What is the evidence to support the use of skeletal muscle relaxants (e.g., methocarbamol, cyclobenzaprine, diazepam) for acute post-operative pain after spinal surgery?

Comment by InpharmD Researcher

A literature search did not reveal evidence to support the use of skeletal muscle relaxants for acute postoperative pain following spinal surgery. The European Society of Regional Anaesthesia (ESRA) 2021 guideline for management of pain after complex spine surgery specifies there is a paucity of studies to determine the effectiveness of muscle relaxants for management of acute postoperative pain. Additionally, a randomized trial did not find a single dose of chlorzoxazone to produce an analgesic effect or reduce opioid consumption compared to placebo in patients with acute pain after spine surgery.
Background

The European Society of Regional Anaesthesia (ESRA) developed a 2021 guideline for the management of pain after complex spine surgery. The authors briefly noted the paucity of studies to determine the effectiveness of muscle relaxants, which is likely the reason why there are no recommendations regarding their use. Instead, recommendations for post-operative pain management consist of epidural analgesia with or without opioids, oral/intravenous (IV) acetaminophen, and oral/IV NSAIDs/COX-2 inhibitors. [1]

The American Pain Society, American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists Committee on Regional Anesthesia guideline for the management of postoperative pain recommend opioids, acetaminophen, gabapentin or pregabalin, and IV ketamine for systemic pharmacologic therapy following spinal fusion. [2]

A retrospective study (N= 1,800) examining whether an adequate use of intraoperative muscle relaxant decreases postoperative pain scores, muscle spasms, or opioid consumptions following the spinal surgery classified eligible patients to either an adequate muscle relaxant group (n= 1,219; use of muscle relaxants/kg/hour within the upper 50 percentile of the observed values) or low muscle relaxant group (n= 581; use of muscle relaxants within the lower 25 percentile of the observed values). While the results did not observe a significant difference in postoperative pain (difference in pain score of 0.03; 97.5% CI, -0.17 to 0.22; p= 0.75) between the two groups, a significant increase in consumption of opioids was noted (42 milligram morphine equivalents [MME] vs. 40 MME; OR 1.30; 97.5% CI, 1.08 to 1.57; p= 0.001) in adequate muscle relaxant group as compared to the low muscle relaxant group. Given that the low muscle relaxant group performed noninferior on pain score (noninferiority p<0.001) but superior on opioid consumption (noninferiority p<0.001), the authors concluded that the inadequate muscle relaxant group had better postoperative analgesia. The study did not disclose muscle relaxants in use, and only the abstract was available, as presented in the 2020 American Society of Anesthesiologists annual meeting. [3]

References:

[1] Waelkens P, Alsabbagh E, Sauter A, Joshi GP, Beloeil H; PROSPECT Working group∗∗ of the European Society of Regional Anaesthesia and Pain therapy (ESRA). Pain management after complex spine surgery: A systematic review and procedure-specific postoperative pain management recommendations. Eur J Anaesthesiol. 2021;38(9):985-994. doi:10.1097/EJA.0000000000001448
[2] Chou R, Gordon DB, de Leon-Casasola OA, et al. Management of Postoperative Pain: A Clinical Practice Guideline From the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists Committee on Regional Anesthesia, Executive Committee, and Administrative Council [published correction appears in J Pain. 2016 Apr;17(4):508-10. Dosage error in article text]. J Pain. 2016;17(2):131-157. doi:10.1016/j.jpain.2015.12.008
[3] Devarajan J et al. Association Between Intraoperative Use Of Muscle Relaxant And Postoperative Pain And Muscle Spasm After Spine Surgery. Paper presented at American Society of Anesthesiologists annual meeting; October 2020; Cleveland, Ohio.
Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

What is the evidence to support the use of skeletal muscle relaxants (e.g., methocarbamol, cyclobenzaprine, diazepam) for acute post-operative pain after spinal surgery?

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→


Please see Table 1 for your response.

 

The effect of chlorzoxazone on acute pain after spine surgery. A randomized, blinded trial

Design

Single-center, prospective, randomized, blinded trial

N= 110

Objective

To explore the analgesic and adverse effects of chlorzoxazone on immediate, acute pain after spine surgery

Study Groups

Chlorzoxazone (n= 54)

Placebo (n= 56)

Inclusion Criteria

Age 18 to 85 years, had undergone spine surgery (cervical and lumbar discectomy, decompression and fusion), pain score ≥ 50 mm on the Visual Analogue Scale during mobilization (movement from recumbent position to sitting bedside), body mass index 18 to 40 kg/m2, American Society of Anesthesiologists (ASA) physical status classification I to III

Exclusion Criteria

Any analgesic treatment within 1 hour prior to inclusion, participation in other medical trials, pregnancy, known porphyria, allergy to drugs used in the trial, daily use of chlorzoxazone or strong opioids (morphine, oxycodone, methadone, fentanyl, or ketobemidone), and alcohol or drug abuse

Methods

Eligible patients were randomized (1:1) to receive chlorzoxazone 500 mg or oral placebo > 1-hour post-operatively in the post-anesthesia care unit (PACU). Patients also received IV patient-controlled analgesias (PCA) containing morphine (bolus 2.5 mg, lock-out time 10 minutes, without infusion) as rescue analgesia during the trial period. If sufficient subjective pain relief was not achieved from the PCA, the patient could request rescue medication (IV morphine 2.5 mg). There was no use of other analgesics or sedative drugs during the trial. For moderate-to-severe nausea or vomiting as determined by the patient, IV ondansetron 4 mg was administered and supplemented with 1 mg doses if needed. Droperidol could be used if ondansetron did not relieve nausea and vomiting.

Duration

 Assessments after intervention: 4 hours

Outcome Measures

Primary outcome: pain during mobilization 2 hours after inclusion

Secondary outcomes: pain at rest and pain during mobilization (measured as area under the curve [AUC] 1 to 4 hours after trial intervention), total morphine usage, and adverse effects

Baseline Characteristics

  

Chlorzoxazone (n= 54)

Placebo (n= 56)

  

Age, years

 58 ± 13 57 ± 15  

Female

34 (63%) 36 (64.3%)  

Pre-operative

VAS at rest, mm

VAS during mobilization, mm

 

55 ± 22

62 ± 21

 

54 ± 27

60 ± 26

  

Daily use of analgesics

None

Paracetamol and/or ibuprofen

Weak opioids*

 

10 (18.5%)

20 (37%)

24 (44.4%)

 

14 (25%)

15 (26.8%)

27 (48.2%)

  

Peri-operative data

Median duration of surgery, minutes (IQR)

Median propofol dose, mg (IQR)

Median remifentanil dose, mg (IQR)

Received sevoflurane

Median amount of bleeding, mL (IQR)

Median isotonic sodium chloride dose, mL (IQR)

Median time from last analgesic administration to start of trial, minutes (IQR)



77 (52 to 123)

645 (400 to 875)

4.1 (2.4 to 5.7)

5/49

100 (8 to 300)

900 (700 to 1,300)

85 (61 to 100)



80 (52 to 147)

700 (457 to 997)

4.6 (2.8 to 6.3)

7/49

188 (50 to 350)

900 (800 to 1,200)

76 (60 to 100)

  

IQR: interquartile range

*codeine or tramadol

Results

Endpoint

Chlorzoxazone (n= 54)

Placebo (n= 56)

95% confidence interval; p-value

Pain during mobilization 2 hours after intervention, mm

 51 ± 21 54 ± 25 -8 to 10; 0.59

AUC 1 to 4 hours after intervention, mm

Pain at rest

Pain during mobilization

 

43 ± 18

54 ± 21

 

41 ± 19

54 ± 22

 

-6 to 8; 0.74

-7 to 9; 0.84

Median total morphine usage, mg

10 (7 to 21)

13 (5 to 19)

-3 to 6; 0.82

It was not reported whether values in parentheses for total morphine usage was a range or interquartile range.

Adverse Events

Common Adverse Events: There was no significant difference in total number of vomiting episodes 0 to 4 hours after trial medication, 10 episodes vs. 13 episodes in the chlorzoxazone and placebo groups, respectively (p= 0.72), with the number of patients vomiting being 8 in the chlorzoxazone vs. 7 in the placebo groups (p= 0.72). Additionally, there were no significant differences for nausea at any time point and no significant difference between groups in ondansetron use 0 to 4 hours after trial medication. No significant differences in sedation or dizziness 0 to 4 hours after trial medication were observed.

Serious Adverse Events: One patient in the chlorzoxazone group received droperidol for moderate-to-severe nausea/vomiting that could not be controlled with ondansetron.

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

No analgesic effect of single-dose chlorzoxazone was demonstrated in patients with acute pain after spine surgery. Based on these findings, chlorzoxazone cannot be recommended for immediate treatment of acute pain after such procedures.

InpharmD Researcher Critique

Chlorzoxazone, a muscle relaxant, is no better than a placebo for reducing pain scores on mobilization following spinal surgery based on the results of this study. Additionally, while secondary outcomes were not powered to detect a difference, chlorzoxazone does not appear to reduce the amount of morphine consumption post-operatively.



References:

Nielsen RV, Fomsgaard JS, Siegel H, Martusevicius R, Mathiesen O, Dahl JB. The effect of chlorzoxazone on acute pain after spine surgery. A randomized, blinded trial. Acta Anaesthesiol Scand. 2016;60(8):1152-1160. doi:10.1111/aas.12754