Postoperative Pain after Total Joint Arthroplasty: Pathophysiology and Current Pharmacological Pain Management : Biomolecular and Health Science Journal

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Postoperative Pain after Total Joint Arthroplasty: Pathophysiology and Current Pharmacological Pain Management

Soetjahjo, Bintang1,2,; Nefihancoro, Udi Heru1; Ermawan, Rieva1; Saputra, Rhyan Darma1; Pranandaru, Herlambang2

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Biomolecular and Health Science Journal 5(2):p 129-136, Jul–Dec 2022. | DOI: 10.4103/bhsj.bhsj_2_22
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One of the most prevalent, dreaded, and unpleasant side effects of surgery is pain. Patients considering total joint arthroplasty (TJA) often experience moderate-to-severe pain, which places them at risk of opioid abuse or addiction. The pain results from a surgical incision, dissection, or burns that cause tissue trauma or nerve injury such as nerve transection, compression, or stretching during the operative procedure.1 The pain persists after the operation and becomes postsurgical pain. There are two types of postsurgical pain, acute and chronic postsurgical pain (CPSP).

Some recent cohort studies have found 16%–33% of patients reporting chronic pain after total knee arthroplasty (TKA). In the UK, nearly 100,000 primary TKA operations are performed annually and therefore there are potentially 20,000 patients who experience chronic pain after TKA every year.2 By 2030, the incidence of TKA is predicted to increase by 700%, which means 1.5463/100.000 people. Meanwhile, in total hip arthroplasty (THA) in the same period, the comparation also increased from 502 to 1455/100.000. By 2030, the incidence of THA will increase about 200% or about 291/100.000 people.34 Prior research conducted in Indonesia revealed that 3 months–5 years following TKA surgery, 10%–34% of patients reported experiencing unfavorable pain results.5 If not treated immediately, the pain that occurs after arthroplasty surgery can lead to low quality of life of the patients.

Oral analgesics, pre-emptive oral analgesia, postoperative oral analgesia, periarticular injections, nerve blocks, and neurolysis are some multimodal analgesics that have been used to treat post-operative pain.6 For example, opioid analgesia is used to activate the reward pathway by producing a euphoric sensation that helps patients overcome pain after arthroplasty surgery. Here, we will discuss the pain generator that causes postoperative pain, the latest pharmacological management for postoperative pain after TJA, and their effectiveness. However, 50 articles had been chosen for review based on the article that has the most suitable topic for the purpose of the review.


Postsurgical pain postarthroplasty is defined as pain that occurs after arthroplasty surgery, not happened before, or during the surgery. The pain differs in quality and location from pain experienced before surgery and is usually associated with incision pain caused by surgical injury to a major peripheral nerve. Postsurgical pain postarthroplasty is pain that occurs after arthroplasty is performed. The pain presents suddenly, probably for a limited time, and is cause related to an injury that may create while surgery.


Acute postsurgical pain (APSP) after TJA is a normal phase that is felt by the patient after undergoing arthroplasty surgery. Acute pain is provoked by identifiable stimuli and disappears as soon as the tissue injury or damage that had caused it is healed. APSP after TJA was usually easy to locate. This correlates with the mechanism of APSP as the signal of tissue irritation.7 APSP after TJA is described as pain that occurs in the first 72 h postoperatively.8 APSP after TJA can be controlled and most of the cases resolve within 1 week.9

There is some risk factor associated with APSP after TJA, such as preoperative pain, enhanced response to quantitative sensory testing, preoperative use of opioid analgesics, greater pain catastrophizing, depression, and increase in anxiety.8 Postsurgical pain can be perceived for several weeks after hospital discharge. This period is called the subacute pain period. This period is still not well known, despite its big role in rehabilitation so that the patients can be back to their presurgical condition.910 The intensity of pain may increase during this period, showing the combination of nociceptive and neuropathic pain mechanisms. Besides that, the emotional aspects of pain or unpleasantness toward pain also increase, which might be the key predictor of CPSP development [Figure 1].101112

Figure 1:
Nociceptive and Neuropathic pain mechanism, peripheral and central changes during the pain. Nociceptive pain occurs when there are peripheral tissue injury, meanwhile neuropathic pain occurs when there are neuron fibers in the spinal cord or central neuron that are injured11 12

The patient responds to pain with physiological changes, which are identical to changes during the stress response. High-intensity acute pain is a major psychological burden.1314 Causal treatment together with effective symptomatic analgesic therapy usually reduces acute pain. If an effective analgesic therapy is initiated early on during the acute phase of pain, the risk of progression to the chronic stage is greatly reduced. An example may be an early initiation of analgesic therapy as prevention of postherpetic neuralgia.914


CPSP is described as pain that increases in intensity after a surgical procedure.15 The pain that occurs is persistent until at least a minimum of 3 months and localized in the area of surgery and can widen to the contiguous areas.1617 This is due to the structural disruption that may occur during the surgery, resulting in the longer onset of the discomfort. This pain was not present before surgery, and not increased in intensity from preoperative pain. The patient felt the pain in the surgical area or the referred area surrounding the surgical site.14

The transition from acute to chronic pain is thought to occur by one of three processes: central sensitization, nociceptors modulation or alteration, and altered neuroplasticity. Under normal conditions, once the healing process begins, the noxious stimuli, and discomfort decrease. In situations of chronic pain, however, peripheral and central sensitization commonly progresses to hyperalgesia (increased responsiveness to less painful stimuli) and allodynia (pain response to normally nonpainful stimuli). Another essential element of chronic pain is altered spinal neuroplasticity as a result of glial cells affecting neuronal cytoarchitecture, which may be the result of recurrent nociceptive firing in central neurons (reversible) or nerve damage owing to neuropathy (irreversible).18

In certain chronic pain syndromes, studies have found significant loss of gray matter in the brain, as well as alterations in the shape, sensitivity, and activity of neurons, as well as internal rewiring. These alterations might appear clinically as fibromyalgia or complicated regional pain syndrome. Moreover, there is a large reduction in neurotransmitter receptors and their activity, which may explain why central opioid agonists are ineffective in neuropathic pain.18


Due to the majority of postsurgical pain caused is the nociceptive pain process, pain management is needed to manage the patient’s displeasure because of the pain. There is some pain management for acute and CPSP. 15

From the beginning of the enhanced recovery after surgery era, epidural analgesia was considered as optimal analgesic treatment in the postoperative pain management method. However, some studies claim that epidural analgesia usage in orthopedic surgeries, such as total knee arthroplasty, prolongs postoperative recovery after surgery and causes a motor blockage that manifests as knee buckling, and later, perambulation. Hence, there is evidence-based-alternative postoperative pain that has a good result and smaller adverse effects.19

Current strategies to manage APSP emphasize the use of multimodal analgesia approaches as rational, opioid-sparing methods of achieving safer, more balanced pain therapy with improved quality of analgesia and fewer side effects.20


As described in Figure 2, every single analgesic agent works at a different point of the pain signaling pathway.913 Nonselective inhibitors of cyclooxygenase synthesis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), reduce inflammation while simultaneously having an anti-nociceptive effect. As described in Figure 3, analgesic agent has several site of action. It targets two cyclooxygenase isoforms, cyclooxygenase 1 (COX-1) and COX-2 which are elevated due to increased prostaglandin Level.151921 On the other hand, acetaminophen can reduce the pain sensation by crossing the blood–brain barrier, increasing serotonin levels in several areas of the brain. Another drug agent, opioids, can reduce postoperative pain by actions at several levels of the nervous system, in particular, inhibition of neurotransmitter release from the primary afferent terminals in the spinal cord and activation of descending inhibitory controls in the midbrain.22 There are many methods of therapy that can be used to overcome the pain after performing TJA.20

Figure 2:
Chronic postsurgical pain mechanism9 13
Figure 3:
Site of action analgesic agent10 15 19 21 22



Acetaminophen is the most widely used and inexpensive analgesic for postoperative patients and should be used as part of a multimodal analgesic protocol. Some research suggests its effects are mediated through a combination of serotonin, opioid, eicosanoid, and nitric oxide pathways.20

Acetaminophen is generally safe, though hepatotoxicity can occur with doses exceeding 4 gm daily. While evidence has shown greater bioavailability and support for the use of IV acetaminophen, oral administration is more cost-effective.23 A recent prospective randomized-controlled trials (RCT) study of 120 patients undergoing lower extremity arthroplasty compared intravenous (IV) to oral acetaminophen and found no analgesic advantage to IV administration.72425

Acetaminophen is not suggested for those patients who have a history of liver disease and allergy to acetaminophen. This contraindication is due to the pharmacokinetics of acetaminophen which is extensively metabolized by the liver through three main hepatic pathways: glucuronidation, sulfation, and CYP450 2E1 oxidation.21

Acetaminophen can be safely mixed with other NSAIDs, such as aspirin and naproxen (Aleve).26 Follow the same guidelines as if you were taking acetaminophen and ibuprofen together. Ibuprofen, however, should not be mixed with other NSAIDs. This is because all NSAIDs use the same mechanisms to relieve pain.21 Meanwhile, the combination of acetaminophen and morphine produces an additive analgesic effect.1

In the acetaminophen mechanism of action, there is evidence of a central effect through prostaglandin production pathways. Acetaminophen passes from the blood–brain barrier and increases serotonin in different parts of the brain. Acetaminophen inhibits the pain by acting as a reducing co-substrate at the POX site. This condition will stop the alteration of PGG2 to become PGH2. When levels of arachidonic acid are low, acetaminophen is a potent inhibitor of PG synthesis, by blocking the physiological regeneration of POX.27 This mechanism indirectly will reduce the production of PGE2, PGI2, and TXA2 so the pain mechanism will be blocked.28293031

Nonsteroidal anti-inflammatory drugs

Nonselective inhibitor

NSAIDs as nonselective inhibitors decrease inflammation by nonselectively diminishing cyclooxygenase production and also have an anti-nociceptive effect. The two cyclooxygenase isoforms, COX-1, and COX-2 are targets of NSAIDs). These drugs are competitive active site inhibitors of both COXs. Although both COXs exist as homodimers, only one partner is used at a time for substrate binding. NSAID act through inhibition of cyclooxygenase and prostaglandin synthesis, so when the level of cyclooxygenase and prostaglandin levels is reduced, the inflammation process that happened in the nociceptive pain mechanism will be stopped, so the patient can overcome the pain that may be felt.27

Taking NSAID and acetaminophen as a combination is safe and does not bother both of these agents’ actions as analgesia treatment, as explained in the previous section. Meanwhile, repeated administration of NSAIDs progressively leads to tolerance to the NSAID, cross-tolerance to morphine, and the risk of a withdrawal syndrome.20

The adverse effect that might occur after NSAID consumption for the gastric adverse effects is preventing the creation of prostaglandin that protects the gastric mucosa. The renal adverse effect such as in a patient with renal dysfunction, prostaglandins play a greater role and can be the source of problems when reduced via NSAIDs. Complications that can occur due to this are acute renal dysfunction, fluid and electrolyte disorders, renal papillary necrosis, and nephrotic syndrome/interstitial nephritis, and cardiovascular adverse effects such as myocardial infark, thromboembolic events, and atrial fibrillation. The hepatic adverse effect such as NSAID-associated risk of hepatotoxicity.323334

Cyclooxygenase-2 selective inhibitors

COX-2 inhibitors selectively inhibit the cyclooxygenase-2 enzyme, which mediates central and peripheral sensitization. A primary advantage of selective COX-2 inhibition is a decreased risk of bleeding and gastric ulceration. Bleeding risk is a special concern in the setting of prophylactic anticoagulation for venous thromboembolism prevention after TJA. In one study, perioperative celecoxib use significantly improved resting pain scores at 48 and 72 h postoperatively, opioid consumption was less, and active range of motion was improved in the first 3 days after total knee arthroplasty without increasing the risk of bleeding. a more recent double-blinded RCT of 107 patients undergoing TKA with 200 mg celecoxib twice daily for 6 weeks showed a significant reduction of postoperative opioid consumption, diminished VAS scores at 3, 6, and 12 weeks, improved Knee Society Scores at 3 and 6 weeks, and increased knee flexion at 1 year.2026

The adverse effects of COX-2 inhibitor to the gastrointestinal are mild irritation, bleeding, and perforation. Not indicated to patients who have had a history of peptic ulcer disease, and also on steroids or blood thinners. Cardiovascular effects such as myocardial infarction (MI), cardiovascular-related mortality, and stroke. Renal effects such as vasoconstriction at the afferent arteriole level of the kidney.353637

Opioids analgesia

The explanations about opioid drugs as analgesic agents to treat postsurgical pain after TJA are published in 448 journals that were found in several search engines. About 6 latest journals are used in this article to explain the usage, mechanism of action, and an indication of opioid and nonopioid drugs to treat postsurgical pain after TJA. Opioids are drugs that interact with specific receptors in the central nervous system to relieve pain. Detailed mechanism were described in Figure 4 and 5. Beyond their direct mechanism of action to control pain, opioids are also known to activate the reward pathway by producing a euphoric sensation that helps patients overcome pain. This euphoric sensation is addictive.20

Figure 4:
Neurons are identified by the main neurotransmitters that they release. Cellularly, MOR agonists increase Ca2+ influx and improve K+ current to decrease excitability and transmitter release at the designated locations. As a result, opiate-induced inhibition in the NAc or VTA on GABAergic interneurons reduces GABA-mediated inhibition and increases outflow from the ventral pallidum (VP), which appears to be correlated with a positive reinforcing state (enhanced reward).12 NAc: N. Accumbens, VTA: Ventral tegmental area. MOR: Micro opioid receptor, GABA: Gamma aminobutyric acid
Figure 5:
Mechanism of action of opioid analgesia: The effects of mu opiates in PAG matter prevent GABA from being released from tonically active systems that would otherwise control the projections to the medulla (1), which activates PAG outflow and activates the forebrain (2), spinal (3) and monoamine receptors that control spinal cord projections (4) which supply sensory input to higher centers and affect mood.12 PAG: Periaqueductal gray, GABA: Gamma aminobutyric acid

Oral opioids have been shown to provide equal pain control to intravenous opioids with fewer side effects.1938 However, recently, some studies reported that long usage of opioids can risk the patient who suffering APSP have a prolonged recovery and lead to CPSP.12 On the other hand, they have many adverse effects, including nausea, vomiting, sedation, gastrointestinal ileus, immunosuppression, and respiratory depression, that may delay patient recovery.1920


Total knee arthroplasty

Multimodal analgesia is used to treat postoperative pain after TKA. This method is justified by the fact that it cuts down on the usage of opioids and their negative side effects. Overall pain management is improved with a combined strategy. Preemptive use of analgesics and/or anti-inflammatory drugs is one part of multimodal pain treatment. Over the last decade, the multimodal pain management protocol after TKA has undergone several changes, including the adoption of pre-emptive analgesia, the use of local periarticular injections, and the introduction of a comprehensive postoperative pain protocol, all of which have been used to reduce postoperative pain.39 This is reinforced by the fact that a 30-day post-discharge multimodal pain regimen dramatically lowers opioid usage, opiate refills, and protocol failures without compromising pain control in the postoperative term, according to group-randomized trial research.40

Tsuji et al. recently, published a prospective RCT that looked at the efficacy of two patches (flurbiprofen patch and S-flurbiprofen patch) after TKA in terms of pain control, hospitalization time, maximal knee flexion, and rate of renal dysfunction and other complications due to the patches, and found that the patches had beneficial effects for postoperative analgesia after TKA. Although dermatitis is a possibility, no additional severe problems have been reported. Patches might be a good choice for extra postoperative analgesia after TKA.41

Total hip arthroplasty

Due to their ability to relieve pain and inflammation, NSAIDs are among the most extensively used analgesic treatments for THA in the world. NSAIDs work by inhibiting prostaglandin synthesis by either reversible or irreversible acetylation of the COX enzyme.42 However, a multimodal strategy has been promoted as the best way to address pain in THA patients throughout the perioperative phase. Multimodal analgesia is achieved by combining analgesics with different mechanisms of action, resulting in additive or synergistic analgesia with fewer side effects than when individual analgesics are used alone.43 Intravenous acetaminophen as an alternative for postoperative pain management with multimodal analgesia can provide patients with a considerable analgesic benefit while avoiding the hazards associated with narcotic treatment. Furthermore, it is anticipated that the reduction in opioid use owing to the concurrent usage of acetaminophen would result in lower medical costs.44

Total shoulder arthroplasty

The use of opioid-only analgesics for shoulder surgery is frequently associated with opioid-related side effects. Nausea and vomiting, respiratory depression, somnolence, pruritus, sleep difficulties, urine retention, constipation, and tolerance are some of the side symptoms that may interfere with postoperative rehabilitation attempts. With half of the patients utilizing little or no intravenous opiates, a multimodal analgesia therapeutic route studied for total shoulder arthroplasty showed outstanding outcomes and low pain ratings. To limit opioid intake, the multimodal strategy often includes localized blocking, local anesthetics, and a mix of acetaminophen, NSAIDs, tramadol, and gabapentinoids after surgery.45

Total ankle arthroplasty

For postoperative pain management following foot and ankle surgery, a variety of anesthetic approaches have been tried. Regional sciatic nerve blocks have several advantages over general, epidural, and local ankle blocks, including fewer problems, higher patient satisfaction, and lower postoperative opioid doses. Despite single-shot sciatic blocks being an effective strategy to decrease postoperative pain after foot and ankle surgery, the length of analgesia is usually just 12–18 h after treatment.43

Total elbow arthroplasty

NSAIDs can be used alone or in conjunction with narcotics. Narcotic drugs are seldom needed for a long time following elbow replacement, and when they are, it is important to keep the amount under close control to minimize unwanted side effects. High-voltage galvanic stimulation has been shown to help manage the inflammatory process by causing involuntary muscle spasms to alleviate edema in some cases. If active or vigorous muscular contraction is prohibited, such as when the triceps muscle is damaged or disconnected, high-current intensity should be avoided.464748

Total wrist arthroplasty

Opioid analgesics, which were long regarded as the gold standard for avoiding acute postoperative pain, are being phased out in favor of a multimodal strategy that includes a mixture of nonopioid analgesic medications with various mechanisms of action. Multimodal analgesia including preemptive analgesics for perioperative pain management in upper extremity surgery such as total wrist arthroplasty had a lower complication rate and additional pain rescue, and had similar analgesic effects and functional outcomes, compared with IV-PCA. As shown in this study, multimodal analgesia including pre-emptive analgesics can be useful and an acceptable alternative in upper extremity surgery, which is associated with relatively lower postoperative pain.49


Postsurgical pain is defined as pain that occurs after surgery, not happened before, or during the surgery. The pain differs in quality and location from pain experienced before surgery and is usually associated with incision pain caused by surgical injury to a major peripheral nerve. More journals are reporting on two types of postsurgical pain, acute and CPSP.

The treatment of postsurgical pain is divided into three types of drugs, acetaminophen, NSAIDs, and opioid analgesia. The usage of these types of drugs can be used as pre-emptive analgesia or given as multimodal analgesia. The most frequent treatment that is used to treat postoperative pain after joint replacement is multimodal analgesia. This method is used to decrease the side effect that may occur after opioid administration.


The authors would like to acknowledge the Department of Orthopaedic and Traumatology Dr. Moewardi General Hospital/Faculty of Medicine, Universitas Sebelas Maret through The Biomolecular and Health Science Journal.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


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Pain; postoperative pain management; postsurgical pain; total joint arthroplasty

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