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Ropivacaine
Indications
Anesthetics are classified as amide and ester local anesthetics. Ropivacaine is an amide anesthetic.[1]
FDA-Approved Indications
Ropivacaine is FDA-approved for surgical anesthesia and acute pain management. This medication is used in an epidural block for surgery, such as cesarean sections.[2] Ropivacaine is also used in major nerve blocks and local infiltration. For acute pain management, ropivacaine is used in epidurals (continuous infusion or intermittent bolus) for postoperative or labor pain control.
Off-Label Uses
Researchers have also evaluated ropivacaine’s use for chronic pain management.[3][4] According to the American Society of Pain and Neuroscience (ASPN), radiofrequency ablation treats intractable pain in the lumbar facet joints. This is usually preceded by diagnostic nerve blocks utilizing local anesthetic solutions, including lidocaine or ropivacaine.[5] One meta-analysis shows that ropivacaine with dexmedetomidine significantly extends postoperative analgesia duration and sensory and motor block while reducing sufentanil use and postoperative nausea and vomiting across various surgeries.[6] An outpatient study looking at bupivacaine and ropivacaine in managing chronic low back pain found no significant differences in analgesia, motor blockade, or hemodynamic changes between bupivacaine 0.125% and ropivacaine 0.2%. Ropivacaine was also found to be effective for severe refractory migraines through trigger point inactivation.[7] Ropivacaine has also been used for erector spinae block for thoracoscopic lobectomy.[8]
Evidence
In epidural administration for cesarean section, clinical trials show that ropivacaine (0.75% or 0.5%) has a clinically similar onset of sensory and motor block to bupivacaine 0.5%. The median duration of analgesia that ropivacaine supplied to the T6-S3 dermatomes is similar to bupivacaine but with a much shorter duration of motor block (0.9 hrs vs. 2.5 hrs). For intrathecal administration, hyperbaric solutions of ropivacaine are faster in onset and recovery than isobaric ropivacaine, but the spread and duration of the hyperbaric ropivacaine block are very variable.[9] Coadministration with opioids reduces the amount of local anesthetic needed and prolongs analgesia without lengthening the period of the motor block.[10]
Mechanism of Action
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Mechanism of Action
Ropivacaine is a long-acting amide local anesthetic that exhibits a mechanism of action similar to other local anesthetics in that it reversibly inhibits sodium ion influx in nerve fibers. Amides preferentially bind and inactivate sodium channels in the open state, thereby blocking the propagation of action potentials. The dose-dependent inhibition of potassium channels potentiates this action.
Ropivacaine has a few properties that make it unique. Ropivacaine is less lipophilic than other local anesthetics, such as bupivacaine, and is less likely to penetrate large myelinated motor fibers. Therefore, ropivacaine selectively acts on the nociceptive A, B, and C fibers over the AB (motor) fibers. Ropivacaine is also manufactured as a pure S(-) enantiomer; the S(-) enantiomer has significantly less cardiotoxicity and neurotoxicity.[11][12][13]
Pharmacokinetics
Absorption: The ropivacaine concentration is determined by various factors, including the total dose and concentration of the administered drug, route of administration, and vascularity. Ropivacaine demonstrates both complete and biphasic epidural absorption. The low absorption rate is the rate-limiting factor in the clearance of ropivacaine; therefore, the terminal half-life is prolonged following epidural injection compared to the intravenous route. In some patients, after the administration of ropivacaine 300 mg for brachial plexus block, plasma concentrations reach levels regarded as critical for central nervous system toxicity. For dosages exceeding 300 mg utilized for local infiltration, the terminal half-life can be greater than 30 hours.
Distribution: Ropivacaine has a distribution volume of approximately 41 L (± 7). The medication primarily binds to plasma proteins, and approximately 94% binds with α1-acid glycoprotein. Plasma concentrations may rise during infusion through the epidural route. The rise is linked with an increase in α1-acid glycoprotein after surgery. Ropivacaine can easily cross the placenta.
Metabolism: Ropivacaine is subjected to extensive hepatic metabolism, mainly by aromatic hydroxylation to 3'-hydroxy-ropivacaine by CYP1A2 and N-dealkylation by CYP3A4.[1]
Elimination: Ropivacaine is excreted renally; approximately 86% of the drug is excreted in urine. The terminal half-life is 1.8 hrs (± 0.7) after IV administration and 4.2 hrs (± 1) after epidural administration.
Administration
Available Dosage Forms and Strengths
Ropivacaine is available as 2 mg/mL, 5 mg/mL, 7.5 mg/mL, and 10 mg/mL solutions.
Adult Dosage
Ropivacaine is administered in incremental doses. Factors that affect the dosing of any administered local anesthetic include the area to be anesthetized, the vascularity of tissues, the number of neuronal segments to be blocked, and the depth and duration of anesthesia required.[14]
An adequate test dose of 3 to 5 mL of short-acting local anesthetic with epinephrine should be used before the complete block is induced. A test dose should be repeated if the patient is moved in a way that may have displaced an epidural catheter.
For lumbar surgery epidural blocks, the ropivacaine doses considered necessary to produce a successful block are 15 to 30 mL of 0.5% solution, 15 to 25 mL of 0.75% solution, and 15 to 20 mL of 1% solution.
When used in lumbar epidural blocks for cesarean section, the doses for ropivacaine are 20 to 30 mL of 0.5% solution and 15 to 20 mL of 0.75% solution.
When performing thoracic epidural blocks for surgical anesthesia, the dose of ropivacaine is 5 to 15 mL of 0.5% solution and 5 to 15 mL of 0.75% solution.
When performing major nerve blocks, the dosages are 35 to 50 mL of 0.5% solution and 10 to 40 mL of 0.75% solution.
For field blocks (eg, minor nerve blocks and infiltration), ropivacaine is administered in a 1 to 40 mL dose of a 0.5% solution.
When managing postoperative pain, peripheral nerve blocks are continuously infused at 5 to 10 mL/hr of 0.2% solution. For pain management through lumbar or thoracic epidurals, the continuous infusion dose of ropivacaine is at 6 to 14 mL/hr of 0.2% solution.
The risks of reaching a toxic plasma concentration or inducing local neural injury should be considered for prolonged blocks. A 24-hour cumulative dose of up to 770 mg of ropivacaine is generally well-tolerated in adults for postoperative pain management. Ropivacaine should be used with caution when administering it to debilitated patients for more than 70 hours.[15][16][17][18]
Specific Patient Populations
Hepatic impairment: Amide local anesthetics are metabolized by the liver. Ropivacaine should be administered cautiously to patients with hepatic impairment to avoid toxic plasma levels.
Renal impairment: Ropivacaine and its metabolites are excreted by the kidneys, posing a greater risk of toxicity in patients with renal impairment. The lowest effective dose of ropivacaine should be used. Clinicians are encouraged to check renal function before administration.
Pregnancy considerations: According to the American College of Obstetricians and Gynecologists (ACOG), epidural analgesia combines a local anesthetic, such as bupivacaine or ropivacaine, with an opioid to reduce the concentration of each agent and minimize adverse effects. The maximum recommended dose of ropivacaine is 2 mg/kg.[19] Ropivacaine can cause maternal hypotension or fetal bradycardia in toxic doses.
Breastfeeding considerations: Ropivacaine transfers poorly to breast milk and is minimally absorbed by breastfed infants. Some reports suggest that local anesthetics combined with analgesics during labor might affect breastfeeding, but evidence varies due to different combinations and dosages. Studies show that ropivacaine and fentanyl have minimal impact on breastfeeding, although some mention delays in milk production and initiation. Generally, when given proper support, epidural analgesia has a minimal effect on breastfeeding but may delay the onset of lactation.[20] Local anesthetics are considered compatible with breastfeeding.[21] The product labeling advises risk-benefit evaluation and patient counseling.
Pediatric patients: The American Academy of Pediatrics recommends immediate availability of a 20% lipid emulsion for local anesthetic toxicity if a high dosage of amide anesthetics like ropivacaine is suspected in systemic vasculature. Topical local anesthetics are encouraged, but practitioners should avoid excessive doses on mucosal surfaces to prevent systemic uptake and possible toxicity (seizures, methemoglobinemia) while following the manufacturer’s surface area application guidelines.[22]
Older patients: With advancing age, the upper level of analgesia and the intensity of motor blockade increase, and mean arterial pressure decreases. Since the kidneys excrete ropivacaine and metabolites, older patients with impaired renal function are at higher risk for toxic reactions. Dosage selection should start low, and renal function may need monitoring in these patients.
Adverse Effects
Ropivacaine is generally well-tolerated. A pooled analysis from controlled clinical trials (n=1,661), in which patients received ropivacaine concentrations from 0.125% to 1% for nerve blocks, indicates that the most common adverse reactions are hypotension (32%), nausea (17%), vomiting (7%), bradycardia (6%), and headache (7%).[23] A similar side effect profile occurred in patients who received bupivacaine concentrations of 0.25% to 0.75%. Overall, adverse events with ropivacaine are rare when it is properly administered.
Patients aged 61 years and older who received epidural ropivacaine 1% had a higher incidence of bradycardia than patients aged 41 to 60 years (58% vs. 15%); they also had a higher incidence of hypotension than patients aged 18 to 40 years (74% vs. 20%).
The overall incidence of adverse reactions in children aged 1 to 15 months is low; the most common adverse effects of ropivacaine in this age group were nausea and vomiting.
The most common fetal or neonatal adverse reactions following the administration of ropivacaine to women undergoing cesarean section or labor were fetal bradycardia (12%), neonatal jaundice (8%), and unspecified neonatal complications (7%).[24]
Drug-Drug Interactions
- Methemoglobinemia: Ropivacaine can increase the risk of methemoglobinemia when used concurrently with certain drugs, such as nitroglycerin, sulfonamides, chloroquine, cyclophosphamide, and hydroxyurea.
- Amide-type local anesthetics: Clinicians should exercise caution when combining ropivacaine with other local anesthetics, as toxic effects may be additive.[1]
- CYP1A2 inhibitors: Strong CYP1A2 inhibitors, like fluvoxamine, can reduce ropivacaine clearance and increase plasma levels.[25] Drugs metabolized by CYP1A2, like theophylline and imipramine, may interact with ropivacaine due to competitive inhibition.
- CYP3A4 inhibitors: Co-administration with CYP3A4 inhibitors like ketoconazole may result in a slight reduction in ropivacaine clearance.
- Class III antiarrhythmic drugs: Caution is advised when using ropivacaine with class III antiarrhythmics due to the potential for additive effects on cardiac conduction and increased risk of arrhythmias.
Contraindications
The only absolute contraindication to ropivacaine is for patients with a known hypersensitivity to ropivacaine or any amide-type local anesthetic.[14]
Warnings and Precautions
- Unintended intravenous injection: Accidental intravenous injection of ropivacaine may cause cardiac arrhythmia or arrest, especially in older patients with heart disease. Prolonged resuscitation may be required.
- Risk of chondrolysis: Intra-articular use of ropivacaine after surgery may lead to chondrolysis, particularly in the shoulder joint.[28]
- Risk of methemoglobinemia: Patients with G6PD deficiency, cardiac or pulmonary comorbidities, and infants younger than 6 months are at an increased risk for methemoglobinemia. Immediate treatment with oxygen, methylene blue, or other measures may be needed.
- Epidural anesthesia: Unintentional subarachnoid injection may occur. Test doses and syringe aspirations are recommended to detect intravascular or intrathecal injection before administering the complete dose.
- Brachial plexus block: Ropivacaine plasma concentrations may reach toxic levels with high doses. Caution is advised.
- Peripheral nerve block: Large volumes injected in highly vascular areas increase the risk of systemic absorption and toxicity.
- Head and neck area: Local anesthetic injection in the head or neck can cause severe reactions, including confusion and respiratory issues, especially with intra-arterial infusion.
- Cardiovascular impairment: Ropivacaine should be administered cautiously to patients with cardiovascular conditions.
- CNS toxicity: Symptoms like restlessness, anxiety, dizziness, and seizures may indicate CNS toxicity. Close monitoring is required after injection.[29]
Monitoring
Attention should be paid to vital signs (heart rate, blood pressure, oxygen saturation) after administering a test dose to ensure that the local anesthetic is not intravascular. Cardiovascular and respiratory vital signs should be monitored after each local anesthetic injection. Restlessness, anxiety, perioral paresthesias, metallic taste, tinnitus, tremors, and blurred vision are a few of the early signs of central nervous system toxicity.[30] Inadequate response to local anesthetics can result from suboptimal dosing or procedural errors. Without these factors, true LA resistance may be due to mutations in voltage-gated sodium channels. Ropivacaine administration is often associated with conditions like Ehlers-Danlos syndrome and Emery-Dreifuss muscular dystrophy.[31][32][33]
Toxicity
Signs and Symptoms of Overdose
Local anesthetic system toxicity (LAST) primarily affects the central nervous (CNS) and cardiovascular systems. Local anesthetics can assign a cardiovascular collapse (CC) to CNS ratio, which is the ratio of the drug required to cause cardiovascular collapse compared to the drug dose needed to produce seizures. Ropivacaine has a higher CC-to-CNS ratio (indicating a higher margin of safety) than bupivacaine and levobupivacaine. Ropivacaine has a greater arrhythmogenic cardiac effect and less of an effect on contractility. A prolonged PR interval and QRS widening can be observed. Ventricular fibrillation and cardiac arrest have been reported.[34][35][36]
Management of Overdose
The first step in an overdose is to secure the airway and obtain IV access. For seizures, benzodiazepines should be administered. According to the American Society of Regional Anesthesia (ASRA), LAST resuscitation differs from standard ACLS protocols, and delay in resuscitation is not recommended. ASRA recommends a smaller initial dose of epinephrine (≤1 μg/kg). Avoid calcium channel blockers, β-blockers, or vasopressin.[37]
Lipid emulsion therapy is an established treatment for LAST. Lipid emulsion is thought to work as a lipid sink that controls a rapid increase in ropivacaine concentration.[34] At modestly toxic doses of ropivacaine, lipid emulsion therapy did not appear to significantly impact the time to early signs of neurologic toxicity in volunteers. However, peak concentration was reduced by 26% to 30% in those receiving lipid emulsion therapy. Simulations suggest lipid emulsion therapy may help mitigate the rapid increase in local anesthetic concentration.[38] Lipid emulsion treatment has proven effective in animal studies for cardiac arrest induced by local anesthetics like levobupivacaine and ropivacaine, with varying response times. The lipophilicity of the anesthetics may influence these differences. Further research is needed to optimize treatment.[39] According to a review article, lipid emulsion is effective in ropivacaine toxicity. Adverse effects of lipid emulsion therapy include dyspnea, hyperlipidemia, allergy, and hypercoagulability.[40][41]
Enhancing Healthcare Team Outcomes
Multimodal analgesia involves using medications that act on different sites and pathways in an additive or synergistic manner to give pain relief with minimal or no opiate use. Opioids are associated with adverse effects such as nausea, vomiting, respiratory depression, and dependence syndromes. Local anesthetics play a large role in multimodal analgesia. Regional anesthesia can significantly reduce post-operative pain frequency and improve overall patient satisfaction.
The anesthesiologist and nurse anesthetist ensure correct dosing and monitor for adverse effects. Nurses monitor the patient and assist in post-anesthesia care. The hospital pharmacist ensures proper dosing and checks for drug interactions. The emergency medicine/critical care team provides immediate intervention in case of overdose or cardiac events.
Ropivacaine is more beneficial than other local anesthetics because it is less cardiotoxic. This characteristic makes it a safer option for pain relief for patients being sent home postoperatively. Administration of ropivacaine often requires a team of health professionals, including prescribing clinicians, pharmacists, and nurses.[42][43] When properly administered and monitored by an interprofessional team engaged in a collaborative effort and open communication, ropivacaine is a safe option for pain relief with very few adverse events.
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