to achieve analgesia in the posterior capsule of the knee that is achieved by blocking the popliteal plexus formed by the articular sensory branches of the tibial and obturator nerves arranged around the popliteal artery and vein without involving the motor branches of the tibial and peroneal nerves, avoiding the motor block resulting from performing a block of the sciatic nerve at the popliteal level.

From all of the above, we can deduce that both techniques are effective individually, but even more so, as is logical, in combination, allowing the entire joint territory to be covered with the least possible impairment of motor function, which will be of particular relevance in terms of starting the patient's mobilisation earlier, which is definitely an advantage over traditional femoral and sciatic nerve block techniques.

However, the duration of nerve blocks is less than 24h, which is a problem, since the period of maximum incidence of postoperative pain has not yet been completed and it is possible that just at this time (12-24h after the block, when the effect of the block ends) what is known as "rebound pain" may appear, considered a possible adverse effect of peripheral nerve blocks that is becoming increasingly important, as studies dedicated to its study emerge.

There are multiple definitions of rebound pain in the literature, but objectively, we can say that it is a quantifiable difference between scores on pain scales when the block works and when it stops working. Its incidence is not well established, although some studies report that it appears in up to 40% of cases receiving some type of peripheral nerve block, although its incidence in the type of patient on whom this study is to be performed has not been specifically defined in the literature available to date. As for its characteristics, we can say that it appears suddenly at 12-24h, lasting 3-6h, described by many patients as a burning sensation that worsens at night. Logically, this will have a negative impact on the patient's recovery, and will require the use of rescue drugs, mainly intravenous opioids.

To date, the pathophysiological mechanisms by which it occurs continue to be the subject of debate. It is definitely a sum of mechanical and chemical factors (neurotoxicity of local anaesthetics, hyperactivity of nerve fibres, hyperexcitability of nociceptors, direct mechanical damage, etc.) in patients with predisposing factors (young people, women, orthopaedic surgery, pre-existing pain, etc.).

Once its existence is known, the two most important aspects will be its proper diagnosis and definition, on the one hand, and its prevention and treatment, on the other.

In terms of its detection, rebound pain will be diagnosed when a difference in pain scale scores is observed at the end of the peripheral blockade effect, which is usually 12-24 hours after it has been performed. To quantify it, most studies use serial scores on the numerical pain scale (NRS), and even the "rebound pain score" has been described, which is obtained by subtracting the lowest pain score in the first 12 hours before the end of the block action from the highest pain score in the first 12 hours after the end of the block action.

In prevention and treatment, a multifactorial approach will be essential, employing pharmacological and non-pharmacological strategies (mainly patient education). Among the pharmacological strategies, there are multiple strategies that have been shown to reduce the rate of rebound pain but among which there is no clear consensus: the use of adjuvants such as dexamethasone or alpha2-agonists, which not only prolong the duration of the block but also seem to exert a neuromodulatory effect; use of continuous infusion catheters instead of a single puncture; combination of various types of peripheral blockade or intra-articular infiltration. Another option, this one highly recommended in general, is the initiation of analgesic treatment prior to the end of the blockade effect, since once it occurs, it will be very difficult to control, making it necessary to rescue with intravenous drugs, mainly major opioids such as morphine in the form of a PCA pump, an analgesic modality that has demonstrated its effectiveness but which has a number of negative aspects such as: the need for personnel capable of handling the device and a learning process on the part of the patient; the possibility of programming and medication administration errors; an increase in economic cost; in addition to the consequent limitation of mobility derived from the connection to the PCA device or the delay in discharge due to the patient being under intravenous treatment.

However, a new possibility has emerged in the form of the transdermal fentanyl patch (TFP); a skin patch that constantly releases fentanyl into the bloodstream according to the dose applied, traditionally used in the control of chronic pain but whose efficacy has already been demonstrated in multiple types of surgery such as abdominal, urological and orthopaedic procedures such as hip and knee surgery. Fentanyl is a major opioid with 75-100 times the potency of morphine. Because it is highly lipid soluble and has a low molecular weight (337da), it is ideal for administration in this transdermal format; it also produces fewer cardiovascular effects than other opioids and has a lower risk of histamine release than morphine. Once applied, the patch has a slow onset of action with a plasma peak in about 12-15h and stable plasma concentrations thereafter for approximately 72h of duration. It has many advantages over other forms of analgesia, such as ease of administration, reduced possibility of dosing error, no need for venous access, low risk of infection and easier to obtain than devices such as the PCA pump.

The main drawback to its use as a form of postoperative analgesia lies in its slow onset of action, since, as mentioned, its plasma peak would be reached at 15h, which makes it unsuitable for acute pain control. However, if applied at the time of surgery, it could superimpose its analgesia on the end of the analgesic effect of the peripheral nerve block, thus avoiding the appearance of rebound pain or at least reducing its rate of appearance.

Therefore, several positive aspects could be derived from this alternative: convenience in its dosage, reduction of resources necessary for the adequate control and functioning of a morphine PCA and improvement in postoperative pain control, resulting in an increase in the degree of patient satisfaction and autonomy and a shorter hospital stay.

With all of the above, we propose the hypothesis that the transdermal fentanyl patch is an effective postoperative analgesic strategy in primary knee arthroplasty after the disappearance of the analgesic effect of the peripheral nerve blocks Canal of the Adductors + IPACK, achieving a decrease in the rate of "rebound pain", our main objective being therefore the following:

Main objective:

• To evaluate the decrease in the rate of rebound pain after primary knee arthroplasty with the use of transdermal fentanyl patch versus morphine PCA.

To do all this we will use objective and validated tools. For the measurement of the first objective we will use the "Rebound Pain Score", described above.

As for the secondary objectives that we propose to evaluate in this work, on the one hand, we want to focus on assessing the functional recovery of patients, for which we will use the QoR 15 scale, developed from the QoR40 (27), which has proven to be a suitable tool for measuring postoperative recovery (28); and on the other hand, to compare the two pharmacological modalities under study in terms of analgesic quality and adverse effects. Therefore, the following would be our secondary objectives:

Secondary objectives:

• To assess the non-inferiority in terms of functional recovery after primary knee arthroplasty of the transdermal fentanyl patch versus morphine PCA.
• To assess the analgesic non-inferiority in terms of postoperative analgesia after primary knee arthroplasty of the 25mcg/h transdermal fentanyl patch versus morphine PCA.
• To assess the non-inferiority in terms of incidence of adverse effects in postoperative total knee arthroplasty of 25mcg/h transdermal fentanyl patch versus morphine PCA.