Treatment for rituximab-induced rigors is not well studied, with meperidine being the primary treatment extrapolated from data on postanesthetic shivering. The use of opioids for rigors has limited evidence despite widespread use. Meperidine is usually preferred due to the unique binding of both kappa- and mu-opioid receptors. For postanesthetic shivering, responses have been seen after 5 minutes with meperidine and clonidine. Morphine has been successfully studied as an alternative to meperidine for rituximab-induced rigors in an effort to reduce meperidine usage in recently published papers (Tables 1-2). [1], [2]
Even though not strictly related to rituximab-induced rigors, several studies have evaluated alternative medications for rigors in the settings of post-anesthesia, post-epidural, and post-spinal anesthesia. Alternative medications that have shown promise in the treatment of rigors include tramadol and butorphanol. No universal dosage for those medications was given but rather dependent on the practice site. Opioids still hold a higher reputation as reliable anti-shivering agents, including tramadol and butorphanol as alternatives to meperidine. [3], [4], [5]
A 2023 systematic review and meta-analysis examined the efficacy of intravenous (IV) nalbuphine for managing post-anesthesia shivering. The analysis included 10 randomized trials, encompassing a total of 700 patients, of whom 350 received nalbuphine, and 350 were assigned to a control or placebo group. The studies investigated using nalbuphine in varying doses, primarily under spinal anesthesia conditions, with comparators such as tramadol, dexmedetomidine, ondansetron, and meperidine. Nalbuphine had a significantly higher success rate in controlling postoperative shivering compared to placebo (risk ratio [RR] 2.37; 95% confidence interval [CI] 1.91 to 2.94; p= 0.04), with minimal recurrence of shivering (RR 0.47; 95% CI 0.26 to 0.83; p= 0.01). However, nalbuphine’s efficacy was comparable to other active controls, such as opioids and dexmedetomidine. Additionally, nalbuphine demonstrated a significantly lower incidence of postoperative nausea and vomiting (PONV) than control groups (RR 0.67; 95% CI 0.47 to 0.95; p= 0.02). The trial sequential analysis confirmed nalbuphine’s superiority over placebo, thus providing strong evidence for its use in clinical practice for managing post-anesthesia shivering, with a favorable safety profile. [6]
A 2022 systematic review and meta-analysis sought to evaluate the efficacy of pharmacological agents administered intra-operatively to manage shivering in patients undergoing elective surgery under regional anesthesia. A total of 10 randomized trials were included, which utilized tramadol, dexmedetomidine, clonidine, meperidine, nalbuphine, magnesium sulfate, nefopam, and butorphanol; tramadol and dexmedetomidine were the most commonly utilized medications. Control of shivering was reported in seven trials, though the reporting method was heterogeneous (e.g., success rate, response rate). The most effective drug appears to be IV dexemedetomidine 0.5 mcg/kg when given immediately after the appearance of shivering. Clonidine has been used similarly, with some adverse events. Tramadol, pethidine, and butorphanol were considered effective opioid interventions in the management of shivering. Comparisons of the agents to meperidine were not provided, however, and data in general are limited. [7]
A 2004 systematic review assessed the relative efficacy of pharmacological interventions in preventing postoperative shivering. The review included randomized comparisons of prophylactic, parenteral, single-dose antishivering interventions against inactive controls (placebo or no treatment). A total of 27 trials (N= 1248) were analyzed, and the average incidence of shivering in the control group was 52%. Clonidine (65-300 mcg), meperidine (12.5-35 mg), tramadol (35-220 mg), and nefopam (6.5-11 mg) were tested in at least three trials each. All were found to be more effective than control. Clonidine, meperidine, and nefopam showed weak evidence of dose responsiveness. For small-dose clonidine (65-110 mcg), the relative risk (RR) was 1.32 (95% CI 1.16 to 1.51), while medium-dose clonidine (140-150 mcg) had an RR of 1.83 (95% CI 1.47 to 2.27), and large-dose clonidine (220-300 mcg) had an RR of 1.52 (95% CI 1.30 to 1.78). The overall RR for clonidine was 1.58 (95% CI 1.43 to 1.74), with a number needed to treat (NNT) of 3.7. For all meperidine regimens combined, the RR was 1.67 (95% CI 1.37 to 2.03), with an NNT of 3. Tramadol had an RR of 1.93 (95% CI 1.56 to 2.39), with an NNT of 2.2, while nefopam had an RR of 2.62 (95% CI 2.02 to 3.40), with an NNT of 1.7. Other interventions, such as methylphenidate, midazolam, dolasetron, ondansetron, physostigmine, urapidil, and flumazenil, were tested in fewer trials with limited patient numbers. Overall, the authors found that using simple pharmacological treatments to prevent postoperative shivering is effective, especially in patients with a high risk of developing this complication. [8]
A 2002 systematic review and quantitative meta-analysis investigated the pharmacological treatment of postoperative shivering. The review analyzed 20 randomized controlled trials (RCTs) published between 1984 and 2000, involving a total of 944 adult patients receiving active drug treatment and 413 controls. Various drugs are used off-label to treat postoperative shivering; however, their relative efficacy is unclear. The meta-analysis found that meperidine 25 mg, clonidine 150 mcg, ketanserin 10 mg, and doxapram 100 mg effectively reduced shivering in at least three randomized trials each after five minutes. Meperidine 25 mg had the lowest NNT of 1.3 after five minutes, suggesting it had a shorter onset than the other drugs tested. However, clonidine 150 mcg and doxapram 100 mg also had NNT <2 at five minutes, indicating they could reduce shivering in two out of three patients within five minutes compared to placebo. Ketanserin efficacy declined over time and was not significantly better than placebo after 30 minutes. Long-term efficacy data and information on adverse effects were generally lacking for most drugs. In conclusion, the limited data suggests clonidine and doxapram were found to be effective short-term treatments for postoperative shivering along with meperidine. [9]
A recent meta-analysis assessed the prophylactic use of IV acetaminophen for preventing postoperative shivering. A total of nine trials involving 856 patients were included in the analysis. The findings indicated that acetaminophen significantly reduced the incidence of postoperative shivering compared to placebo (RR 0.43; 95% CI 0.35 to 0.52). Additionally, subgroup analysis revealed that both a single-dose bolus of IV acetaminophen 1000 mg (RR 0.22; 95% CI 0.10 to 0.45) and IV acetaminophen 15 mg/kg (RR 0.43; 95% CI 0.33 to 0.62) were effective in reducing the incidence of postoperative shivering. Based on these findings, it was suggested that prophylactic infusion of IV acetaminophen may potentially offer advantages in reducing perioperative shivering. [10]
A 2023 meta-analysis evaluated the perioperative administration of dexamethasone to prevent postoperative shivering. The review included 12 randomized controlled trials (N= 1276 patients), all of which assessed the overall incidence of postoperative shivering. The trials included a variety of surgeries, such as orthopedic, urological, and general procedures, performed under both general and spinal anesthesia. The results indicated that patients in the dexamethasone group experienced a significantly lower incidence of postoperative shivering (RR 0.39; 95% CI 0.23 to 0.63; p<0.00001) compared to the control group. Additionally, dexamethasone reduced the grade of shivering, which was classified into five grades (0-4) based on clinical manifestations. Specifically, the reduction was significant for grade 2 (RR 0.48; 95% CI 0.33 to 0.69; p<0.0001), grade 3 (RR 0.14; 95% CI 0.06 to 0.37; p<0.0001), and grade 4 (RR 0.13; 95% CI 0.04 to 0.38; p= 0.0002); however, it was not significant for grade 1 (RR 0.94; 95% CI 0.60 to 1.48). Overall, the authors concluded that the administration of dexamethasone is associated with a lower incidence of postoperative shivering; however, further studies are warranted. [11]
Finally, a 2020 meta-analysis of 13 RCTs involving 864 patients compared the efficacy and safety of IV dexmedetomidine versus tramadol for the treatment of shivering following spinal anesthesia. The researchers systematically reviewed data to evaluate the shivering control effectiveness, time to cease shivering, recurrence rate, and incidences of side effects such as nausea, vomiting, hypotension, bradycardia, and sedation. Dexmedetomidine demonstrated a significantly higher effective rate of shivering control (RR 1.03; 95% CI [1.01, 1.06]; p= 0.01; I2= 14%) and had a notably faster onset of action, with a mean difference of -2.14 minutes to cease shivering compared to tramadol (p<0.00001). The recurrence rate of shivering was also lower in the dexmedetomidine group (RR 0.45), suggesting it offers more durable relief from postoperative shivering. Additionally, the analysis revealed that dexmedetomidine was associated with fewer side effects related to nausea and vomiting, highlighting its potential for increased patient comfort in post-anesthetic care. However, dexmedetomidine also exhibited a higher incidence of sedation, as well as adverse cardiovascular events, including hypotension and bradycardia, compared to tramadol. Despite these risks, the sedative effects of dexmedetomidine may be beneficial in specific surgical settings where patient comfort and immobility during spinal anesthesia are desirable. This comprehensive analysis suggests that dexmedetomidine offers advantages over tramadol in terms of rapid shivering control and reduced recurrence, though care should be taken due to its hemodynamic effects. The comparative efficacy of dexmedetomidine or tramadol to meperidine remains uncertain. [12]