Does adding muscle relaxant make post-operative pain better? a narrative review of the literature from US and European studies

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Anesth Pain Med. 2023;18(4):340-348

Publication date (electronic) : 2023 October 30

doi : https://doi.org/10.17085/apm.23055

Ricardo Verdiner^,1, Narjeet Khurmi¹, Christopher Choukalas², Colby Erickson³, Karl Poterack¹

¹Department of Anesthesiology, Mayo Clinic, Phoenix, AZ, USA

²Department of Anesthesia and Perioperative Care, University of California, San Francisco, USA

³Midwestern Osteopathic Medical School, Glendale, CA, USA

Corresponding Author: Ricardo Verdiner, M.D. Department of Anesthesiology, Mayo Clinic, 5777 E. Mayo Blvd, MH 2 602, Phoenix, AZ 85054, USA Tel: 1-480-342-6453 E-mail: verdiner.md@gmail.com

Received 2023 April 25; Revised 2023 June 9; Accepted 2023 June 13.

Abstract

INTRODUCTION

Centrally acting skeletal muscle relaxants (CASMR) are well-studied and widely prescribed as adjuncts for acute and chronic pain. Given the recent interest in multimodal analgesia and reduction in opioid consumption, there has been an increase in their use for outpatient pain control [1]. However, no extensive literature is available on this prescription pattern. This review will cover the use of centrally acting muscle relaxants administered pre-, intra-, or post-operatively via any route other than neuraxial for the purpose of perioperative analgesia. This review will not cover muscle relaxants that work peripherally (such as dantrolene, rocuronium, or cisatracurium) or the use of benzodiazepines, which may mediate postoperative analgesia through other means. The goal of this review is to examine how CASMRs might reduce postoperative pain, describe clinical conditions (i.e., for which types of surgeries) where CASMRs might benefit patients, and describe the known risks including complications of CASMRs when used in conjunction with other medications commonly administered in the perioperative period.

We performed a literature search for the use of methocarbamol (Robaxin^®, Pfizer, Canada), cyclobenzaprine (Flexeril^® Merck Sharp & Dohme, USA), tizanidine (Zanaflex^® Athena Neurosciences, USA), metaxalone (Skelaxin^®, Core Pharma LLC, USA), baclofen (Lioresal^®,Ciba, Switzerland), and orphenadrine as perioperative analgesics. Only English articles or abstracts were used. The content was then organized into categories describing the pharmacology, acute vs. chronic pain management, and type of surgery.

PHARMACOLOGY

Despite multiple comparative studies conducted since the 1950s, the exact mechanisms of many CASMRs remain unknown. Some animal studies have suggested that their effects may be due to the inhibition of interneuronal activity and blocking polysynaptic neurons in the spinal cord and descending reticular formation in the brain [2,3]. Other studies have suggested that depression of neuronal activity may be a consequence of their sedative effects [4]. Tizanidine has been shown to have an affinity for alpha-2 receptors in the central nervous system (CNS), which is presumed to be the primary mode of action of this drug (Table 1) [5].

Table 1.

Centrally Acting Muscle Relaxants and Potential Site of Action

PHARMACOKINETICS

Most CASMRs have an onset of approximately one hour. The duration varies from 4–6 h to as much to 24 h, depending on the specific agent. Owing to the similarities found in this class, as well as the unreported profiles of some of its constituents, a brief summary has been provided in table format (Table 2) [5].

Table 2.

Onset of Action, Duration and Half-life of Central Acting Skeletal Muscle Relaxants

CLINICAL EFFICACY (NONOPERATIVE)

CLINICAL EFFICACY (OPERATIVE)

As CASMRs have been used effectively in non-surgical patients with pain of musculoskeletal origin [19], there is anecdotal evidence of their migration to surgical pain. Our literature search revealed 12 randomized, blinded, prospective studies across a variety of surgical specialties in which CASMRs were tested for surgical pain (Table 3). Additionally, our literature search included several retrospective reviews and case reports describing the use of centrally acting muscle relaxants in postoperative pain management. The CASMRs studied were cyclobenzaprine, tizanidine, baclofen, metaxalone, and methocarbamol. Supporting data on post-operative pain are described based on various surgical populations studied.

Table 3.

Surgery Specific Studies Using Centrally Acting Muscle Relaxants and Their Conclusions

BREAST SURGERY

A randomized controlled trial by Al Yafi et al. [20] assessed the effectiveness of cyclobenzaprine for postoperative pain control in patients undergoing subpectoral breast reconstruction. Stretching of the pectoralis major muscle during these procedures is associated with high levels of pain and muscle spasms. Despite the association with muscle spasms, there was no statistically significant reduction in pain scores or consumption of oral opioids in the cyclobenzaprine group at any point during the study.

In 1997, Schneider [21] reported observational data on methocarbamol use during breast augmentation surgery. On a subjective level, most patients (84%) felt that methocarbamol significantly improved their discomfort compared to opiates alone. Seventy-seven percent of the patients reported that they would select methocarbamol if only one medication could be selected for postoperative pain control.

Hidalgo and Pusic [22] studied methocarbamol and intercostal nerve blocks in bilateral submuscular breast augmentation surgery in a prospective randomized trial. The authors reported no significant differences in patient characteristics between the treatment groups that received methocarbamol and those that received an intercostal nerve block. Due to the lack of difference between pain scores by the visual analog scale (VAS) after 3 h, the authors concluded that postoperative muscle spasms, if present, subside significantly–2–3 h postoperatively.

SPINE SURGERY

As previously mentioned, muscle relaxants have been useful in treating acute back pain. Their utility in treating acute back pain has raised the possibility that they may also be useful in the treatment of acute postoperative back pain [23]. In 1954, Selvin [23] performed a study comparing use of Myanesin^® (mephenesin) in patients with staged multiple spinal fusion surgeries. The results showed no appreciable difference in postoperative opioid consumption in the groups who did and did not receive Myanesin^®.

Nielsen et al. [24] studied the effect of chlorzoxazone on acute post-operative pain in patients who underwent spinal surgery (cervical and lumbar discectomy, decompression, and fusion). The results showed no significant difference between the treatment and placebo groups regarding the primary endpoint of pain during mobilization. Additionally, there was no difference between the two groups when assessing pain at rest, pain during mobilization at any assessment time point, or the total use of morphine after the intervention. Ultimately, the authors could not recommend the use of chlorzoxazone for analgesia in acute postspinal surgery settings.

In 2019, Chin and Lewis [25] published a case report highlighting the possibility of opioid-free analgesia for posterior spinal fusion surgery using ultrasound-guided erector spinae plane (ESP) blocks and postoperative baclofen. In the case report, a 35-year-old female underwent revision T2–T8 posterior spinal fusion. The patient reported adequate analgesia without opioid use during surgery or postoperative hospital stay.

In 1987 Blumenkopf [26] did a single-blind, randomized, prospective study of 50 patients to assess the benefits of using antispasmodic agents (diazepam and baclofen) with meperidine versus a typical postoperative pain management regimen of meperidine alone. The overall results demonstrated no significant difference in opioid consumption on post-operative day 1, 2, and 3 between the two groups. However, there were significantly fewer reports of muscle spasms in group 2 on post-operative day two and three.

TOTAL KNEE ARTHROPLASTY

Johnson [27] and Gong et al. [28] hypothesized that adding a muscle relaxant, eperisone, to the postoperative pain management protocol would enhance analgesia by affecting the “spasm-pain-spasm” cycle. They predicted that less muscular spasm would lead to better analgesia and allow for enhanced postoperative rehabilitation, along with a better range of motion in the surgically repaired joint. The results were the same for all three groups on post-operative day 1. However, on post-operative days 3–14 group A (non-steroidal anti-inflammatory agent + celecoxib + eperisone) and B (non-steroidal anti-inflammatory agent only) had significantly reduced VAS scores compared with group C (placebo). Group A had a significantly better range of motion on post-operative days 3–14 compared to the other groups. Total morphine consumption was also the lowest in Group A.

CRANIOTOMY

In 2019, Ban et al. [29] published a literature review of multimodal pain management strategies for postoperative pain management after craniotomy. They recognized that opioids were fundamental to postoperative analgesia, but had some pitfalls, including excessive somnolence, nausea/vomiting, and hypoventilation/apnea. Because of these issues with opioid analgesia, a multimodal approach to post-craniotomy pain was advocated, including regional anesthesia (scalp blocks) and non-opioid pharmacies (N-methyl-D-aspartic acid antagonists, Gabapentinoids-pentinoids, Acetaminophen, NSAIDs, local anesthetics, central alpha blockers, and centrally acting skeletal muscle relaxers, such as methocarbamol).

MAJOR ABDOMINAL SURGERY

Orphenadrine is a muscarinic antagonist used specifically as a skeletal muscle relaxant without impairing normal muscle tone and voluntary movements. In 1979, Fry [30] demonstrated that patients who received orphenadrine had a significantly longer interval until the first request for analgesia than the control group.

HERNIA REPAIR SURGERY

Alpha-2 agonists such as dexmedetomidine and clonidine have been extensively studied for perioperative analgesia [31-33]. Tizanidine is a centrally acting alpha-2 agonist with muscle-relaxant, sedative, and anxiolytic properties. It has been used to treat pain associated with muscle spasms, and myofascial and neuropathic pain [34-36]. In 2016, Yazicioğlu et al. [37] studied tizanidine use after inguinal hernia repair in a randomized double-blind study. The primary objective was to assess the relative efficacy of tizanidine versus placebo in terms of pain scores, analgesic consumption, and time to return to daily routine. A numerical rating scale (NRS) was used to assess the pain management efficacy. The treatment group had significantly lower NRS pain scores at 6, 12, and 24 hours postoperatively, both at rest and during movement. This was also observed on post-operative days 1–4. The treatment group consumed less oral acetaminophen for breakthrough postoperative pain and had a longer median time to the initial request for supplemental oral analgesia than the control group.

HEMORRHOIDECTOMY

Topical baclofen has been reported to be effective in the treatment of neuropathic pain, especially when combined with other medications, such as amitriptyline and ketamine [38-40]. Ala et al. [41] studied topical baclofen 5% in a randomized double-blind placebo-controlled trial in patients undergoing open hemorrhoidectomy for 3rd and 4th degree hemorrhoids. The results showed significantly lower pain scores 1 and 2 weeks after surgery in the baclofen group. Additionally, the baclofen group consumed significantly fewer oral analgesics at weeks 1 and 2 than the placebo group.

THYROIDECTOMY

Ahiskalioglu et al. [42] examined a multimodal approach for postoperative pain management in patients who underwent thyroidectomy. In a double-blind study, the administration of additional preoperative oral tizanidine reduced the incidence of posterior neck pain and occipital headache in the early postoperative phase.

DENTAL SURGERY

The removal of impacted mandibular third molars (M3) is associated with swelling, pain, and trismus. CASMR reduces muscular spasticity [43]. Kirmeier et al. [44] hypothesized that tizanidine aids in relaxing the muscles near the operative site of M3 extraction, leading to reduced trismus and pain. However, in that prospective trial, the authors could not recommend the addition of tizanidine to reduce trismus, pain, or facial swelling.

De Santana Santos et al. [45] aimed to evaluate the efficacy of cyclobenzaprine for M3 extraction. They conducted a prospective, randomized, double-blind, placebo-controlled study using a split-mouth design (the right and left sides of the mouth were randomly assigned to two treatment groups). There was no difference in the need for additional pain medication for breakthrough pain between the two groups.

PECTUS SURGERY

Inge et al. [46] reviewed patients undergoing surgical correction of pectus excavatum over a 42 month period. Postoperative hospital length of stay was lower in the minimally invasive group. The majority of pain during minimally invasive repair of the pectus was assumed to be triggered by the diffuse strain of the muscles of the anterior chest wall, which led the authors to favor the use of centrally acting muscle relaxers.

COMPLICATIONS

The most commonly reported adverse effects of CASMRs are sedation, dry mouth, fatigue, dizziness, and nausea. These side effects have raised concerns regarding their potential for abuse [47,48]. In a study by Gouveia et al. [12], they observed that patients taking opioids reported the worst quality of life followed by those patients taking CASMRs.

Strong evidence in support of CASMR in acute musculoskeletal pain has led to the broadening of its prescribing indications among practitioners [49,50]. Patients with acute or chronic pain are often prescribed muscle relaxants as adjuvants to NSAIDs and/or opioid regimens. The CNS-depressant effects of this drug class should prompt caution when prescribing them. One study by Golden et al. [51] suggested that patients with a mean age of 80 years were at an increased risk of fracture injuries. Their adjusted odds ratio of 1.40 was similar to the risk in those prescribed short-acting benzodiazepines (odds ratio 1.33). The odds ratio remained significant even after adjusting for the increased incidence of psychotropic medications and their diagnoses in this population. In another study by Spence et al. [52], patients with a mean age of 75 years had a 1.32 fold increased risk of injury when taking CASMR. The four most common injuries were fractures (30%), contusions (27%), falls (21%), and lacerations (13%). Sixty one percent of those injured were female.

Another limitation is the risk of abuse or overdosing. CNS depressant effects have been reported to potentiate the effects of opioids and benzodiazepines. Carisoprodol, a skeletal muscle relaxant, has been shown to bind to the non-benzodiazepine-binding site of GABA-A receptors in both in vivo and in vitro studies [53]. Owing to their synergistic activities, some authors have discouraged the concomitant use of benzodiazepines, CASMR, and opioids in standard practice [54,55]. A recent study by Li et al. [56] illustrates this risk. In their population-based cohort study, they generated an overdose hazard ratio of 1.21 (95% confidence interval, 1.00–1.48) when pooling both opioid naïve and chronic patients who were prescribed CASMR with opioids. A significant risk was noted in the 55–65 year age group and in those prescribed the opioid/CASMR combination for more than 14 days [57,59].

CONCLUSION

As previously mentioned, CASMRs are being prescribed more frequently in outpatient settings for pain relief. It is reasonable to postulate that increasing concerns about opioid epidemics do not mitigate this trend. Unfortunately, their safety and effectiveness have not been consistently demonstrated in high-quality studies. The best evidence of improved pain control is nonoperative acute musculoskeletal pain. In the perioperative setting, the best evidence of improved pain control is in patients undergoing total knee arthroplasty and abdominal surgery, including inguinal herniorrhaphy and hemorrhoidectomy. In these specific cases, randomized controlled trials have suggested that the use of CASMRs, such as tizanidine, may reduce pain scores, facilitate early ambulation, and reduce the overall use of other analgesics. Unfortunately, in the majority of the surgery types studied, including neck/spine, breast, and oral surgeries, the results did not show any benefits.

In addition to the limited effectiveness of CASMRs, their use increases the risk of injury, and may be accompanied by abuse. Considering their limited efficacy, side effects, abuse potential, and risk of injury, clinicians must carefully consider the use of CASMRs in the perioperative setting.

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