Article Text

Methocarbamol versus diazepam in acute low back pain in the emergency department: a randomised double-blind clinical trial
Free
  1. Meisam Sharifi1,
  2. Ali Abdorazzaghnejad2,
  3. Mahtab Yazdchi1,
  4. Maryam Bahreini3,4
  1. 1 Department of Emergency Medicine, Tehran University of Medical Sciences, Tehran, Iran
  2. 2 Department of Emergency Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
  3. 3 Emergency Medicine, Tehran University of Medical Sciences, Tehran, Iran
  4. 4 Faculty of Medicine and Health Sciences, McGill University, Montreal, Québec, Canada
  1. Correspondence to Dr Maryam Bahreini, Emergency Medicine, Tehran University of Medical Sciences, Tehran, Iran; bahreinimaryam{at}gmail.com

Abstract

Background Acute low back pain (LBP) is a common complaint in the emergency department and achieving effective analgesia can be challenging.

Methods In this multicentre randomised double-blind clinical trial conducted at three EDs in Iran from August to November 2020, we assessed the efficacy and adverse effects of two muscle relaxants in patients aged 18 years or older who suffered LBP in the last 6 weeks. Group 1 received intravenous methocarbamol and group 2 received intravenous diazepam followed by a weight-based dose of intravenous morphine in both groups. Exclusion criteria mainly included non-spine aetiologies, cord compression, acute gastrointestinal bleeding, renal/hepatic insufficiency, pregnancy, breast feeding and unstable vital signs. Pain scores and adverse events were measured by a Numeric Rating Scale (NRS) at baseline and after 30 and 60 min by one of the researchers who was not involved with patient visits and was blinded to the intervention. We used t-test to assess the mean difference of NRS at 30 and 60 min.

Results Out of 101 enrolled patients, 50 participants received methocarbamol and 51 diazepam. The baseline mean pain scores and demographic characteristics were not different between the study groups. Pain scores were reduced by both agents after 60 min, with slightly greater pain reductions in the diazepam group in comparison with methocarbamol (mean difference −6.1, 95% CI −6.5 to −5.7 vs mean difference −5.2, 95% CI –5.7 to −4.7, respectively, p<0.001). ED length of stay of patients did not differ between the groups (methocarbamol 5.9 vs diazepam 4.8 hours, p=0.365). Patients receiving diazepam were more likely to report drowsiness (2 (4.0%) vs 15 (29.4%), p=0.001).

Conclusions In patients with LBP, the pain was relieved in the methocarbamol and diazepam groups after 60 min. Although diazepam was more effective, its use was associated with a slightly higher risk of drowsiness.

Trial registration number The protocol of this clinical trial was prospectively registered in the irct.ir (IRCTID: IRCT20151113025025N4; https://irct.ir/trial/50148) .

  • ED
  • acute care
  • analgesia
  • assessment

Data availability statement

Data are available on reasonable request.

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

WHAT IS ALREADY KNOWN ON THIS TOPIC

  • The ideal analgesic for the treatment of low back pain in the ED has not been determined.

  • Both diazepam and methocarbamol have been used, but evidence of effectiveness is lacking.

WHAT THIS STUDY ADDS

  • In this randomised, double-blind study, pain relief at 60 min was slightly better in patients receiving diazepam compared with methocarbamol in combination with weight-based morphine in patients with acute low back pain in the emergency setting. However, those receiving diazepam had more side effects.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

  • Diazepam appears to be more effective than methocarbamol in acute low back pain relief in the ED although may result in more drowsiness.

Introduction

Background and importance

Low back pain (LBP) remains one of the most common musculoskeletal disorders, imposing a high economic burden especially in industrialised and developed countries and has been ranked among the top five most common complaints for medical visits in the USA.1 2 It affects up to 80% of individuals during their lifetime and accounts for over 3% of all emergency visits.3 Acute LBP is usually referred to as back pain within 6 weeks of onset.1

Involuntary muscle spasm is thought to represent a protective mechanism that prevents movement that would otherwise cause injury in acute LBP. However, the muscle spasm may be painful and debilitating.4 Muscle relaxants are supposed to cause global central nervous system depression and one potential mechanism is anticholinergic inhibition of the midbrain reticular activating system leading to depressed polysynaptic reflexes and decreased muscle tone.4

Several analgesic drugs have been used to relieve acute LBP in the ED. Common medications include systemic opioids such as morphine which is only effective for a short time after administration in acute LBP, while non-steroidal anti-inflammatory drugs (NSAIDs) are effective but can cause gastrointestinal (GI) complications.1 Oral muscle relaxants were efficacious in non-specific LBP given in the ED or prescribed after discharge but parenteral muscle relaxants in the ED have rarely been evaluated.5 6 Candidates among the parenteral muscle relaxants include diazepam and methocarbamol. While most physicians are familiar with diazepam, methocarbamol is a centrally acting skeletal muscle relaxant that has been shown to be beneficial for the treatment of LBP associated with a myofascial component.4

There is still no definitive regimen to effectively control acute LBP of muscular and ligamentous injuries in the ED.7 Acute LBP and ongoing discomfort are not often adequately relieved with a single-dose analgesic in the ED, mandating multiple doses of medications and a prolonged length of stay to reach acceptable pain control.8 The ideal analgesic for LBP may not be a single agent and the present evidence is only available from low-quality studies.1 As acute LBP is difficult to relieve and the commonly used medications have not shown substantial benefits, we performed an randomised controlled trial (RCT) using a combination of medications as is routine practice in our EDs. In this study, we aimed to assess the effectiveness of methocarbamol versus diazepam in patients also receiving weight-based morphine and to evaluate their side effects in acute non-traumatic LBP in the ED.

Methods

Study design and setting

This is a prospective, double-blinded, multicentre randomised clinical trial comparing two treatment regimens for ED patients with acute atraumatic LBP.

Ethical approval for this study was obtained from the University of Medical Sciences Institutional Review Board (IR.TUMS.MEDICINE.REC.1397.564).

The study was conducted between August 2020 and November 2002 in three urban university hospitals in Iran with 45 000, 60 000 and 72 000 annual ED visits.

Selection of participants

Eligible patients were adults (age >18 years) with acute non-traumatic musculoskeletal LBP, defined as pain below the costal margin and above the inferior gluteal folds, with or without radicular pain, which had commenced or worsened over the last 6 weeks. Based on the physicians’ opinion, the pain was attributable to spinal joints, discs, muscle or soft tissues without known or suspected serious pathology. Exclusion criteria were non-spine related etiologies, cord compression, acute gastrointestinal bleeding (GIB), active peptic ulcer disease, renal or hepatic insufficiency, pregnancy or breast feeding, unstable vital signs (pulse rate <50 or >150 beats/min, systolic blood pressure <90 or >180 mm Hg) and patients who received analgesics in the past 24 hours other than over-the-counter medications.

Patients admitted to the EDs during shifts of the investigators (MS, MY and MB) were screened for eligibility. The shift assignments for three investigators were among morning, evening, and night shifts in the course of the study period. Patients provided written informed consent.

After recruitment, a thorough medical history was obtained from patients and vital signs were examined and documented. We asked about the history of smoking and opioid dependence, the latter defined as powerful and compulsive opioid use, increased opioid tolerance, withdrawal syndrome when discontinued, and repeated occurrences within 12 months.9 Baseline back pain intensity was assessed using the Numeric Rating Scale (NRS) starting with 0 (no pain) and ending with 10 (the worst possible pain).10 11 We reported the worst pain at rest or interfering with ambulation.

Data and pain scores were obtained by a third-year emergency medicine resident (MS). The resident was not involved with visiting patients and was blinded to the interventions. By this method, neither the patient nor the person collecting the data was aware of the assigned group.

Patient and public involvement

No patient was involved.

Intervention

The randomisation in blocks of four was performed based on a computerised sequence with a 1:1 allocation. Syringes were labelled according to a computerised random sequence with this process supervised by MB. The study medications were prepared and administered according to these instructions:

Group 1: Methocarbamol 100 mg/10 mL intravenous infusion over 3 min, then morphine 0.1 mg/kg intravenously.

Group 2: Diazepam 5 mg diluted with 9-mL normal saline and infused over 3 min, then morphine 0.1 mg/kg intravenously.

A nurse who was not aware of the study protocol prepared the medications as per the aforementioned instructions and based on a computerised sequence. She then gave the medications to the nurse in charge to administer. After the nurse announced the code for the medication, the muscle relaxant was slowly administered intravenously over 3 min by the nurse in charge. This was followed by weight-based morphine for all patients.

Patients received rescue analgesics if their pain persisted (0.1 mg/kg intravenously additional morphine sulfate) 30 min after the administration of study drugs.

All patients were checked for vital signs, NRS score and development of adverse effects at 0, 30 and 60 min after intravenous injection. According to the current management practice policy in our ED, pain management is applied for musculoskeletal LBP and paraclinical investigations are not used unless it is required to assess for other potential diagnoses.12 Patients are discharged if they are satisfied with pain relief and would be able to ambulate at home.

Outcome measures

The primary study endpoint was the difference in pain relief in the two study groups as measured by the postintervention NRS scores after 60 min. Secondary endpoints included the comparison of the number of patients remaining in severe pain category between two groups. Moreover, we rated the adverse effects until patients’ discharge and length of stay in the ED.

Statistical analysis

The minimum sample size was 48 patients in each group based on two-sided 95% CI, power of 90%, a mean score difference of NRS equal to 1 between the two groups at 60 min and an SD of 1.5 for NRS, based on the comparison of two independent means formula.

Primary analysis

Continuous variables were described as mean±SD, categorical variables were expressed as frequency (percentage) and quantitative outcomes were compared among the groups. Furthermore, we compared them by the percentage of patients remaining in severe pain. Adverse events were documented when reported and included headache, somnolence, dizziness, nausea, vomiting, pruritus, anaphylactoid reaction and injection site erythema. In addition, we compared the patients’ length of stay in the ED. Categorical data were analysed using χ2 test or Fisher’s exact test, as appropriate. An intention-to-treat analysis was used to compare the primary study outcome in the two groups. We used independent t-test to assess the mean difference in the two groups and reported a 95% CI for the mean differences. P-value <0.05 was considered statistically significant. All tests were performed using SPSS 25.0 software (IBM, Armonk, New York, USA).

Results

We enrolled 101 patients, of whom 50 received methocarbamol and 51 diazepam (figure 1). The mean age of the participants was 44.8 years (SD=14.2); 12.2% and 8.0% were more than 65 years old in methocarbamol and diazepam groups, respectively (table 1).

Table 1

Demographic characteristics

Figure 1

The CONSORT (Consolidated Standards of Reporting Trials) flow diagram of the study participants.

Table 2 shows pain scores at baseline and 30 and 60 min after drug administration. The mean baseline pain scores of individuals in the methocarbamol and diazepam groups were 8.8 (SD=1.3) and 8.6 (SD=1.3), respectively (table 2). The mean baseline pain scores were not different between men and women: 8.8 (1.2) vs 8.6 (1.4) (95% CI for the difference: −0.3 to 0.8, p=0.326).

Table 2

Mean pain scores among the study groups

Pain relief from baseline to 60 min was slightly better in the diazepam group in comparison with methocarbamol (mean difference −6.1, 95% CI −6.5 to −5.7 vs mean difference −5.2, 95% CI −5.7 to −4.7, p<0.001) Table 3. Moreover, based on the exploratory analyses of repeated measures analysis of variance, pain relief was observed in both groups receiving medications, with the mean pain reduction slightly greater in the diazepam group (p=0.048) (figure 2). For both analyses, the differences were modest but statistically significant.

Table 3

Change in pain among the study groups

Figure 2

Pain scores of the study groups at baseline and after 30 and 60 min of drug administration.

Initially, 92.0% in the methocarbamol group and 88.2% of patients in the diazepam group experienced severe baseline pain (scores 7–10). Fewer patients in the diazepam group still had severe pain after 30 min (11.8% vs 34.0%, p=0.016) and after 60 min (2.0% vs 16.0%, p=0.005) compared with the methocarbamol group (figure 3).

Figure 3

The extent of remaining pain, 30 and 60 min after receiving analgesics between two groups.

Rescue analgesia was delivered to eight and six patients in the methocarbamol and diazepam groups, respectively, which was not a statistically significant difference (p=0.538) (table 2).

Central nervous system (CNS) adverse effects such as drowsiness and somnolence were reported for 2 (4.0%) patients receiving methocarbamol and 15 (29.4%) patients receiving diazepam (p=0.001). The mean (SD) length of stay in the ED in the methocarbamol and diazepam groups were 5.9 (6.5) and 4.8 (4.8) hours, respectively, which did not show a significant difference between groups (p=0.365). Nausea was reported by three patients receiving methocarbamol and one receiving diazepam (p=0.362). One patient in the diazepam group reported a new cough. No headache, vomiting, pruritus or other adverse events were reported.

Discussion

In this randomised double-blind clinical trial, we compared intravenous methocarbamol versus diazepam to control LBP in the ED. There was slightly greater pain relief in LBP in patients receiving diazepam compared with patients receiving methocarbamol after 60 min.

In this study, pain relief in both groups was greater than the minimally clinically important difference (MCID) previously defined as a decrease of 1.7 on the NRS scale.13

There was no significant difference in pain relief between the two regimens at 30 min after administration.13 In the diazepam group, fewer patients suffered severe pain after 30 and 60 min. Overall, few patients needed rescue medication and this was not different between the study groups.

There is conflicting evidence to guide the choice of analgesic options for LBP in the emergency setting. According to a recent systematic review of interventions for LBP in the ED, the overall quality of evidence was low to moderate. Ketoprofen gel, intramuscular ketorolac or meperidine for non-specific LBP and intravenous paracetamol or morphine for sciatica were superior to placebo. In addition, morphine was superior to paracetamol and intravenous dexketoprofen at 15 and 30 min. Oral prednisone and intravenous dexamethasone were ineffective for non-specific LBP and sciatica, respectively.14

Many studies on acute LBP have evaluated the efficacy of oral administration of medications in outpatient settings, which may be less efficacious and act less expeditiously than parenteral medication.1 Some short-term trials (less than 4 weeks) have shown small analgesic effects of acetaminophen, NSAIDs and muscle relaxants which were less than the MCID,13 and there were reports of the inefficacy of systemic corticosteroids in acute and chronic LBP.8 A randomised placebo-controlled multicentre study showed the efficacy of oral methocarbamol in comparison to placebo.15 A recent review reported low-certainty evidence that oral muscle relaxants were moderately effective.16 Intramuscular diazepam was found to be more effective than placebo followed by 5 days of oral diazepam by a single low-quality RCT.8

Several guidelines state that muscle relaxants are a treatment option in LBP if the pain mechanism is thought to be muscle spasm, keeping in mind their potential side effects or they can be administered if LBP is not relieved by NSAIDs, paracetamol or weak opioids.17 18 A systematic review of guidelines found that many recommend the use of muscle relaxants or opioids on an individual basis.17

We found more CNS adverse effects with diazepam than with methocarbamol. Both benzodiazepine (BZD) and non-BZD skeletal muscle relaxants, therefore, may be inappropriate for older patients given the risk of drowsiness, delirium, fall and subsequent trauma.1 It is also possible that relaxants can prolong ED length of stay although in our study, despite causing more drowsiness, patients in the diazepam group did not stay longer.17 Opioids cause high rates of short-term sedation and constipation with variable efficacy in acute or chronic LBP, and there is a concern for misuse.8 However, other medications have side effects: the risk of GIB due to NSAIDs is a concern and suggests the prescription of other medications in selective patients.8 GI complications including nausea, abdominal pain, diarrhoea and dyspepsia are more commonly associated with NSAIDs even though they are reported with muscle relaxants as well.19

Limitations

Longer term follow-up would be helpful to show the efficacy of these medications especially among older adults for whom, delirium, fall and decreased mobility are major concerns. The administration of morphine was according to our policy of pain management and may be the cause of pain relief. However, the most pain relief was seen after 60 min in both groups even though morphine is usually effective for only a short time after administration. In addition, differences between the complaints of dizziness, lightheadedness, somnolence or drowsiness were not distinguished during this study. We did not record the duration of symptoms although we included patients with acute LBP within the last 2 weeks. It is also possible that patients report pain relief to leave the ED having been assessed and reassured that nothing dangerous could happen, although we would expect this phenomenon to have been equally distributed between the two groups.

Conclusions

Methocarbamol and diazepam, in combination with weight-based morphine, provided relief for acute back pain 60 min after administration but diazepam was slightly more effective. However, diazepam resulted in a higher rate of self-reported drowsiness.

Supplemental material

Data availability statement

Data are available on reasonable request.

Ethics statements

Patient consent for publication

Ethics approval

This study involves human participants and was approved by Tehran University of Medical Sciences Ethics Committee: IR.TUMS.MEDICINE.REC.1397.564. Participants gave informed consent to participate in the study before taking part.

Acknowledgments

The authors kindly thank Dr Mohammad Jalili and Amir Sharifi Sistani for their thoughtful comments on the manuscript. We would like to thank Dr Joe Nemeth for all his kind and valuable support.

References

Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

Footnotes

  • Handling editor David Metcalfe

  • Contributors The guarantors, AA, MB, MY and MS conceived the study, designed it and supervised the conduct of the study and collected data. MB, AA, MY and MS undertook recruitment of participants and managed the data, including quality control. MB, MS and AA provided statistical advice on study design and analysed the data; MB, AA, MS and MY drafted the manuscript, and all the authors contributed substantially to its revision and all take responsibility for the paper as a whole.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.