1. Galimba, Jhunne


Postoperative pain in total knee arthroplasty is a challenge that affects the facets of an optimal recovery process. Adequate pain management can be achieved with traditional methods, such as parenteral opioids, epidural analgesic, and peripheral nerve blocks, but is often associated with disruptive side effects, mostly attributed to the opioids. Periarticular multimodal drug injection is an efficient alternative form of postoperative analgesia with minimal risk for opioid-related side effects. The purpose of this article is to describe the use and effectiveness of periarticular multimodal drug injection for postoperative pain management and accentuate the potential consequent effects of effective pain control. Comparative differentiation of this method with other forms of pain management modality is illustrated with strong emphasis on safety and efficacy.


Article Content

Total knee arthroplasty (TKA) is one of the most frequently performed orthopaedic surgeries in the United States (Jacobson et al., 2008). There is no argument that the projected number for TKAs over the next several years will continue to grow due to the increasing number of individuals afflicted with osteoarthritis. In fact, according to the Arthritis Foundation, there are approximately 33 million Americans diagnosed with osteoarthritis today, and this number is steadily increasing partly related to comorbid conditions such as obesity and diabetes (Arthritis Foundation, 2009). Even though there are several different treatments available that will slow down the progression of osteoarthritis, in time, these individuals will likely succumb to the last form of treatment, which is joint arthroplasty.


There are different types of joint arthroplasty; however, this article will solely focus on TKA. Even though the literature illustrates that TKA unarguably has helped improve the active lives of thousands of individuals, there are individuals who remain hesitant to undergo TKA. One common reason often cited by individuals who have elected to delay TKA centers on the individual's fear of considerable postoperative pain (Ranawat & Ranawat, 2007). According to Colwell (2008), TKA may generate severe pain as compared with other orthopaedic procedures related to traumatic tissue injury, especially the bone. The advancement in surgical techniques and improvement of joint prosthetic components are some key elements that have promoted less tissue manipulation, which, in turn, contributes to better pain control and a faster recovery process (Goyal, Parikh, & Austin, 2008).


The value of pain control is of the highest priority for the surgery recipients. According to Parvataneni, Ranawat, and Ranawat (2007), more than 50% of joint replacement patients receive inadequate pain control, with half of these patients experiencing severe pain. This percentage should not be acceptable and requires immediate intervention if we are to promote an optimal recovery process. Furthermore, effective pain control not only improves the patient's well-being but also promotes early mobilization, which, in turn, decreases the potential for postoperative complications such as pneumonia and deep vein thrombosis, shortens hospital stay, and increases patient satisfaction (Parvataneni et al., 2007). Although there are varieties of pain management modalities that can be utilized, a unique periarticular multimodal drug injection may just be the most effective and safest alternative pain control modality for postoperative TKA. Thus, the intent of this article is to discuss the use of periarticular multimodal drug injection as an effective alternative to traditional postoperative pain management modalities, as this treatment provides efficient localized analgesia thereby promoting earlier mobilization and thus decreasing the need for intravenous narcotics, which is often associated with undesirable systemic side effects (Busch et al., 2006).



Pain is a subjective experience that results in complex physiological responses, which can be triggered by tissue injury such as surgical trauma (Parvataneni et al., 2007). The degree to which pain is experienced depends on the processing of a noxious stimulus. The pain process or nociceptive process involves the peripheral and central nervous systems. Pain during surgery is magnified due to induced hypersensitivity of the peripheral nervous system wherein afferent nociceptive neurons' threshold is decreased and hypersensitivity of the central nervous system occurs, resulting in increased excitability of the spinal neurons (Busch et al., 2006). Although pain is a complex phenomenon and is poorly understood to some degree, research studies have allowed us to trace the nociceptive pain process, from impulse initiation to response modulation (Parvataneni et al., 2007).


As a result of research, various aspects of pain management are now better understood, prompting the delivery of a multimodal approach in pain control (Peters, Shirley, & Erickson, 2006). For this reason, postoperative surgical pain management is continuously being refined to better serve its purpose, as well as to promote patient comfort and well-being. In TKA, various pain management modalities, such as parenteral analgesia, epidural analgesia, or peripheral nerve blocks, are utilized. These modalities may be given to patients in their individual form, targeting a specific area of the nociceptive process. What if different areas of the nociceptive process are targeted simultaneously? Periarticular multimodal drug injection is an effective method that promotes simultaneous and localized targeted pain relief at different levels of the nociceptive process maximizing pain control, and it may also be used as an adjunct to other forms of conventional methods, such as oral analgesic and parenteral opioids, for breakthrough pain (Parvataneni et al., 2007). To better understand the importance and significance of periarticular multidrug injection, description and differentiation of the other 3 commonly used forms of pain management modality are warranted.


Parenteral Analgesia

Parenteral opioids have been the mainstay for pain management, and one of the most common ways of managing parenteral analgesic infusion is through a patient-controlled analgesic (PCA) pump (Colwell, 2008). Its use and benefits in immediate postoperative pain control have been well documented, and its utilization may also promote patient empowerment in managing one's postoperative pain. The process of analgesia is initiated when opiates bind with the opioid receptors strategically located in the central nervous system (Goyal et al., 2008). According to Trueblood and Manning (2007), the effectiveness and side effects of parenteral narcotics may also be dose dependent. Unfortunately, the pain control benefits may sometimes be clouded by various systemic side effects such as nausea, hypotension, pruritus, constipation, urinary retention, and respiratory depression (Trueblood & Manning, 2007). Pain control may be further enhanced by increased parenteral narcotic dosing but may ultimately increase the potential for detrimental systemic side effects. According to Colwell (2008), side effects such as postoperative nausea and vomiting have tremendous negative consequences for patients. Pain may well be controlled by parenteral narcotics, but the associated side effects may also delay the patient's overall recovery process and decrease patient satisfaction.


Epidural Analgesia

Depending on the established practice or facility protocol, epidural analgesic infusion can contain either narcotics or anesthetic or both. The infusion of opioids or local anesthetic alone may result in higher dosages, which can increase the potential for associated side effects. The combination of a local anesthetic and opioid analgesic promotes a synergistic effect and a resulting decrease in dosages for both medications (Goyal et al., 2008). According to Horlocker, Kopp, Pagnano, and Hebl (2006), epidural analgesia promotes better pain control and increased knee flexion when compared with parenteral analgesia.


The epidural analgesia is an effective approach, and the benefit of postoperative pain control is considerable; however, there is also a plethora of potential risks for major complications. For example, epidural analgesia can cause hypotension, bradycardia, nausea and vomiting, spinal headache, neurogenic bladder, and possible infection from epidural catheter insertion (Goyal et al., 2008). The potential for urinary tract infection is increased due to use of a urinary catheter related to diminished bladder control associated with epidural analgesia. According to Goyal et al., whereas pain control is enhanced by combining epidural anesthetic and epidural opioids, the side effects may also be augmented. Epidural analgesic approach is also associated with nerve injuries, such as peroneal nerve palsy, and gluteal compartment syndrome, which can significantly delay mobilization and overall recovery process (Vendittoli et al., 2006). The risk for spinal hematoma is also increased due to the recommended use of postoperative prophylactic anticoagulation to reduce risk for venous thromboembolic events, which is often the reason for the hesitancy of its use (Horlocker et al., 2006).


Peripheral Nerve Blocks

The use of regional nerve blocks involves the use of an anesthetic, such as ropivacaine. There are three peripheral nerve locations where the anesthetic can be introduced: (1) femoral nerve, (2) posterior lumbar plexus, and (3) sciatic nerve (Goyal et al., 2008). The mechanism of action involves the temporary interruption of the impulse transmission in the sensory nerve pathway (Banks, 2007). There are different ways to administer a nerve block, which range from single injection, multiple injections, to continuous infusion of an anesthetic through a catheter surgically placed against the target nerve (Banks, 2007; Vendittoli et al., 2006). This has been an effective pain control modality for TKA, and its use has promoted a decrease in the amount of narcotic utilization (Ranawat & Ranawat, 2007). According to Banks (2007), the innovations that help facilitate safe insertions of peripheral nerve catheters have also contributed to the renewed enthusiasm of their use.


Although peripheral nerve blocks provide effective pain management, its efficiency may well depend on the technical proficiency of the anesthesiologists (Ranawat & Ranawat, 2007). Moreover, one must also consider the delayed postoperative rehabilitation that is associated with peripheral nerve blocks (Ranawat & Ranawat, 2007). Utilizing this modality may have enhanced pain control for TKA and decreased the usage of parenteral narcotics, but there are some significant complications and risks to consider. The complications include systemic effects such as seizures from neurotoxicity, intravascular catheter migration, hypotension from cardiovascular collapse, infection at the catheter insertion site, and nerve damage from accidental needle trauma (Banks, 2007). In a study by Kandasami, Kinninmonth, Sarungi, Baines, and Scott (2008) that researched continuous femoral nerve block for TKA, it was found that this method increases the potential for delayed mobilization, increased hospital stay, and increased risk for falls.


Discussion of Periarticular Multimodal Drug Approach

The use of periarticular injection of multimodal drug combination of ropivacaine, ketorolac, and adrenaline intraoperatively, and postoperatively via intra-articular catheter for TKA is a technique that was developed by Dr. Kohan and Dr. Kerr of Sydney, Australia. This new method was called local infiltration analgesia or LIA (Kerr & Kohan, 2008). In this study, Kerr and Kohan used this method from January 1, 2005, to December 31, 2006, in 325 patients who were to undergo hip resurfacing, primary total hip replacements, and primary total knee replacements with limited postoperative use of parenteral and intramuscular narcotics. The results established not only efficacy of the drug combination used but also the safety of this method. The utilization of this approach was found to promote enhanced pain relief, and it increased patient satisfaction. It was also found that the multimodal drug utilized and the method of localized infiltration promotes early mobilization and independence, in part because it does not affect the motor functions of the leg muscles. It was also noted that the resulting reduction of hospital stay and its straightforward application and practicality not only promoted decreased potential for nosocomial infection but also promoted cost-efficiency (Kerr & Kohan, 2008). According to Kerr and Kohan, all 325 patients experienced no complications directly related with the use of LIA in the first 10 postoperative days. Although this was a nonrandomized study, the method and the drugs used became the model for future randomized clinical trials.


Periarticular multimodal approach involves the local injection of multiple medications in the immediate tissues surrounding the surgical joint (Busch et al., 2006). In a randomized study performed by Busch et al. (2006), unilateral TKA was performed on 64 patients, with 32 patients in the control group and 32 patients in the treatment group. The treatment group received a periarticular multidrug solution that consisted of anesthetic ropivacaine; nonsteroidal anti-inflammatory drug (NSAID) ketorolac; opioid epimorphine; and catecholamine epinephrine in conjunction with PCA morphine. Ketorolac is used to decrease the release of inflammatory mediators that induce peripheral hypersensitivity; ropivacaine is used to inhibit the afferent flow of the nociceptive impulse in the peripheral nervous system; epimorphine binds with adjacent peripheral opiate receptors to block the sensory impulse transmission to the central nervous system; and epinephrine is used to slow down the systemic absorption of the previous medications mentioned (Busch et al., 2006).


The periarticular drug combination promotes pain relief augmentation related to the synergism of each medication, which potentially results in decreased use of parenteral opiates (Parvataneni et al., 2007). In the study performed by Busch et al. (2006), the multidrug solution was locally injected intraoperatively, containing 400 mg of ropivacaine, 30 mg of ketorolac, 5 mg of epimorphine, and 0.6 ml of 1:1,000 epinephrine. The solution was divided into multiple doses and was injected at specific sites around the joint capsule at certain intervals during surgery (Busch et al., 2006). The injection sites included the sequential infiltration to the posterior joint capsule, medial and lateral collateral ligaments, quadriceps and retinacular tissues, and surrounding subcutaneous tissues (Busch et al., 2006).


Using the visual analog pain scale divided in 10-mm increments with 0 mm as no pain and 100 mm as severe pain, the data revealed significantly lower pain level in the treatment group with p = .04 while in postanesthesia care unit and p = .007 at 4 hr postoperatively (Busch et al., 2006). Although PCA morphine was utilized in the study, there was a significant decrease in morphine consumption in the first 24 hr with p < .01 at 6 hr, p = .016 at 12 hr, and p < .001 at 24 hr postoperatively (Busch et al., 2006). The strategic injection of the periarticular solution allowed considerable localized analgesic coverage around the pain origin, the surgical knee (Busch et al., 2006).


Infusion of a postoperative dose may also be achieved via intraoperative insertion of an intra-articular catheter strategically placed around the joint capsule, which may result in extended pain relief. In a randomized study by Vendittoli et al. (2006), unilateral TKA was performed on 42 patients, with 22 patients in the treatment group and 20 patients in the control group. The same medications as highlighted in the Busch et al. (2006) study were utilized in the treatment group with the exception of epimorphine; however, morphine PCA was still used (Vendittoli et al., 2006). After injecting the multidrug solution intraoperatively to the treatment group, an intra-articular catheter was inserted, which was used to deliver an additional dose of ropivacaine solution on postoperative day 1. The results of this study revealed a significant decrease in morphine consumption in the treatment group within the first 48 hr postoperatively, with p = .0003. Utilizing the visual analog scale, it was found that there was significant pain control during exercise, with p = .02, and at rest, with p = .01, within the first 48 hr postoperatively. Although the treatment group achieved significantly better pain control than did the control group, no significant differences in the amount of passive and active knee flexion were found in the first 5 days postoperatively (Vendittoli et al., 2006).


It is important to note that these two studies used large ropivacaine dosages, more than the manufacturer's recommended dose. Both studies used 400 mg of ropivacaine intraoperatively, and the Vendittoli group used an additional 150 mg on postoperative day 1 infused via intra-articular catheter. The researchers also affirmed that care must be taken when introducing an intra-articular catheter, in order to prevent joint contamination (Vendittoli et al., 2006). According to Vendittoli et al., there is a risk of infection with the use of intra-articular catheter, which prompted the discontinuation of the catheter after a single multidrug dose was given on postoperative day 1. Additional ropivacaine dosage may also add to potential toxicity. Increased serum plasma levels of ropivacaine, which has a half-life of 1.7 hr, may cause cardiotoxic effects, such as hypotension and bradycardia, and neurotoxic effects, such as seizures, headache, and blurred vision (Vendittoli et al., 2006). For this reason, the ropivacaine levels were monitored at specific intervals in both studies after the release of the intraoperative tourniquet on the surgical leg (Busch et al., 2006; Vendittoli et al., 2006). The results concluded that the addition of a catecholamine slowed down the systemic absorption, promoted drug localization, and prolonged the anesthetic effect (Busch et al., 2006; Vendittoli et al., 2006). In the study by Vendittoli et al., the ropivacaine maximum plasma levels in the treatment group ranged from 0.646 to 1.346 [mu]g/ml, which is below the toxicity level of 1.5 [mu]g/ml. In the Busch et al. (2006) study, ropivacaine levels were evaluated on 5 patients in the treatment group at specific time intervals within 4 hr after the tourniquet was released. The blood tests revealed a maximum level of 60 ng/ml of unbound ropivacaine, which is considerably below the toxic level of 150 ng/ml (Busch et al., 2006). There was no neurotoxicity or cardiotoxicity noted in both studies (Busch et al., 2006; Vendittoli et al., 2006). In addition, the vasoconstrictive effect of a catecholamine such as epinephrine may also promotes decreased postoperative bleeding and hematoma formation (Parvataneni, Shah, Howard, Cole, Ranawat, & Ranawat, 2007).


The simultaneous infusion of ropivacaine and epinephrine modified some of the pharmacokinetics, keeping it localized for a longer period (Busch et al., 2006; Vendittoli et al., 2006). This effect may also be true with ketorolac. According to Kerr and Kohan (2008), the systemic absorption of ketorolac is slowed by cryotherapy, vasoconstriction, and dense surgical dressing. The addition of ketorolac plays a vital role in pain relief amplification. Ketorolac, the only injectable NSAID, provides a good "1-2 punch"; whereas ropivacaine is busy blocking nociceptive nerve conduction, ketorolac simultaneously blocks the formation of pain-stimulating inflammatory mediators during tissue injury augmenting pain control (Kerr & Kohan, 2008). Although renal toxicity can be associated with the use of NSAID, ketorolac used by all studies mentioned was in accordance with the recommended dose of 30 mg in one periarticular solution and was not utilized on those who had contraindications such as renal insufficiency. In the case study of Kerr and Kohan (2008), the use of oral NSAID as the primary postoperative oral analgesic in conjunction with intra-articular use of ketorolac did not show any decline in renal functions of all 325 patients during the study period.


Several other studies have employed this multimodal approach with their own combination of medications. In addition to ropivacaine, ketorolac, morphine, and epinephrine, some have added corticosteroids and cefuroxime as antibiotic prophylaxis, such as the study performed by Ranawat's group (Ranawat & Ranawat, 2007). Although different studies have used different drug combinations and dosages, periarticular multimodal drug injection has shown consistent safety and efficacy. In addition, the delivery of additional dosages of ropivacaine, ketorolac, and epinephrine can be achieved with the limited use of an intra-articular catheter, which promotes added extension of its benefits (Kerr & Kohan, 2008; Vendittoli et al., 2006).


Like most medications, there are contraindications involved, such as allergic reactions and renal insufficiency. Thus, medication administration should be carefully scrutinized to make sure that it is appropriate for a surgical candidate to receive the multimodal treatment. The studies performed by Busch et al. (2006) and Vendittoli et al. (2006) showed that postoperative pain management for TKA may be a challenge but is successfully manageable. In summation of both studies, morphine consumption was decreased, which may have contributed to decreased postoperative nausea episodes in their treatment group; patient satisfaction was increased; and most of all, significant pain control was achieved without any apparent complications from the multimodal drug injection (Busch et al., 2006; Vendittoli et al., 2006).


Overall, when comparing this method in terms of efficacy, safety, and effectiveness with other pain management modalities such as parenteral analgesia, epidural analgesia, or peripheral nerve block, it is reasonable to state that periarticular multimodal drug injection provides effective pain control for TKA, with considerable efficacy and safety. Parenteral analgesia may remain a standard part of the pain management protocol, but its use may certainly be minimized with the utilization of periarticular multimodal drug injection, promoting decreased opioid-related systemic side effects. According to Ranawat and Ranawat (2007), the right combination of multimodal drugs for the right surgical candidate offers the best outcome in postoperative pain control with the least unwanted side effects.



Different pain management modalities are available, and unfortunately, there is no strong consensus, particularly among orthopaedic surgeons and anesthesiologists, as to which is the best approach for pain management (Goyal et al., 2008). The inception of the periarticular multimodal drug injection modality may be the postoperative analgesic of choice for TKA. The results of several studies regarding its utilization demonstrate effectiveness and consistency; however, its absolute potential has not been fully realized. Hence, more clinical trials are under way to determine the most effective periarticular drug cocktail for analgesia. With efficacy and safety at the forefront for pain management, periarticular multimodal drug approach deserves our immediate attention. It has been found to be a viable option, which should be included within the wide range of perioperative multimodal approaches, such as comprehensive patient education, preemptive analgesia, and other forms of pain medication adjuncts, in order to give a surgical patient the best opportunity for the most positive recovery process. With the flexibility of its use not limited to TKA, it may also have a future in managing pain for other major orthopaedic procedures such as total shoulder arthroplasty and fracture repairs. Although it is still at its early stages of use, the development of the periarticular multimodal drug regimen has created a new dimension in pain management. In fact, we may ultimately discover that the use of periarticular multimodal drug injection may well be considered one of the most effective treatment modalities for orthopaedic postoperative pain.




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