a b s t r a c t

Objective: We aimed to investigate the effect of oral magnesium supplementation for acute low back pain. Methods: This is a three-arm, prospective randomized open label clinical trial, which included two hundred and forty patients. We based our sample size calculation assumptions on a recently published clinical trial, thus we enrolled 80 patients for each group. NSAID alone group included (400 mg etodolac twice a day), NSAID + mg group included NSAID – magnesium combination treatment (400 mg etodolac twice a day with 365 mg oral mag- nesium supplementation) and NSAID + paracetamol group included NSAID – paracetamol combination treat- ment (400 mg etodolac twice a day with 500 mg paracetamol twice a day). Follow-up visits after initiation of relevant treatment were performed at 4th and 10th days and outcome measures included pain (Visual analogue scale – VAS), mobility of lumbar spine and functional outcome (RMDQ).

Results: Thirty-one patients were considered lost to follow-up or excluded due to use of other medications and final analysis was performed with 209 participants in three groups (71 patients in NSAID alone group, 68 patients in NSAID + mg group and 70 patients in NSAID + paracetamol group). NSAID + mg showed a significantly higher improvement in RMDQ and VAS scores at Acute stage (at 4th day visit) compared to two other study groups However, there was no significant difference between three groups in terms of mean improvement of RMDQ, VAS scores and lumbar mobility between initial visit and 10-day.

Conclusion: Results of this study suggest that addition of magnesium to acute low-back pain treatment does not significantly improve final clinical outcomes.

Level of evidence: Level I, prospective randomized controlled study.

(C) 2021

1. Introduction

Acute non-specific Low back pain is one of the most common reasons of admission to emergency department [1]. It is more common in countries with high-income economies, where 60-80% of the popula- tion complain about back pain at some point in their life [2]. Acute LBP term defines symptoms with duration shorter than 6 weeks and Chronic back pain is defined as pain which occurs for more than 3 months [3]. According to Pathophysiologic mechanisms, pain may be classified as nociceptive or neuropathic. While Neuropathic pain is more common in chronic lumbar syndrome, acute low back pain is mainly nociceptive. Back pain is one of the main reasons for labor loss and a major cost for society. Pain relief is usually the first step in patients’ management and enhances early rehabilitation and recovery. Numerous medica- tion options are available for acute LBP relief such as non-steroid

* Corresponding author at: Department of Orthopaedic and Traumatology, Istanbul Faculty of Medicine, Istanbul University, Capa Fatih, Istanbul 34093, Turkey.

E-mail address: dr.serkanbayram89@gmail.com (S. Bayram).

anti-inflammatory drugs (NSAIDs), myorelaxant drugs, opioids, and ben- zodiazepines [4]. The superiority of using these drugs alone or in combi- nation has not been determined [5,6]. Magnesium is a physiological voltage-dependent blocker of N-methyl-D-aspartate (NMDA)-coupled channels which can influence inflammatory pain and neuropathic pain through several different mechanisms [7-9]. Although the intravenous magnesium is widely used especially for management of postoperative pain, administration of oral magnesium supplementation for musculo- skeletal pain management is not common.

In this study, we aimed to investigate the effect of oral magnesium supplementation for acute low back pain.

1. Materials and methods
   1. Study design

This study was conducted at our emergency department between September 2018 and March 2020. This research has been approved by the IRB (Institutional review board) of the authors’ affiliated institutions.

https://doi.org/10.1016/j.ajem.2021.03.078

0735-6757/(C) 2021

This study was registered as a randomized controlled trial to the US National Institute of Health (clinical.trials.gov, registration number is NCT-04626063). We conducted a three-arm, prospective randomized open label clinical trial to compare NSAID alone group, NSAID + paracetamol group and NSAID + magnesium supplementation group (described below) for treatment of acute LBP. Patients were included after providing informed consent predicated on their understanding of expected complications and Treatment outcomes. Consolidate Standards of Reporting Trials (CONSORT) guidelines were followed reporting the results of the study [10].

• 1. Patient selection

Patients from a single university hospital were recruited for this study between September 2018 and March 2020. Inclusion criteria were defined as (1) age > 18 years old, (2) duration of symptoms <2 weeks and (3) functionally impairing LBP which we defined as a score of >5 on Roland-Morris Disability Questionnaire (RMDQ).

Exclusion criteria included (1) age > 65 years old (this group of pa- tients is prone to develop chronic back pain due to spinal degeneration),

(2) history of trauma, (3) presence of radicular pain physical examina- tion which was defined as pain radiating below the gluteal folds, (4) his- tory of primary vertebral tumor or metastasis, (4) patients who were pregnant or lactating, (5) presence of any contraindication or allergy to investigational medications, (6) history of chronic analgesic use,

(7) history of autoimmune diseases or inflammatory rheumatic disor- ders, (8) history of cardiopulmonary restrictions, severe kidney or liver function disorders and (9) history of prior surgery of lumbar spine.

• 1. Sample size

We based our sample size calculation assumptions on a recently published clinical trials [11,12]. and widely accepted minimum clini- cally important improvement of 5 points on the RMDQ (14) with alpha and beta values were set at 0.05 and 0.20 respectively. Sample size calculation revealed that 50 patients were needed in each study group. To account for protocol violations, lost-to-follow-up and to

ensure sufficient power for the intention to treat analysis (in previous work, up to 1/3 of enrolled patients did not use the investigational med- ication), we enrolled 80 patients for each group.

• 1. Patient randomization and study groups

A computer generated random list was established with an online sequencer (https://www.random.org/sequences) according to which participants were randomly assigned to one of three study groups with 1:1:1 allocation ratio. NSAID alone group included isolated NSAID treatment and received 400 mg etodolac twice a day. NSAID + mg group included NSAID and magnesium treatment and received a combi- nation of 400 mg etodolac twice a day with 365 mg oral magnesium supplementation once a day. NSAID + paracetamol group included combination of 400 mg etodolac twice a day with 500 mg paracetamol twice a day (Fig. 1). We effort to prevent the placebo effect by compar- ing the NSAID + mg therapy with both a NSAID + paracetamol therapy and an NSAID alone therapy. Treatment was performed by two authors at first evaluation in emergency department (ED) and patients were followed-up by another author throughout the study. At their first ad- mission, all patients were informed about the study and follow-up ap- pointments were arranged for 4th and 10th day of the treatment at this time. All Follow-up evaluations were performed at ED. External medication was not allowed with the exception of topical analgesics. Patients who received any intravenous or intramuscular analgesia dur- ing the treatment period were excluded from study. Co-medications for any accompanying chronic condition (diabetes, hypertension etc.) were unchanged.

• 1. Outcomes

Clinical evaluation of participants was performed at first admission to emergency department, at 4th and 10th days after the initiation of designated treatment. Outcome measures included pain, mobility of lumbar spine and functional outcome. Pain intensity was assessed using a Visual Analogue Scale . Lumbar spine mobility was assessed using the “finger to floor” test. Participants were asked to stand on erect

Table 1

Demographic data of each group

Non-steroid anti-inflammatory group

Non-steroid anti-inflammatory

+ magnesium group

Non-steroid anti-inflammatory + paracetamol group

	Mean +- SD	Min-Max		Mean +- SD	Min-Max		Mean +- SD	Min-Max
Age, years	37,94 +- 12,5	18-65		36,57 +- 13,1	18-65		36,01 +- 13,31	18-64
Gender, F/M	42 / 38			44 / 36			39 / 41
Height, cm	167, 97 +- 8,4	150-186		170,85 +- 7,7	155-185		168,87 +- 6,6	156-182
Weight, kg	74,74 +- 12,5	50-110		77,06 +- 12,1	53-105		75,57 +- 9,88	54-98
BMI, kg/m2	26,43 +- 3,75	19-35		25,42 +- 3,9	18-35		26,55 +- 3,66	19-36
pain duration before treatment (days)	3,93 +- 2,3	0-9		3,5 +- 2,1	0-8		3,76 +- 2	0-7

SD: Standard deviation; Min: Minimum; Max: Maximum; cm: centimeter, kg: kilogram; BMI: Body mass index.

posture with knees extended and then to bend forward in an attempt to reach for the floor with their fingertips without losing knee extension. Distance between patient’s fingertips and the floor was then measured with a measuring tape. Functional outcome was evaluated using Roland-Morris Disability Questionnaire (RMDQ) score. RMDQ is a 24- item LBP functional scale and is recommended for research purposes [13]. Higher scores signify greater low back-related functional impair- ment. An improvement of 5 points was considered clinically significant. The Roland-Morris Disability Questionnaire is most sensitive for pa- tients with mild to moderate disability due to acute, sub-acute, or chronic back pain. The Oswestry Injury Index is recommended for pa- tients with severe disability [14].

• 1. Statistical analysis

The data was analyzed using SPSS 22.0 version for Windows (SPSS Inc., Chicago, IL). Mean, median, standard deviation, range, maximum and minimum were used as descriptive statistical methods to evaluate study data. Normality of distribution was tested using the Shapiro- Wilk test, histograms and probability plots. Comparison between study groups was made by One-way ANOVA test and post-hoc analysis was performed with Bonferroni test. The chi-square test was used to compare the groups with respect to categorical variables. Statistical sig- nificance level was set at p = 0.05 with 95% confidence interval for all analyses.

1. Results

686 patients admitted to emergency department with LBP com- plaint during the recruitment period and were assessed for eligibility. 446 patients were excluded and 240 participants who met the inclusion criteria were randomized and allocated into three study groups. 31 pa- tients were considered lost to follow-up or excluded due to use of other medications and final analysis was performed with 209 participants in three groups (71 patients in group A, 68 patients in group B and 70

patients in group C). Of these patients, 10 patients were not completed to 4-day follow-up and 21 were 10-day follow-up (Fig. 1).

Baseline demographic data of all groups are reported in Table 1. No significant difference in age, gender, weight, height, body mass index and pain duration before admission (days) (p = 0.69; p = 0.89; p = 0.45; p = 0.06; p = 0.97 and p = 0.66 respectively) was observed between study groups.

The analysis of functional scores revealed that mean improvement of RMDQ score between initial visit and 4th day, was 6.5 +- 7.3 in NSAID alone group, 9.2 +- 5.6 in NSAID + mg group and 6.7 +- 4.7 in NSAID + paracetamol group. NSAID + mg group showed a significantly higher improvement in RMDQ scores compared to NSAID alone group and NSAID + paracetamol group during this period (p = 0.027 and p = 0.034 respectively). Even though NSAID + paracetamol group showed slightly higher improvement in RMDQ scores compared to NSAID alone group, the difference was not significant (p = 0.92).

Results of VAS scores between initial visit and 4-day showed similar

results as improvement of RMDQ between initial visit and 4-day. The NSAID + mg group showed significantly higher improvement compared to NSAID alone group and NSAID + paracetamol group (p = 0.044 and p = 0.048, respectively). Comparison of NSAID alone group and NSAID + paracetamol group showed no significant differ- ence (p:0,94).

There was no significant difference between three groups in terms of mean improvement of RMDQ, VAS scores and lumbar mobility between initial visit and 10-day (p = 0.133, p = 0.058 and p = 0.092 respec- tively). Although mean improvement in lumbar mobility was compara- ble between NSAID alone group and NSAID + mg group, NSAID + mg group showed significantly higher improvement compared to NSAID

+ paracetamol group between initial visit and 4th day (p = 0.033) (Table 2).

Results of all clinical outcomes were also illustrated in Figs. 2-4. 23.9% (50/209) of patients did not show clinically significant improve- ment in terms of functional outcomes (a change of 5 points in RMDQ score) at 10th day. Even though the distribution of these 50 patients did not show any significant difference (p = 0.30), there were less

Table 2

Comparison of improvement of RMDQ, VAS and finger to floor test between initial visit and 4-day follow up and initial visit and 10-day follow up

Non-steroid

anti-inflammatory alone group

Non-steroid

anti-inflammatory + magnesium group

Non-steroid

anti-inflammatory + paracetamol group

	Mean +- SD	95% CI		Mean +- SD	95% CI		Mean +- SD	95% CI
Improvement in RMDQ between initial visit and 4-day follow up	6.5 +- 7.3	4.7-8.1		9.2 +- 5.6	7.8-10		6.7 +- 4.7	5.5-7.8
Improvement in VAS between initial visit and 4-day follow up	2.9 +- 1.95	2.39-3.3		3.49 +- 1.72	3.07-3.91		2.91 +- 1.64	2.52-3.32
Improvement in finger to floor between initial visit and 4-day follow up, cm	16 +- 20.2	11.03-20.06		17.4 +- 14.40	13.97-20.8		11.2 +- 13.95	7.75-14.35
Improvement in RMDQ between initial visit and 10-day follow up	11.3 +- 6.43	9.71-12.76		13.4 +- 5.9	11.9-14.8		11.4 +- 5.12	10.1-12.5
Improvement in VAS between initial visit and 10-day follow up	4.56 +- 2.49	3.97-5.15		5.26 +- 2.20	4.73-5.72		4.60 +- 2.14	4.09-5.11
Improvement in finger to floor between initial visit and 10-day follow up, cm	22.5 +- 22.5	16.8-27.5		25.2 +- 17.6	20.97-29.4		18.3 +- 17.1	14.01-22.1

Fig. 2. Change in Roland Morris Disability Questionnaire score.

patients in NSAID + mg group who did not show significant functional improvement after treatment (20 patients in NSAID alone group, 12 pa- tients in NSAID + mg group and 18 patients in NSAID + paracetamol group.

No major complication was observed (allergic reaction or shock) in any group. However, 22 patients (6 patients in NSAID alone group, 9 pa- tients in NSAID + mg and 7 patients in NSAID + paracetamol group) re- ported minor side effects including abdominal pain, dyspepsia and diarrhea at final visit.

1. Discussion

Currently, search for effective and fast treatment of acute non- specific LBP still continues due to its high prevalence and several drugs are investigated on this issue. This study investigated oral magne- sium supplementation which is widely used in orthopedic and Physical therapy clinic practice. In this randomized controlled trial, patients with acute, non-traumatic musculoskeletal LBP without radicular symptoms who were treated with a combination of NSAID and magnesium had

significantly higher functional and Pain outcomes compared to NSAID alone treatment or NSAID + paracetamol combination treatment at acute stage (4th day). However, all three Treatment protocols showed comparable functional and pain outcomes at 10th day of treatment. Ad- ditionally, even though the difference was not significant, there were less patients in NSAID + magnesium group who did not show clinically significant improvement in functional scores compared to two other study groups.

Due to its relatively lower risk of side effects and benefits compara- ble to other analgesics, there are several reviews recommending para- cetamol as first-line of treatment for acute LBP management [15,16]. NSAIDs are widely used in management of acute non-specific LBP. Most of physician prefer NSAIDs as first-line of treatment with or with- out paracetamol combination. In their study, Miki et al. compared effi- cacy of acetaminophen and NSAIDs in setting of acute Musculoskeletal pain [17]. They assessed outcomes of 35 patients in each group at acute stage (2nd and 4th day visits) and found comparable analgesic ef- fects of acetaminophen and NSAIDs in setting of acute LBP. Another study by Ostojic et al. reported that both isolated NSAID and NSAID +

Fig. 3. Change in pain intensity was assessed using a visual analogue scale.

Fig. 4. Change in lumbar spine mobility was assessed using the “finger to floor” test.

paracetamol combination treatments had successful results, but combi- nation therapy showed better improvement of pain compared to iso- lated NSAID therapy at acute stage. However, pain relief was comparable between treatments at final follow-up visit (10th day) [18]. In contrast to their study, we found that there was no significant difference between isolated NSAID and NSAID + paracetamol combina- tion treatments throughout the follow-up period.

Magnesium is one of the main multifunctional intracellular mole- cules which participates in more than 300 enzymatic processes as a co- factor [19]. While it is mostly stored in bones and in intracellular compartments of the muscles or Soft tissues, just less than 1% of total magnesium is in circulation [20] Inhibition of calcium ion passage into cells by blocking NMDA receptors is considered main mechanism of its analgesic effect, thus many studies suggest that magnesium is causally related to pain reduction and analgesic requirement [21]. Mag- nesium can also be used pre- or intra-operatively to decrease post- operative pain and reduce analgesic requirements by local injection, intra-articular injection or as an systemic agent by intravenous applica- tion [22-24]. As an oral supplement, the recommended daily dose of magnesium is 310-400 mg [25]. In our study, all patients received stan- dard 365 mg of oral magnesium supplementation. Although magne- sium is widely used in daily practice, there are very few studies evaluating its use as an analgesic. In their study, Bagis et al. investigated the effect of magnesium citrate treatment on fibromyalgia symptoms [26]. The study was carried out with three treatment arms: isolated magnesium citrate, isolated amitriptyline and magnesium citrate- ami- triptyline combination. After a treatment of 8 weeks, results showed that magnesium citrate therapy was effective on tender points and in- tensity of fibromyalgia; but combining it with amitriptyline was found to be effective on all parameters. Another study by Tarleton et al. inves- tigated the effect of magnesium on chronic pain in a large, representa- tive cohort [27]. They suggested that adjusted magnesium intake for body weight appeared to be protective against chronic pain. Addition- ally, they reported that dietary or supplemental magnesium intake might be a safe, low cost alternative.

To the best of our knowledge, the present trial is the first study to in- vestigate the effect of oral magnesium supplementation on acute LBP. Results of this trial suggest that NSAID-magnesium combination ther- apy showed higher improvement in functional and pain scores at acute stage compared to other regimens thus indicating faster analgesic effect of NSAID-magnesium combination. Suggestion of an Alternative medication for acute LBP management depicts most prominent strength

of this trial. Moreover, following a strict methodology, we believe that this randomized prospective trial makes valuable contribution to litera- ture and current clinical decision making.

This trial has some limitations. First, the trial was not blinded and this may be associated with evaluation or subject bias. Second, blood magnesium levels were not measured during or before treatment pe- riod. Third, we did not consider the effect of other Analgesic drugs for LBP before at the time of enrollment in our study. Fourth, we did not perform an intention-to-treat analysis and that by excluding patients who took Rescue medication, this condition may be biasing the results. Lastly, factors such as socioeconomic status, occupation, presence of workers’ compensation claims and physical activity of participants dur- ing treatment period which could have affected outcomes were not con- sidered as exclusion criteria.

1. Conclusion

The results of this prospective randomized controlled study suggest that significant improvement in clinical outcomes is achievable regard- less of chosen agents in treatment of acute LBP and addition of magne- sium to treatment protocol does not provide any benefit at final term. Combination of NSAIDs and magnesium might be advantageous to ob- tain relatively faster improvement but we believe that findings of this study are insufficient to reach such a conclusive judgement on this topic and further research are needed.

Ethical approval

Approval was given by the institutional review board (IRB No: (2018/1330)) and that informed consent was obtained from each patient.

Funding

The authors received no financial support for the research, author- ship, and/or publication of this article.

Declaration of Competing Interest

Each author certifies that he or she has no commercial associations (eg, consultancies, stock ownership, equity interest, patent/licensing

arrangements, etc) that might pose a conflict of interest in connection with the submitted article.

Acknowledgement

None.

References

1. Deyo RA, Mirza SK, Martin BI. Back pain prevalence and visit rates: estimates from

U.S. National Surveys. Spine (Phila Pa 1976). 2006;31(23):2724-7.

1. Waddell G, Burton AK. Occupational health guidelines for the management of low back pain at work: evidence review. Occup Med. 2001;51(2):124-35.
2. Qaseem A, Wilt TJ, McLean RM. Forciea MA; clinical guidelines Committee of the American College of physicians. Noninvasive treatments for acute, subacute, and Chronic low back pain: a clinical practice guideline from the American college of physicians. Ann Intern Med. 2017;166(7):514-30.
3. Basmajian JV. Acute back pain and spasm. A controlled multicenter trial of combined analgesic and antispasm agents. Spine. 1989;14(4):438-9.
4. Williams CM, Maher CG, Latimer J, McLachlan AJ, Hancock MJ, Day RO, et al. Efficacy of paracetamol for acute low-back pain: a double-blind, randomized controlled trial. Lancet. 2014;384(9954):1586-96.
5. Koes BW, van Tulder MW, Lin CW, Macedo LG, McAuley J, Maher C. An updated overview of clinical guidelines for the management of non-specific low back pain in primary care. Eur Spine J. 2010;19(12):2075-94.
6. Recio-Pinto E, Castillo C. Peripheral N-methyl-D-aspartate receptors as possible tar- gets for chronic pain treatment. Techn Reg Anesth Pain Manag. 2010;14(2):48-58.
7. Hewitt DJ. The use of NMDA-receptor antagonists in the treatment of chronic pain. Clin J Pain. 2000;16(2 Suppl):S73-9.
8. Bujalska M, Makulska-Nowak H, Gumulka SW. Magnesium ions and opioid agonists in vincristine-induced neuropathy. Pharmacol Rep. 2009;61(6):1096-104.
9. Moher D, Hopewell S, Schulz KF, Montori V, Gotzsche PC, Devereaux PJ, et al. CON- SORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:c869.
10. Friedman BW, Dym AA, Davitt M, Holden L, Solorzano C, Esses D, et al. Naproxen with cyclobenzaprine, oxycodone/acetaminophen, or placebo for treating acute low Back pain: a randomized clinical trial. JAMA. 2015;314(15):1572-80.
11. Stratford PW, Binkley J, Solomon P, Finch E, Gill C, Moreland J. Defining the mini- mum level of detectable change for the Roland-Morris questionnaire. Phys Ther. 1996;76(4):359-65.
12. Davies CC, Nitz AJ. Psychometric properties of the Roland-Morris disability question- naire compared to the Oswestry disability index: a systematic review. Phys Ther Rev. 2016;96(10):1620-37.
13. Deyo RA, Battie M, Beurskens AJ, Bombardier C, Croft P, Koes B, et al. Outcome mea- sures for low back pain research. A proposal for standardized use. Spine. 1998;23 (18):2003-13.
14. Koes B, Schreijenberg M, Tkachev A. Paracetamol for low back pain: the state of the Research Field. Expert Rev Clin Pharmacol. 2020;13(9):1059-66.
15. Schreijenberg M, Luijsterburg PA, Van Trier YD, Rizopoulos D, Koopmanschap MA, Voogt L, et al. Efficacy of paracetamol, diclofenac and advice for acute low back pain in General practice: design of a randomized controlled trial (PACE plus). BMC Musculoskelet Disord. 2017;18(1):56.
16. Miki K, Ikemoto T, Hayashi K, Arai YC, Sekiguchi M, Shi K, et al. Randomized open- label [corrected] non-inferiority trial of acetaminophen or loxoprofen for patients with acute low back pain. J Orthop Sci. 2018;23(3):483-7.
17. Ostojic P, Radunovic G, Lazovic M, Tomanovic-Vujadinovic S. Ibuprofen plus paracet- amol versus ibuprofen in acute low back pain: a randomized open label multicenter clinical study. Acta Reumatol Port. 2017;42(1):18-25.
18. Kehres DG, Maguire ME. Structure, properties and regulation of magnesium trans- port proteins. Biometals. 2002;15(3):261-70.
19. Konrad M, Schlingmann KP, Gudermann T. Insights into the molecular nature of magnesium homeostasis. Am J Physiol Renal Physiol. 2004;286(4):F599-605.
20. Banerjee S, Jones S. CADTH Rapid Response reports: magnesium as an alternative or adjunct to opioids for migraine and chronic pain: a review of the clinical effective- ness and guidelines. Ottawa, ON, Canada: Canadian Agency for Drugs and Technolo- gies in Health; 2017.
21. Bondok RS, Abd El-Hady AM. Intra-articular magnesium is effective for postopera- tive analgesia in arthroscopic knee surgery. Br J Anaesth. 2006;97(3):389-92.
22. Ryu JH, Sohn IS, Do SH. Controlled hypotension for middle ear surgery: a comparison between remifentanil and Magnesium sulphate. Br J Anaesth. 2009;103(4):490-5.
23. Oguzhan N, Gunday I, Turan A. Effect of magnesium sulfate infusion on sevoflurane consumption, hemodynamics, and perioperative opioid consumption in lumbar disc surgery. J Opioid Manag. 2008;4(2):105-10.
24. Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Die- tary Reference Intakes Dietary reference intakes for calcium, phosphorus, magne- sium, vitamin D, and fluoride. Washington, DC: The National Academies Collection: Reports funded by National Institutes of Health; 1997.
25. Bagis S, Karabiber M, As I, Tamer L, Erdogan C, Atalay A. Rheumatol Int. 2013;33(1): 167-72.
26. Tarleton EK, Kennedy AG, Rose GL, Littenberg B. Relationship between Magnesium Intake and Chronic Pain in U.S. Adults. Nutrients. 2020;12(7):2104.