Neuromuscular blocking agents and skeletal muscle relaxants

C H A P T E R

12 Neuromuscular blocking agents and skeletal muscle relaxants Abigail Dee Antigua, PharmD, BCCCP1, Kacee Barnett, PharmD North Florida Regional Medical Center, University of Florida College of Pharmacy, Gainesville, FL, United States 1 Corresponding author: [email protected]

NEUROMUSCULAR BLOCKING AGENTS General Neuromuscular blocking agents (NMBAs) are used in clinical practice for conditions requiring paralysis such as rapid sequence intubation (RSI), acute respiratory distress syndrome (ARDS), and general anesthesia. The mechanism for how NMBAs work to improve outcomes in ARDS is unclear. A secondary analysis of 446 patients from the ARDS network evaluated whether NMBAs attenuate biomarkers of epithelial and endothelial lung injury and systemic inflammation in ARDS patients. They found that NMBAs are associated with decreased biomarkers of epithelial and endothelial lung injury and systemic inflammation in ARDS patients receiving low tidal volume ventilation and those with a P/F ratio less than or equal to 120 [1R]. A meta-analysis of 5 trials with 551 patients looked at the effect of NMBAs on ARDS. They found that NMBAs significantly reduce intensive care unit (ICU) mortality (RR, 0.73; 95% CI, 0.58–0.93; 4 trials, 455 patients) and 21- to 28-day mortality (RR, 0.63; 95% CI, 0.49–0.82; 4 trials, 527 patients). At 48 h, NMBAs improved oxygenation (95% CI 7.45–48.51; 4 trials, 212 patients). However, NMBAs had no effect on reduction of oxygenation at 24 h (95% CI,
5.89 to 59.55; 4 trials, 447 patients), or plateau pressure (95% CI,
0.46 to 1.31; 4 trials, 455 patients) as well as positive end expiratory pressure (95% CI,
0.47 to 0.67; 4 trials, 455 patients) at 48 h [2M]. NMBAs have been associated with post-operative complications such as residual paralysis and morbidity. A single center, retrospective cohort study of 128 886 surgeries on 99 280 patients investigated the incidence of post-operative complications in the PACU associated

Side Effects of Drugs Annual, Volume 41 ISSN: 0378-6080 https://doi.org/10.1016/bs.seda.2019.06.001

with use of NMBAs and assessing its association with healthcare resource utilization. They found incidences of major complications of 2.1% and minor complications of 35.2%. ICU admission rate was 1.3% in patients without any complications, vs 5.2% in patients with any minor and 30.6% in patients with any major complication. Patients who received a NMBA and neostigmine, compared to without neostigmine, had a lower incidence of any major complication (1.7% vs 6.05%), rate of re-intubation (0.8% vs 4.6%) and unplanned ICU admission (0.8% vs 3.2%) [3C]. The 6th National Audit Project (NAP6) on perioperative anaphylaxis reviewed 266 reports of grades 3–5 anaphylaxis over 1 year from all NHS hospitals in the United Kingdom (UK) in order to assess the overall incidence, culprits, and complications. They found the estimated incidence of perioperative anaphylaxis was approximately 1 in 10 000 anesthetics from 199 culprit agents (65/199 NMBAs). Succinylcholineinduced anaphylaxis, mainly presenting with bronchospasm, was two-fold more likely than other NMBAs. Atracurium-induced anaphylaxis mainly presented with hypotension. Non-depolarizing NMBAs had similar incidences to each other. Onset was rapid for NMBAs [11M]. A French study assessed NMBA induced anaphylaxis. A total of 680 confirmed cases and 944 non-confirmed cases were identified. Succinylcholine was the most implied NMBA (64%). Incidence rates of succinylcholine and rocuronium were, respectively, 10- and 13-folds higher than those of the others NMBAs. Cisatracurium incidence rates remained stable over the period, while succinylcholine and atracurium increased, and rocuronium first decreased but re-increased after 2006. Shared

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© 2019 Elsevier B.V. All rights reserved.

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12. NEUROMUSCULAR BLOCKING AGENTS AND SKELETAL MUSCLE RELAXANTS

characteristics were the poorly documented previous exposure to NMBAs and an insufficient adherence of patients to perform skin tests [12M]. Organs and systems: Respiratory There is increasing evidence suggesting that use of NMBAs during general anesthesia might be linked to postoperative pulmonary complications (PPCs), such as respiratory insufficiency resulting to failure to extubation; therefore, this study aimed to assess whether the use of NMBAs is associated with PPCs. This multicenter, prospective observational cohort study looked at 22 803 patients from 211 hospitals in 28 European countries found that NMBA use was associated with an increased incidence of PPCs in patients who had undergone general anesthesia (1658 [7.6%] of 21 694). They also found that the use of neuromuscular monitoring (ORadj 1.31, 95% CI 1.15–1.49; ARRadj
2.6%, 95% CI
3.9 to
1.4) and the administration of reversal agents (1.23, 1.07–1.41;
1.9%,
3.2 to
0.7) were not associated with a decreased risk of PPCs [4MC]. Organs and systems: Musculoskeletal A meta-analysis performed in China of 14 studies aimed to identify independent risk factors for ICU acquired weakness (ICUAW). The study found that NMBAs (OR, 2.03; 95% CI, 1.22–3.40) were significantly associated with ICUAW [5M]. Organs and systems: Gastrointestinal NMBAs have historically been used to induce paralysis in patients with open abdomens due to their association with decreased time to fascial closure following damage control laparotomy (DCL). This retrospective cohort study of 222 patients evaluated fascial closure in patients with (n ¼ 125) or without (n ¼ 97) NMBA. They found no difference in median time to closure (NMBA + 2; NMBA
2 days) or the incidence of complications (NMBA + 64%; NMBA
59%) [6R]. Susceptibility factors: Sleep apnea A meta-analysis of 5 studies totaling 1126 patients sought to determine whether patients with obstructive sleep apnea (OSA) are at higher risk of postoperative NMBA complications than non-OSA patients. Two of the three studies (1 RCT, 2 observational studies) reported that OSA patients given NMBAs may be at higher risk of developing PPCs compared to non-OSA patients. Two studies (1 RCT, 1 observational study) reported that OSA patients who were reversed with sugammadex vs neostigmine had less PPCs and chest radiographic changes (low to moderate quality evidence) [7M].

Monitoring therapy: Skin testing Due to NMBA’s association with perioperative hypersensitivity, skin testing and basophil activation tests (BAT) have been used for detection of NMBA allergy. This retrospective study of 31 patients experiencing perioperative immediate hypersensitivity occurring within 5 min of NMBA injection aimed to assess the role of BAT compared with the results of skin testing. In the allergy group (19 of 31 patients), skin test results were positive in 100% (19 of 19) of the cases, while BAT was positive in 78.9% (15 of 19). NMBA cross-reactivity was identified through skin testing and BAT in 36.8% (7 of 19) and 26.3% (5 of 19) of the cases, respectively. In the non-allergy group, skin test results were negative in 100% of the cases while BAT result was positive in one patient [8c].

DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS Succinylcholine (suxamethonium) (SEDA-36, 173; SEDA-37, 155; SEDA-38, 105; SEDA-40, 183) Organs and systems: Cardiovascular A single-center, retrospective case–control study of 29 patients evaluated risk factors associated with periintubation cardiac arrest (PICA). Patients were categorized dependent on emergent intubation in the operating room (OR) vs PICA from other types of inpatient cardiac arrest outside the (OR). They found the use of succinylcholine was independently associated with PICA (P ¼ 0.043) [9c]. Organs and systems: Neuromuscular A case study reports an alert 20-year-old male, trauma patient with head laceration, who developed suspected malignant hyperthermia (MH) after administration 1.5 mg/kg succinylcholine. Following administration of succinylcholine, the patient experienced prolonged muscle fasciculations, primarily of his pectoral and abdominal muscles, and abruptly desaturated to 60% despite ongoing oxygenation with a non-rebreather mask and nasal cannula. Patient was successfully intubated and was initiated on the MH protocol, which included administration of 2.5 mg/kg dantrolene followed by 250 mg every 6 h for 24 h. His temperature at time of initial dose was 37.1°C (98.8 °F) and his creatinine phosphokinase was 3529 U/L. He was admitted to the trauma ICU, extubated within 36 h, and discharged on day 7, neurologically intact with outpatient follow-up [10A].

NON-DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS

NON-DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS Drug administration: Drug dosage regimen Combined use of rocuronium and cisatracurium has synergistic effects. This randomized, controlled clinical trial of 81 patients aimed to determine whether reduced doses are effective during co-administration intraoperatively. Three groups received an intubation dose (n ¼ 27; rocuronium, 0.3 mg/kg, and cisatracurium, 0.05 mg/kg), a small dose reduction (n ¼ 27; 10% dose reduction), or a large dose reduction (n ¼ 27; 20% dose reduction). The large dose reduction group had a longer duration to onset (399.3  147.8 s) and shorter duration of activity (39.4  6.8 min) compared to the intubation dose (212.8  56.0 s and 51.3  8.47 min, respectively) and small reduction dose (230.7  60.6 s and 47.9  10.7 min, respectively). No other significant differences were found. The authors recommend reducing doses of both drugs by approximately 10% to maintain neuromuscular relaxation during minor surgery [13c].

Atracurium Susceptibility factors: Rubinstein–Taybi syndrome There are currently no known interactions between nondepolarizing NMBAs in patients with Rubinstein–Taybi Syndrome (RTS). This case study reports a patient with RTS who underwent general anesthesia and experienced an unexpected prolonged atracurium effect. The authors ruled out other causes and concluded that the RTS played a role in the prolonged effect of atracurium [14A].

Cisatracurium (SEDA-40, 184) Organs and systems: Cardiovascular This single center, randomized study of 88 patients observed QTc interval changes during anesthetic induction with or without cisatracurium administration. The QTc interval after cisatracurium injection was not significantly different compared to the non-cisatracurium group after anesthetic induction at 2 min (P > 0.05). The QTc interval was not significantly changed by laryngeal mass airway (LMA) insertion in either the cisatracurium group (P > 0.05) or the non-cisatracurium administration group (P > 0.05) [15c].

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in mice. The authors determined that cisatracurium activates MRGPRX2 and triggers mast cell degranulation, leading to anaphylactoid reactions. Therefore, strategies targeting MRGPRX2 might potentially block cisatracurium-induced pseudo-allergic reactions [16E].

CW002 (SEDA-40, 184) Drug administration: Drug dosage regimen CW002 has been studied in a variety of animal models and human volunteers as a new benzoquinolinium fumarate diester non-depolarizing NMBA of an intermediate duration of action. It is designed to interact more slowly with endogenous L-cysteine than gantacurium and is degraded by L-cysteine adduction and alkaline hydrolysis (t1/2 ¼ 11.4 min). Furthermore, CW002 can be rapidly reversed by L-cysteine which has been shown in different animal models. Preclinical and human studies showed that a single bolus of CW002 resulted in minimal cardiopulmonary side effects and no histamine release. A human study showed the ED95 in humans is 0.077 mg/kg. In a dose of 1.8 ED95 (0.14 mg/kg) of CW002, the onset time for neuromuscular block was approximately 90 s. The clinical duration was almost 33.8 min (range 28.8–36.1 min), time from 25% to 75% recovery of T1 (interval 25%–75%) 14 min. The spontaneous recovery to a train-of-four 0.90 was 73 min [17R].

CW011 General CW011 is a non-halogenated olefinic diester analogue of gantacurium. An in vitro study showed that this drug had predictable slower L-cysteine adduction, and therefore a longer lasting neuromuscular blocking effect than gantacurium is to be expected. In an animal study, the duration of neuromuscular block was approximately 20.8 min, half of cisatracurium duration and three times longer than gantacurium. CW011 showed a high potency and the calculated ED95 was 0.025 mg/kg. Based on this study, it was concluded that the rate of L-cysteine adduction was inversely related to the duration of action of a CW011-induced neuromuscular block in monkeys. To date, no studies in humans are available [17R].

Gantacurium (SEDA-38, 108) Organs and systems: Respiratory

General

The mechanisms underlying the anaphylactoid reactions caused by cisatracurium have not been fully explained. This in vivo study investigated the MRGPRX2related pseudo-allergic reactions induced by cisatracurium

Gantacurium is the first compound of a new class of non-depolarizing NMBAs: the asymmetric mixed-onium chlorofumarates. Gantacurium is ultra-short acting with rapid onset and a wide safety margin. It is metabolized

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by chemical degradation, which involves cysteine adduction and pH-sensitive hydrolysis. Cysteine adduction results in replacement of chlorine by cysteine causing a heterocyclic ring formation, which cannot interact with the post-junctional acetylcholine receptor. Therefore, the metabolites of gantacurium showed no neuromuscular properties. There is no renal or hepatic involvement in the elimination of gantacurium. Reversal of a gantacurium-induced neuromuscular block is possible with administration of cysteine. In human volunteers, the ED95 of gantacurium is 0.19 mg/kg. The onset of action is less than 3 min and could be shortened to approximately 1.5 min by increasing the dose to 4 ED95. At these doses, the duration of action of gantacurium is approximately 15 min. Transient cardiovascular side effects were observed at doses of 3 ED95 or higher. Humans showed significant histamine release when gantacurium was administered in doses of 4 ED95. However, at lower doses, there was no evidence of histamine release. Based on these results, gantacurium seems to have nearly identical neuromuscular properties of succinylcholine without the unwanted side effects of this depolarizing neuromuscular blocking drug. Gantacurium is not available in clinical practice at this time [17R].

Mivacurium (SEDA-40, 184) Susceptibility factors: Vis-à-tergo This prospective single-center interventional study aimed to investigate the influence of mivacurium (n ¼ 30), atracurium (n ¼ 35), and rocuronium (n ¼ 30) on intraocular pressure (IOP), ocular pulse amplitude (OPA), and vis-à-tergo (VAT) in patients undergoing penetrating keratoplasty (PKP) under general anesthesia. Mivacurium decreased IOP by 2.2 mmHg [SD  2.2mmHg; P < 0.001]. Atracurium decreased the IOP by an average of 5.8 mmHg (SD  1.8 mmHg; P < 0.001) and rocuronium caused an IOP reduction of 7.2 mmHg (SD 2 mmHg; P < 0.001). The relative IOP decrease was 12% with mivacurium, 29% with atracurium, and 37% with rocuronium (P < 0.001). OPA decreased by 0.6mmHg with mivacurium (SD 0.6 mmHg; 26%; P < 0.001), 1.3 mmHg with atracurium (SD 1.3 mmHg; 40%; P < 0.001), and 1.2 mmHg with rocuronium (SD  0.7 mmHg; 42%; P < 0.001). The relative OPA decrease was 26% with mivacurium, 40% with atracurium, and 42% with rocuronium (P < 0.001). VAT occurred in 36% of cases. Mivacurium was used in 77% of these cases, atracurium in 26%, and rocuronium in 6.6% (P < 0.001). The authors concluded that mivacurium is associated with a higher risk of VAT during PKP [18c].

Rocuronium (SEDA-38, 107; SEDA-40, 185) Organs and systems: Respiratory This is a case study of a 7-year-old asthmatic boy who experienced anaphylactic shock during the induction of

anesthesia. He experienced ventilation difficulty, decreased blood pressure, and tachycardia immediately after the administration of rocuronium. An asthma attack was suspected, and an inhaled β2 stimulant (salbutamol sulfate) was administered without symptom improvement. However, oxygen saturation and heart rate began to improve as a result of using noradrenaline to increase blood pressure. It was not until urticaria was confirmed on the limbs when stripping off the patient’s surgical drapes to secure an arterial line that the signs of anaphylactic shock were noticed. Due to hemodynamic improvement and stability, adrenaline was not administered. An intradermal test was performed later, and the patient tested positive for a rocuronium reaction [19A]. Second generation effects: Pregnancy This study set out to compare the onset and duration of rocuronium-induced neuromuscular blockade in second trimester pregnant women (n ¼ 47) and non-pregnant women (n ¼ 47) receiving general anesthesia. Rocuronium was dosed at 0.6 mg/kg. They found the onset of rocuronium-induced neuromuscular blockade did not differ significantly between the groups. The duration was significantly longer in the pregnant group (45.7  12.9 min vs 40.6  10.4 min, P < 0.037). During the recovery period from the blockade, the mean arterial pressure was significantly lower in pregnant group [20c]. Another study compared rocuronium and succinylcholine for RSI of general anesthesia for caesarean section and found no difference in maternal outcome. There was, however, a significant difference in Apgar scores. This study sought to explore this difference in a randomized trial with 488 women who received either rocuronium 1 mg/kg (n ¼ 245) or succinylcholine 1 mg/kg (n ¼ 243). There were 525 newborns who received rocuronium (n ¼ 263) or succinylcholine (n ¼ 262). There was a statistically significant difference in the proportion of Apgar scores <7 at 1 min (ROC 17.5% vs SUX 10.3%, P ¼ 0.023) but no difference at 5 min (ROC 8% vs SUX 4.2%, P ¼ 0.1) or 10 min (ROC 3.0% vs SUX 1.9%, P ¼ 0.58) [21C]. Drug administration: Drug dosage regimen Recent data shows that a neuromuscular block induced by administration of high doses of rocuronium improves surgical conditions in certain procedures. However, there are limited data on the effect such practices on postoperative outcomes. This retrospective cohort study in the Netherlands compared unplanned 30-day readmissions in patients that received high-dose (217  49 mg, n ¼ 130) vs low-dose (37  5 mg, n ¼ 130) rocuronium administration during general anesthesia for laparoscopic retroperitoneal surgery. They found that unplanned 30-day readmission rate was significantly lower in the high-dose compared to the low-dose rocuronium cohort (3.8% vs 12.7%; P ¼ 0.03; odds ratio ¼ 0.33, 95% C.I. 0.12–0.95) [22C].

SUGAMMADEX (SEDA-37, 157; SEDA-38, 108, SEDA-40, 185)

Interactions: Drug–drug interaction A case study of a healthy 74-year-old male who underwent transurethral resection of a benign prostatic hyperplasia under total IV anesthesia is reported. Three boluses of epinephrine 5 μg were administered due to repeated drop in heart rate and blood pressure. The rocuroniuminduced neuromuscular block was intensified after each dose of epinephrine. This was verified by acceleromygraphy. This is the third reported case of an intensification of a rocuronium-induced neuromuscular block by epinephrine [23A].

NEUROMUSCULAR BLOCKERS: REVERSAL AGENTS Calabadion General Calabadions are a new neuromuscular blocking reversal class shown to have fast and dose-dependent reversal of cisatracurium and rocuronium. Calabadion 1 is the first-generation calabadion with the ability to reverse neuromuscular block with the binding affinity of sugammadex to rocuronium (Ka 3.8  107 M
1). Calabadion 1 (90 mg/kg) was able to reverse a rocuronium- and cisatracurium-induced neuromuscular block to recovery to a train-of-four (TOF) ratio >0.90 within 1–2 min in a rat model. There were no signs of recurarization and there were no effects on heart rate, blood pressure, or pH. Furthermore, calabadion 1 was rapidly eliminated by the kidneys; it also formed an inclusion complex with local anesthetics in aqueous solution in vitro, which may play a role in the treatment of local anesthetic toxicity. Calabadion 2 is the second-generation acyclic member with an 89-fold stronger affinity toward rocuronium than sugammadex. Calabadion is a recent developed drug which is able to encapsulate both steroidal and benzylisoquinolinium neuromuscular blocking drugs. Calabadion complexes are enhancing solubility, binding affinity toward cations as a result of electrostatic interactions, and lowering the concentration of neuromuscular blocking drugs that are molecular containers and acyclic members of the cucurbituril family. These molecules are flexible and can expand their cavity thereby able to encapsulate larger molecules like benzylisoquinolinium molecules. Calabadions can form host-guest including rocuronium, vecuronium, and cisatracurium [17R].

Neostigmine Special review A study evaluated the effect of neostigmine for 21 awake volunteers, who were randomized to receive two doses of IV

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neostigmine 2.5 mg with glycopyrrolate 250 mcg (n ¼ 14) or normal saline 0.9% (placebo group, n ¼ 7). All 14 volunteers in the neostigmine group received the first dose, mean (SD) 35 (5.8) mcg/kg, and 9 of these volunteers agreed to receive a second dose, 34 (3.5) mcg/kg. The results were decreased grip strength after the first dose of neostigmine compared to placebo (P ¼ 0.0016), decreased single twitch height (
14% vs
4.8%, P ¼ 0.0077), a restrictive spirometry pattern with decreased predicted forced expiratory volume in 1 s (
15% vs
0.47%, P ¼ 0.0011), and decreased predicted forced vital capacity (
20% vs
0.59%, P < 0.05) at 5 min after administration for neostigmine vs placebo. Therefore, in healthy volunteers, therapeutic doses of neostigmine induced significant and dose-depended muscle weakness demonstrated by a decrease in maximum voluntary hand grip strength and a restrictive spirometry pattern secondary to depolarizing neuromuscular blockade [24c]. Due to more adverse events associated with neostigmine, a study evaluated whether a protocol for the management of neuromuscular block that specified appropriate dosing and optimal neostigmine reversal was associated with a reduction in postoperative residual neuromuscular block. The protocol included rocuronium administration guided by surgical requirements, dosing based on ideal body weight, with dose reductions for female sex and age >55 years. Neostigmine was administered in adjusted doses after a TOF was confirmed. Results showed that post-operative residual neuromuscular block at tracheal extubation was 14/40 (35%) for patients on the protocol compared with 22/38 (58%) for patients in the control group (OR 0.39, 95% CI 0.14–1.07, P ¼ 0.068). The incidence of severe post-operative residual neuromuscular block at tracheal extubation showed a highly significant difference (OR ¼ 0.06, CI 0.00–0.43, P ¼ 0.001) [25c].

Organs and systems: Cardiology This is a case report on a 21-year male with history of seizures and developmental delay who presented for a dental surgery under general anesthesia. The patient developed a type 1 AV block following administration of neostigmine and glycopyrrolate to reverse the NMB. The authors suggest that the antiepileptic medications and reversal agents interacted causing the AV block [26c].

SUGAMMADEX (SEDA-37, 157; SEDA-38, 108, SEDA-40, 185) Special review A Cochrane review of 41 studies with 4206 participants compared the efficacy and safety of sugammadex vs neostigmine in reversing neuromuscular blockade caused by nondepolarizing NMBAs in adults. The results showed time to reversal of neuromuscular blockade from second twitch to a

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TOF ratio >0.9 was 2 min with sugammadex 2 mg/kg compared to 12.9 min for neostigmine 0.05 mg/kg, with a mean difference (MD) (95% CI) of 10.2 min (8.5–12 min) (10 studies, n ¼ 835). These results were given Grades of Recommendation, Assessment, Development and Evaluation (GRADE) of moderate quality. Time to reversal of neuromuscular blockade from a post-tetanic count of 1–5 to a TOF ratio >0.9 was 2.9 min with sugammadex 4 mg/kg and 48.8 min with neostigmine 0.07 mg/kg, with a MD (95% CI) of 45.8 min (39.4–52.2) (2 studies, n ¼ 11, GRADE ¼ low quality). There were significantly fewer composite adverse events in the sugammadex group compared with neostigmine, with a risk ratio (95% CI) of 0.60 (0.49–0.74) (28 studies, n ¼ 2298, number needed to treat (NNT) ¼ 8, GRADE ¼ moderate quality). The specific adverse events evaluated were bradycardia (RR (95% CI) 0.16 (0.07–0.34), n ¼ 1218, NNT: 14, GRADE ¼ moderate quality), post-operative nausea and vomiting (RR (95% CI) 0.52 (0.28–0.97), n ¼ 389, NNT: 16, GRADE ¼ low quality), and overall signs of postoperative residual paralysis (RR (95% CI) 0.40 (0.28–0.57), n ¼ 1474, NNT: 13, GRADE ¼ moderate quality), which were all reduced with sugammadex. There was no significant difference regarding the risk of serious adverse events (RR 0.54, 95% CI 0.13–2.25, n ¼ 959, GRADE ¼ low quality). In conclusion, sugammadex reverses neuromuscular blockade more rapidly than neostigmine and is associated with fewer adverse events [27M]. One of the disadvantages of sugammadex is the higher cost compared to neostigmine. A study evaluated the efficacy of sugammadex standard dosing (4 mg/kg) compared to moderate dosing (2 mg/kg) on reversing a pipecuronium. This study was a single-center, randomized, double-blind, 2 parallel-arms, non-inferiority with 50 patients that underwent general anesthesia with propofol, sevoflurane, fentanyl, and pipecuronium. The results showed a reversal time is 1.73  1.03 min (95% CI, 1.33–2.12; n ¼ 25) for the 2 mg/kg group compared to 1.42  0.63 min (mean  SD) (95% CI, 1.17–1.67; n ¼ 25). Post-operative block did not occur. Therefore, 2 mg/kg is non-inferior to 4 mg/kg dosing of sugammadex [28c].

Organs and systems: Cardiology This study evaluated the QT interval, hemodynamic status, QT dispersion after neostigmine or sugammadex. The study institution enrolled 40 patients to either receive neostigmine 40 mcg/kg with atropine 20 mcg/kg, or sugammadex 4 mg/kg. This caused a significant decrease in RR interval after reversal of neuromuscular blockade in the neostigmine group compared to the sugammadex group (P < 0.05). The QT interval decreased and the QTc and QTc intervals increased in the neostigmine group, while there was no change in the sugammadex group. This study concluded that neostigmine might cause electrocardiogram abnormalities that could precede the development of fatal arrhythmias [29c].

In a more specific patient population, a case report on five pediatric heart transplantation patients was described. Dose-dependent life-threatening bradycardia has a high incidence with neostigmine. This case evaluated the efficacy of sugammadex in this population due to limited data available. After receipt of sugammadex to reverse neuromuscular blockade, no cardiac adverse events were observed; therefore, the authors report the possible role of sugammadex in the patient population [30c]. In contrast, a case report was presented on a 60-year-old man who underwent open radial prostatectomy for prostate adenocarcinoma. He had no known cardiac disease or symptoms other than controlled hypertension and remote history of cocaine use. The patient was given sugammadex for reversal of neuromuscular blockade and within 1 min, developed severe, drug-resistant bradycardia followed by pulseless electrical activity arrest. Advanced cardiac life support was initiated and continued for 15 min before return of spontaneous circulation. The authors believe the cause of the cardiac arrest was sugammadex, considering the time of administration, the absence of cardiac disease, and stable operative course [31c].

Organs and systems: Dermatology One case report examined the effect of sugammadex on a large infiltration of subcutaneous rocuronium under the skin after administration for a RSI. The patient was an elderly man with end stage renal failure with limited access available. After administration of sugammadex, the infiltration subsided and reversal was successful [32c].

Organs and systems: Immunologic Sugammadex has a steroid-encapsulating effect; therefore, a study evaluated if sugammadex was altered after administration of steroids. A total of 60 patients between ages 18 and 60 years underwent elective direct laryngoscopy/biopsy. Patients were assigned to two groups: with steroids and no steroids. Patients were monitored using TOF. The reached time to TOF 0.9 after sugammadex administration was significantly shorter in the steroid group compared to no steroids (P < 0.05). The conclusion of the study showed an earlier reversal of neuromuscular block by sugammadex for patients receiving steroids [33c].

SKELETAL MUSCLE RELAXANTS Specialty review Traumatic brain injury (TBI) is known for skeletal muscle spasticity including muscle contracture, joint stiffness, and

BACLOFEN (SEDA-36, 173; SEDA-37, 158; SEDA-38, 110; SEDA-40, 186)

reduced range of movement. Management of this complication included non-pharmacological and pharmacological interventions. A Cochrane review assessed the pharmacological interventions used for managing skeletal muscle spasticity in TBI. RCTs and cross-over RCTs evaluating any intervention for the management of spasticity in TBI. Nine studies were included in this review which involved 134 participants with TBI. Only five studies reported between-group differences, yielding outcome data for 105 participants with TBI. These five studies assessed the effects of a range of pharmacological (baclofen, botulinum toxin A) and non-pharmacological interventions, often in combination. The studies which tested the effect of baclofen and tizanidine did not report their results adequately. It was difficult to draw conclusions about the effectiveness of these interventions due to poor reporting, small study size and the fact that participants with TBI were usually only a proportion of the overall total. Meta-analysis was not feasible due to the paucity of data and heterogeneity of interventions and comparator groups. Some studies concluded that the intervention they tested had beneficial effects on spasticity, and others found no difference between certain treatments. The most common adverse event was minor skin damage in people who received casting [34M].

BACLOFEN (SEDA-36, 173; SEDA-37, 158; SEDA-38, 110; SEDA-40, 186) Specialty review Intrathecal baclofen (ITB) is a commonly used treatment in severe spasticity. The main objective of this study was to assess the impact of ITB on reduction or withdrawal of oral drugs in patients with paroxysmal sympathetic hyperactivity (PSH) after severe TBI. A retrospective study enrolled 20 patients with PSH due to severe traumatic brain injury who were treated with ITB. The incidence rate and timing of complete oral drug withdrawal or reduction of oral baclofen and oral propranolol use after ITB treatment were calculated Moreover, vegetative parameters (heart rate and blood pressure) as well as hypertonic attacks were assessed. The median time of complete oral baclofen disposal was 5  3.7 (CI 95% [2.9–7.1], range 0–14) days after ITB pump implantation in of the 20 patients. The median time of complete oral propranolol disposal was 24  62.97 (CI 95% [
7.87 to 55.87], range 5–191) days in 15 of 20 patients. With ITB treatment, PSH improved promptly in all patients with alleviation of heart rate and blood pressure as well as reduction in attacks with motor phenomena. ITB treatment was safe and without complications [35c].

Organs and systems: Psychiatry Alcohol dependent (ALD) patients with liver disease (n ¼ 104) were randomized to placebo, baclofen 30 or 75 mg/day for 12 weeks. There was a significant effect

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of baclofen on time to lapse (χ 2 ¼ 6.44, P < 0.05, Cohen’s d ¼ 0.56) and relapse (χ 2 ¼ 4.62, P < 0.05, d ¼ 0.52). A significant treatment effect of baclofen was observed for percentage days abstinent (placebo 43%, baclofen 30 mg 69%, baclofen 75 mg 65%; P < 0.05). There was one serious adverse event (overdose) directly related to medication (75 mg). Therefore, baclofen may be an effective treatment option for patients with ALD. However, given the profile of adverse events, the role for this medication might be limited to specialist services [36C]. Another study assessed the efficacy and safety of baclofen for treating people with alcohol use disorder (AUD), who are currently drinking, with the aim of achieving and maintaining abstinence or reducing alcohol consumption. A total of 12 RCTs (1128 participants) were included. The included studies considered baclofen at different doses (range 10–150 mg a day). The authors did not find any difference between baclofen and placebo for the primary outcomes: relapse-return to any drinking (RR 0.88, 95% CI 0.74–1.04; 5 studies, 781 participants, moderate certainty evidence); frequency of use by percentage of days abstinent (MD 0.39, 95% CI
11.51 to 12.29; 6 studies, 465 participants, low certainty evidence) and frequency of use by percentage of heavy drinking days at the end of treatment (MD 0.25, 95% CI
1.25 to 1.76; 3 studies, 186 participants, moderate certainty evidence); number of participants with at least one adverse event (RR 1.04, 95% CI 0.99–1.10; 4 studies, 430 participants, high certainty evidence); the dropout rate at the end of treatment (RR 0.98, 95% CI 0.77–1.26, 8 studies, 977 participants, high certainty evidence) and dropout due to adverse events (RR 1.11, 95% CI 0.59–2.07; 7 studies, 913 participants, high certainty evidence). There was evidence that baclofen increases amount of use (drink per drinking days), (MD 1.55, 95% CI 1.32–1.77; 2 studies, 72 participants, low certainty evidence). Among secondary outcomes, there was no difference on craving (MD 1.38, 95% CI
1.28 to 4.03, 5 studies, 469 participants), or anxiety (SMD 0.07, 95% CI
0.14 to 0.28; 5 trials, 509 participants). There was a higher incidence of baclofen use and depression (SMD 0.27, 95% CI 0.05–0.48; 3 studies, 387 participants). Concerning the specific increased rate of adverse events with baclofen: vertigo (RR 2.16, 95% CI 1.24–3.74; 7 studies, 858 participants), somnolence/sedation (RR 1.48, 95% CI 1.11–1.96; 8 studies, 946 participants), paraesthesia (RR 4.28, 95% CI 2.11–8.67; 4 studies, 593 participants), and muscle spasms/rigidity (RR 1.94, 95% CI 1.08–3.48; 3 studies, 551 participants). Baclofen increased craving compared with acamprosate (MD 14.62, 95% CI 12.72–16.52; 1 study, 49 participants) [37M]. A second systematic review of the current literature on the efficacy of baclofen, particularly the effect of dosing, for the treatment of alcohol dependence (AD) is missing. The authors conducted a systematic review and

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meta-analysis of currently available RCTs. A systematic literature search for RCTs in AD patients comparing baclofen to placebo was performed in September 2017. The effect of baclofen treatment, and the moderating effects of baclofen dosing (low-dose (LDB) 30–60 mg vs highdose (HDB) targeted as >60 mg/day), and the amount of alcohol consumption before inclusion were studied. Three treatment outcomes were assessed: time to lapse (TTL), percentage days abstinent (PDA), and percentage of patients abstinent at end point (PAE). 13 RCTs from 39 records were included. Baclofen was superior to placebo with significant increases in TTL (8 RCTs, 852 patients; SMD ¼ 0.42; 95% CI 0.19–0.64) and PAE (8 RCTs, 1244 patients; OR ¼ 1.93; 95% CI 1.17–3.17), and a nonsignificant increase in PDA (7 RCTs, 457 patients; SMD ¼ 0.21; 95% CI
0.24
0.66). Overall, studies with LDB showed better efficacy than studies with HDB. Furthermore, tolerability of HDB was low, but serious adverse events were rare. Meta-regression analysis showed that the effects of baclofen were stronger when daily alcohol consumption before inclusion was higher. Baclofen seems to be effective in the treatment of AD, especially among heavy drinkers. HDB is not necessarily more effective than LDB with low tolerability of HDB being an import limitation [38M]. There is little information with regards to the efficacy and safety of baclofen among alcohol patients concurrently receiving antidepressants (AD). Patients enrolled were alcohol dependent patients (N ¼ 104) treated for 12 weeks with 30 mg/day of baclofen (21 ¼ AD and 15 ¼ no AD), 75 mg baclofen (19 ¼ AD and 16 ¼ no AD) or placebo (17 ¼ AD and 16 ¼ no AD). Patients were included in the trial if they were concurrently receiving anti-depressants upon enrolment but were excluded if they commenced antidepressants 2 months prior to enrolment. Patients were also excluded in the case of concurrent psychotropic medications, active major mental disorder such as bipolar disorder, psychosis, or history of suicide attempt. For the number of days to first lapse, there was a trend of significance for the interaction baclofen  AD (Log Rank: χ 2 ¼ 2.98, P ¼ 0.08, OR: 0.41, 95% CI: 0.15–1.12). For the number of days to relapse, there was a trend of significance for the interaction of baclofen  AD (Log Rank: χ 2 ¼ 3.72, P ¼ 0.05, OR: 3.40, 95% CI: 1.01–11.46). Placing significant baseline variables into the models as covariates (tobacco, ALD) weakened these interactions (P > 0.15). There were no significant effects of ADs on the frequency of adverse events reported (P > 0.19). Therefore, concurrent receipt of ADs commenced more than 2 months prior to baclofen treatment did not negatively impact on drinking outcomes [39c]. Another drug dependence evaluated was on Gammahydroxybutyrate (GHB). GHB-dependence is a severe, potentially lethal withdrawal syndrome with relapse

rates as high as 60% within 3 months of detoxification. This was an outpatient, multicenter, open-label, nonrandomized, controlled trial in GHB-dependent patients (n ¼ 107) in the Netherlands. Treatment as usual (TAU, n ¼ 70) was compared with TAU plus baclofen 45–60 mg/day for 3 months (n ¼ 37). GHB-dependent patients treated with baclofen after detoxification showed no reduced lapse rates, but reduced relapse and dropout rates, compared with patients receiving TAU only (24 vs 50%). While both ITT and PP analyses revealed similar results, the effectiveness of baclofen prescribed PP was slightly higher than in ITT analysis. Patients reported overall limited side effects, with the most frequently reported being feeling tired (28%), sleepiness (14%) and feeling depressed (14%). No serious adverse events were reported. This study showed potential effectiveness of baclofen in preventing relapse in patients with GHB dependence after detoxification [40C].

Organs and systems: Central nervous system A study evaluated the long-term efficacy and safety of ITB in treating multiple sclerosis (MS)-related spasticity over  20 years. The study was a single center, prospective, observational cohort study of 106 people that included 568 patient years of data. Ashworth, Penn and VAS/NRS mean scores improved post-trial compared with baseline (P < 0.001). Sustained efficacy was reported on Ashworth, Penn and VAS scores over time. After 1 year, 73 (69%) discontinued all oral antispasticity medications. Complication rates were low at 0.05 complications per pump year and mostly mechanical (usually catheter) related. In 8 ambulatory subjects, 7 (87%) continued to walk 1 year after pump insertion, 5 (62%) were still walking at time of analysis (mean follow-up 3.4 years). ITB is an effective and safe long-term treatment for refractory MS related spasticity. Efficacy was sustained over time and the majority of subjects subsequently discontinued systemic medications. In a small cohort, ability to walk was preserved, indicating ITB should be considered earlier in this cohort [41C].

Organs and systems: Nephrology Baclofen is a centrally acting GABAB receptor agonist and is used widely for the treatment of spasticity, persistent hiccups and MS. The renal system is the main route of excretion, thus people with suboptimal renal function are prone to baclofen intoxication. Multiple doses of baclofen have been associated with toxicity, but it is unusual that single doses can do so. This is a case of a 47 year old female patient with end stage renal disease (ESRD) presented with a sudden onset of altered mental status

CARISOPRODOL (SEDA-37, 160; SEDA-38, 111; SEDA-40, 188)

and state of unconsciousness after the ingestion of one tablet of baclofen 25 mg. All other possible causes were ruled out and a diagnosis of baclofen toxicity was considered. The patient showed dramatic improvement after an extra two sessions of hemodialysis. The authors recommend avoiding baclofen use if evidence of chronic renal disease is present and to seek other alternatives for pain management [42c].

BOLULINUM TOXIN (SEDA-36, 174; SEDA-37, 159; SEDA-38, 110; SEDA-40, 187) Organs and systems: Central nervous system Baclofen is approved by the US FDA to treat spasticity, but its sustained use may cause drug addiction. The objective of this study was to compare the efficacy and safety of botulinum toxin type A vs baclofen in spasticity. A total of 336 patients with spasticity caused by spinal cord injury (SCI) were enrolled in a randomized (1:1:1 ratio) placebo, controlled trial. Patients received baclofen (BA group, n ¼ 112), local intramuscular (IM) injection of 500 units botulinum toxin type A (BTI group, n ¼ 112), or physical therapies alone (placebo group, n ¼ 112). Baclofen (1.504  0.045 vs 1.53  0.06, P ¼ 0.003, q ¼ 4.068) and botulinum toxin type A (1.49  0.09 vs 1.528  0.15, P ¼ 0.0224, q ¼ 3.5541) had improved mAS scores after 2 weeks. Baclofen had a more strongly improved DAS score than botulinum toxin type A at 4 (P ¼ 0.0496, q ¼ 3.48) and 6 (P < 0.0001, q ¼ 6.48) weeks. Baclofen and botulinum toxin type A had consistently improved BI scores. Baclofen caused asthenia and sleepiness, while botulinum toxin type A caused bronchitis and elevated blood pressure. In conclusion, botulinum toxin type A may be an effective therapeutic option for spasticity caused by SCI [43C]. OnabotulinumtoxinA (BoNT-A) is a promising therapy for treating neurogenic detrusor overactivity (NDO) in individuals with SCI. This systematic review and meta-analysis aimed to carry out an in-depth review and to make an objective estimation of the efficacy and safety of BoNT-A on NDO after SCI. This analysis included 17 studies involving 1455 patients. Compared with placebo and baseline, BoNT-A was effective in increasing maximum cystometric capacity, volume at first involuntary detrusor contraction, cystometric bladder capacity (all P < 0.00001), compliance (P ¼ 0.001), and the number of patients with complete dryness (P ¼ 0.0003), and decreasing detrusor pressure, the number of patients with no involuntary detrusor contractions, the maximum flow rate, the incidence of detrusor overactivity (all P < 0.00001), and the number of urinary incontinence episodes (P ¼ 0.001). There were no statistically

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significant differences between doses of 200 and 300 units or between injections into the detrusor and submucosa. There were no life-threatening adverse events. BoNT-A is effective and safe in treating NDO after SCI [44M].

Organs and systems: Neurology Restless Legs Syndrome (RLS) is a common movement disorder with an estimated prevalence of up to 12%. Previous small studies with onabotulinumtoxin A (OnaA) for RLS have shown inconsistent results. A total of 21 patients with an International RLS score (IRLS) of >11 (moderate–severe) were enrolled in this blinded, placebo-controlled crossover study. Twenty-one patients completed the evaluations at 4, 6, and 8 weeks after each injection. One-hundred units of Incobotulinumtoxin A (IncoA) or normal saline were injected into tibialis anterior, gastrocnemius, and biceps femoris muscles each side. Improvement from a severe (IRLS > 21) to a mild/ moderate (IRLS  20) score was significant at four weeks (P ¼ 0.0036) and six weeks (P ¼ 0.0325) following IncoA administration compared to placebo. Additionally, there was significant improvement in pain score at six weeks as measured by Visual Analogue Scale (P ¼ 0.04) and the Johns Hopkins Quality of Life Questionnaire (P ¼ 0.01) in the IncoA group. Definite or marked improvement on Patient Global Impression of Change was seen in 7 out of 21 patients in the IncoA group vs 1 out of 21 patients in the placebo group at 4 weeks (P ¼ 0.012). IncoA injection lead to a reduction in severity of RLS symptoms, pain score, and quality of life, without any adverse effects [45c].

CARISOPRODOL (SEDA-37, 160; SEDA-38, 111; SEDA-40, 188) Drug administration: Toxicology A review compared volume of calls involving carisoprodol abuse or misuse to a statewide poison control system before and after the scheduling change. Data were extracted from poison control calls coded as “misuse/ abuse” involving carisoprodol from 4 years before (2008–2011) and 4 years after (2012–2015) the scheduling change. The volume of calls from pre- and postscheduling change in 2012 was compared after adjusting for yearly California census data. The number of calls related to carisoprodol abuse or misuse was significantly decreased in the 4 years following the change compared to the 4 years before. Scheduling of carisoprodol was temporally related to decreased exposures as reported to California Poison Control Centers. Governmental regulation may impact a drug’s potential for abuse [46R].

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DANTROLENE Organs and systems: Neurology Dantrolene, a ryanodine receptor antagonist, is primarily known as the only clinically acceptable and effective treatment for MH. Neuroleptic malignant syndrome is a rare but life-threatening idiosyncratic complication. It is characterized by hyperthermia, muscle rigidity, autonomic disturbances and mental state alterations. This is a case on a 31-year-old female (60 kg) who received a depot preparation of fluphenazine on account of depression with psychotic features observed 2 days prior to elective cholecystectomy under general anesthesia. Surgery and anesthesia were uneventful. Forty-eight hours postoperatively, she developed features suggestive of neuroleptic malignant syndrome complicated by aspiration pneumonitis. This necessitated a prolonged ICU stay requiring mechanical ventilation. She eventually developed deep venous thrombosis of the left upper limb, and required tracheostomy on account of prolonged endotracheal intubation. She fully recovered following bromocriptine and dantrolene therapy. She was discharged home after 60 days on admission and has remained in good health [47c]. A second MH case is on a 52-year-old man presenting to clinic 2 days after an assault for management of jaw pain. A minimally displaced right parasymphyseal fracture and moderately displaced left body fracture of the mandible were diagnosed. There were no known drug allergies. He reported no previous difficulty with anesthesia, as well as no known prior adverse reactions to anesthesia in any relatives. The planned surgical intervention was open reduction-internal fixation of bilateral mandibular fractures. The patient received succinylcholine and desflurane during the procedure. A full 70 min elapsed before initial signs of hypermetabolism were noted, namely, a rise in end-tidal carbon dioxide level. The patient received dantrolene sodium approximately 120 min after induction of anesthesia. Signs of hypermetabolism began to abate within 45 min of commencement of the MH treatment protocol. He was subsequently transferred to the surgical ICU for continued management and had a favorable postoperative course. This case underscores the importance of awareness of MH and its presentation. This condition carries a potential high risk of complications after exposure to triggering anesthetic agents. Taking a complete and detailed history may help to identify potential cases. In this case, it was subsequently discovered that the patient’s biological sister had a nearly fatal reaction to general anesthesia several years prior to this incident. Intraoperative vigilance in the monitoring of vital signs cannot be overemphasized. An increase in end-tidal carbon dioxide values, in

addition to other clinical signs that cannot be easily attributed to other causes, should increase the clinical index of suspicion for a diagnosis of MH [48c].

METHOCARBAMOL (SEDA-38, 111) Special review A study of 100 patients with liver cirrhosis and chronic hepatitis C who presented with frequent muscle cramps (3 cramps per week) was conducted. Half of these patients received methocarbamol and the other half received placebo. This was done through equal randomization. Questionnaires on muscle cramps were answered. Patients were evaluated before, after 1 month of treatment, and 2 weeks after washout of treatment in terms of severity, duration, and frequency of cramps. Liver, renal function, and electrolytes were analyzed. Also, any side effect was detected. Patients who were treated with methocarbamol showed a significant decrease in the frequency and duration of cramps, as well has pain score improvement. However, no significant changes were observed in the placebo group. Few side effects of methocarbamol were recorded, including dry mouth and drowsiness. Methocarbamol seems to be a promising safe and well-tolerated medication, and plays a role in the treatment of muscle cramps in patients with liver cirrhosis [49C].

ORPHENADRINE (SEDA-38, 112) Special review Muscle cramps markedly affect the quality of life in cirrhotic patients with no available effective treatment. This study enrolled 30 liver cirrhosis patients complaining of frequent muscle cramps (3 per week), who were randomized to receive either orphenadrine 100 mg or calcium carbonate 500 mg twice daily as a control for 1 month. Severity, frequency, and duration of the muscle cramps were assessed before and after treatment as well as recurrence after washout of the drug for 2 weeks. Side effects were recorded. One month after treatment with orphenadrine; the frequency of muscle cramps decreased significantly to 0.6  0.74 per week compared to 12.53  6.01 at baseline (P < 0.001), the duration of muscle cramps decreased from 1–0.1 min after treatment (P< 0.001). The pain score improved significantly from a score of 8/10–0/10 (P < 0.001). The side effects were few, such as dry mouth, drowsiness, and nausea, with no significant difference between their occurrences in the two groups. Orphenadrine is safe and effective in treatment of muscle cramps in patients with liver cirrhosis [50c]. A randomized, double-blind, comparative effectiveness trial conducted in 2 urban EDs in 240 patients presenting with

REFERENCES

acute, nontraumatic, nonradicular lower back pain. The primary outcome was improvement on the Roland-Morris Disability Questionnaire (RMDQ) between ED discharge and 1 week later. All patients were given 14 tablets of naproxen 500 mg, to be used twice a day, as needed for low back pain. Additionally, patients were randomized to receive a 1-week supply of orphenadrine 100 mg, to be used twice a day as needed, methocarbamol 750 mg, to be used as 1 or 2 tablets three times per day as needed. The mean RMDQ score of patients randomized to naproxen + placebo improved by 10.9 points (95% CI 8.9–12.9). The mean RMDQ score of patients randomized to naproxen + orphenadrine improved by 9.4 points (95% CI 7.4–11.5). The mean RMDQ score of patients randomized to naproxen + methocarbamol improved by 8.1 points (95% CI 6.1–10.1). None of the between-group differences were considered clinically significant. Adverse events were reported by 17% (95% CI 10%–28%) of placebo patients, 9% (95% CI 4%–19%) of orphenadrine patients, and 19% (95% CI 11%– 29%) of methocarbamol patients. Among ED patients with acute, nontraumatic, nonradicular low back pain, combining naproxen with either orphenadrine or methocarbamol did not improve functional outcomes compared with naproxen + placebo [51R].

TIZANIDINE (SEDA-36, 176; SEDA-38, 112) Adverse events This is a case of a 37-year-old man who suffered irreversible, profound symptomatic bradycardia requiring a pacemaker 3 days after beginning tizanidine/loxoprofen combination therapy for neck pain. This combination therapy is prescribed frequently for joint pain; however, combining loxoprofen with tizanidine could increase the risk of symptomatic bradycardia that is both permanent and severe. Similar cases have not been reported. This case suggests that tizanidine should be used cautiously when combined with loxoprofen, and drug interaction screening should be performed [52c]. Tizanidine withdrawal syndrome is caused by adrenergic discharge due to its α2-agonist mechanism and is characterized by hypertension, reflex tachycardia, hypertonicity, and anxiety. Although tizanidine withdrawal syndrome is mentioned as a potential side effect of cessation, it is not common and there have been few reports. This case presents a 31-year-old woman with tizanidine withdrawal syndrome after discontinuing medication prescribed for a muscle contracture (tizanidine). She showed high adrenergic activity with nausea, vomiting, generalized tremor, dysthermia, hypertension, and tachycardia. Symptoms were reversed and successful reweaning was achieved by restarting tizanidine followed by slow downward titration. Withdrawal

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syndrome should be considered when drugs targeting the CNS are suddenly stopped. Weaning regimens should be closely monitored for acute withdrawal reactions [53c,54].

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12. NEUROMUSCULAR BLOCKING AGENTS AND SKELETAL MUSCLE RELAXANTS

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