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Featured Articles: Systematic Review Article

Efficacy and Safety of Magnesium for the Management of Chronic Pain in Adults: A Systematic Review

Park, Rex BHSc*; Ho, Anthony M.-H. MD, FRCPC, FCCP*; Pickering, Gisele MD, PhD, DPharm; Arendt-Nielsen, Lars PhD; Mohiuddin, Mohammed BSc*; Gilron, Ian MD, MSc, FRCPC*,§,‖

Author Information
doi: 10.1213/ANE.0000000000004673

Abstract

See Article, p 762

Chronic pain affects approximately 1.5 billion people worldwide and has devastating impacts on a person’s quality of life and economic well-being.1–5 Opioids, nonsteroidal anti-inflammatory drugs, antidepressants, and other pharmacological agents remain a central component of pain management.6,7 However, many of these treatments have limited effectiveness and dose-limiting adverse events.6 In the past 2 decades, there have been increases in opioid prescriptions despite concerns regarding its safety and effectiveness in many chronic pain conditions.8 The increase in opioid prescriptions has been associated with increases in mortality and misuse disorders, emphasizing the significant need for safer pain management strategies.9

Emerging evidence supports the use of magnesium in chronic pain management.10,11 Magnesium exerts its analgesic effects by blocking the N-methyl-d-aspartate (NMDA) receptors located on the postsynaptic spinal neurons in the dorsal horn of the spinal cord.12,13 Clinical use of NMDA receptor antagonists, such as ketamine, has been limited due to concerns regarding their safety.14 However, compared to other NMDA receptor antagonists, magnesium has very few, usually mild, side effects and may serve as a safer alternative for chronic pain management.10,15

NMDA receptors are active contributors to pain transmission and mediate a phenomenon termed central sensitization.12,16,17 In central sensitization, there is increased sensitivity of the dorsal horn neurons.12 Central sensitization is associated with the maintenance of chronic pain and manifests as allodynia (pain caused by nonpainful stimuli) and hyperalgesia (increased pain caused by a painful stimulus).12,16 Under physiological conditions, the NMDA receptors are blocked by magnesium ions which prevent calcium access into the cells.18,19 However, when there is nerve injury, inflammation, or sustained depolarization of the postsynaptic membrane, the NMDA receptor channel is activated, and the magnesium blockage is removed.6,12 The resulting intracellular buildup of calcium can promote the initiation of central sensitization as well as a phenomenon termed wind-up, where there is an increased intensity of pain due to increased sensitivity of the dorsal horn neurons to subsequent stimuli.6,12,17 Magnesium administration can restore the physiological plug of the NMDA receptor calcium channels.13,20–22 Through this mechanism, it is expected that magnesium administration can attenuate central sensitization and wind-up and dampen the activity of the dorsal horn neurons, resulting in an antinociceptive effect.

In view of its potentially safe use, understood antinociceptive mechanism, and lack of consensus regarding its clinical effects, we conducted a systematic review to assess the current evidence of efficacy and safety of magnesium for the treatment of chronic pain.

METHODS

The review protocol has been previously published,23 registered in the International Prospective Register of Systematic Reviews (PROSPERO), database (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=103284) on July 30, 2018, and prepared in accordance with recommendations specified in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and the PRISMA Harms Checklist.24,25 The protocol inclusion criteria only included chronic noncancer pain. We have now also included chronic cancer pain in our inclusion criteria as we have no pharmacological or pathophysiological evidence to suggest that a chronic noncancer pain patient would respond to magnesium but not a chronic cancer pain patient.

Types of Studies

We included placebo-controlled, randomized, double-blind trials evaluating magnesium administered for the treatment of chronic pain. We excluded studies that are nonrandomized or nonblinded. Both parallel and crossover studies were included.

Types of Participants

Studies of adults (over 18 years of age) with any type of chronic pain condition were included in the review. Chronic pain was defined as pain that persists for ≥3 months. Chronic pain could include persistent (eg, chronic musculoskeletal pain) and recurrent (eg, migraine) pain.

Types of Interventions

We included studies that administered magnesium for the relief of chronic pain, regardless of the dose or route of delivery. The studies must have compared magnesium to a placebo control. Chronic pain in the included studies was defined as pain that persists for 3 months or longer.

Types of Outcome Measures

Data collection included participant-reported measures of pain intensity or pain relief using validated methods, such as in the form of visual analog scales.

Primary Outcomes

The primary outcomes included any measure of pain intensity or pain relief that has been previously validated. Specifically, we focused on the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) definitions for benefit in chronic pain studies.26

Secondary Outcomes

  1. Any outcome related to pain that indicates improvement (eg, improved functioning),
  2. withdrawals due to any reason (eg, adverse events), and
  3. participants experiencing any adverse events, serious adverse events, or specific adverse events (eg, sedation).

Search Methods for Identification of Studies

We searched Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE from their inception until the date the searches are run. The search excluded studies that were not published in English. To create a sensitive search strategy, the search strategy included terms only related to the health condition (chronic pain) and intervention (any magnesium formulation) of interest. To ensure all chronic pain conditions were captured, search terms for specific chronic pain conditions (eg, fibromyalgia) were added. The CENTRAL, MEDLINE, and EMBASE search strategies are given in Supplemental Digital Content, Appendix 1, https://links.lww.com/AA/D14.

We also hand searched the reference lists of any randomized controlled trials (RCTs) identified for relevance as well as any review articles. We also searched clinical trial databases (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform to identify additional data.

Data Collection and Analysis

F1
Figure 1.:
Study flow diagram.

Two reviewers (R.P. and M.M.) independently evaluated studies for eligibility. Screening was performed on titles and abstracts. We removed studies that clearly did not satisfy the inclusion criteria, and full-text screening was performed on the remaining studies. Disagreements between the reviewers were resolved by discussion and consensus and, if necessary, resolution by the senior author (I.G.). A PRISMA flow chart of this process is presented (Figure 1).

Data Extraction and Management

Two review authors (R.P. and M.M.) extracted data independently using a standardized form and checked for agreement. Disagreements between the reviewers were resolved by discussion and consensus and, if necessary, resolution by the senior author (I.G.). We extracted information about the study design, pain condition, duration of pain, participant inclusion and exclusion criteria, number of participants, number of dropouts, trial duration, follow-up time, formulation and dosing and mode of delivery of magnesium and other study drugs, whether or not body magnesium levels were measured before and during treatment, primary and secondary outcome measures, and results.

Assessment of Risk of Bias in Included Studies

Two reviewers (R.P. and M.M.) independently assessed risk of bias for each study using criteria outlined in the Cochrane Handbook for Systematic Review of Interventions.27 Disagreements between reviewers were resolved with discussion and consensus and, if necessary, resolution by the senior author (I.G.). We assessed the following for each study: (1) random sequence generation, (2) allocation concealment, (3) blinding of participants and personnel, (4) blinding of outcome assessment, (5) incomplete outcome data, (6) selective reporting, and (7) other biases such as size of study.

Measures of Treatment Effect

As IMMPACT definitions for benefit in chronic pain studies are defined as ≥30% (moderate benefit) and ≥50% (substantial benefit) pain relief over baseline, we planned to estimate treatment effect for dichotomous outcomes by calculating the risk ratio with 95% confidence intervals (CIs) to assess statistical difference as well as the number needed to treat. However, because of clinical heterogeneity of included studies, we did not perform any pooled analysis.

Dealing With Missing Data

We planned to utilize the modified intention-to-treat analysis. The modified intention-to-treat population would have included participants who were randomized, received ≥1 dose of their assigned study drug, and provided ≥1 assessment (not including baseline). However, we performed no pooled analysis.

Assessment of Heterogeneity

We planned to handle clinical heterogeneity by combining studies that examined similar magnesium preparations and pain conditions. We planned to assess clinical heterogeneity visually and with the I2 statistic. When the I2 value was higher 50%, we would have considered possible explanations for this. However, we performed no pooled analysis.

Data Synthesis and Analysis of Outcomes

We planned to use a random-effects model for meta-analysis. However, due to clinical and methodological heterogeneity of the included studies, we did not perform any data synthesis.

Quality of Evidence

We planned to rate the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation approach, by using a “summary of findings” table. However, the summary of findings table was not included due to overall limited evidence.

Subgroup Analysis and Investigation of Heterogeneity

We planned subgroup analyses for different pain conditions, magnesium dosing, length of trial, and quality of studies. However, we did not perform any pooled analyses.

RESULTS

Search Results

A flow diagram of the search results is shown in Figure 1. The database search yielded 1062 records. No additional studies were identified in clinical trial registries or reference lists of included studies. After duplicates were removed, there were 713 records. After initial screening of titles and abstracts, we identified 25 relevant records. After reading the full articles for these 25 studies, we excluded 16 studies (Supplemental Digital Content, Appendix 2, https://links.lww.com/AA/D14). Nine studies fulfilled the inclusion criteria and were included in our systematic review.28–36

Included Studies

Of the 9 included studies, 6 studies utilized a parallel design,30–34,36 2 utilized a 2-period crossover design,28,35 and 1 utilized a 3-period crossover design.29 In a 2-period and 3-period crossover design, participants are randomized to a sequence of 2 or 3 treatments, respectively. All 3 crossover studies included a washout period between each treatment to eliminate any potential carry-over effects of the previous treatment. The 9 studies included a total of 418 participants with chronic pain. The chronic pain conditions investigated in the studies included neuropathic pain,29,34 postherpetic neuralgia,28 complex regional pain syndrome, type 1 (CRPS-1),30 CRPS-related dystonia,35 low back pain with a neuropathic component,36 and migraines with33 and without aura.31,32 Treatment periods ranged from an intravenous (IV) infusion over 30 minutes to oral therapy over 12 weeks. Two studies measured plasma or serum magnesium levels before and after each IV infusion,29,30 and 1 study measured blood magnesium between the 2 daily magnesium injections.35

Excluded Studies

We excluded 16 studies after the full articles were reviewed.37–52 Additional details regarding the reason(s) for exclusion can be found in Supplemental Digital Content, Appendix 2, https://links.lww.com/AA/D14.

Risk of Bias

F2
Figure 2.:
Risk of bias graph: review authors’ judgment about each risk of bias item presented as percentages across all included studies.
F3
Figure 3.:
Risk of bias summary: review authors’ judgments about each risk of bias item for each included study.

The results of each individual risk of bias domain is presented with a “Risk of bias” graph shown in Figure 2, and a Risk of bias summary is shown in Figure 3. Small study size (<50 participants per treatment arm) contributed to high risk of bias in all studies.

Effects of Intervention

Table 1. - Main Characteristics of Included Trials of Magnesium for Chronic Pain
Chronic Pain Condition First Author, Year Trial Design, Number of Participants Studied Duration of Pain (Months) Magnesium Formulation, Route of Administration Dosing Treatment Duration Trial Size (Enrolled/Completed)
Chronic postherpetic neuralgia Brill et al,28 2002 2-period crossover, n = 7 Unclear Magnesium sulfate, IV infusion 30 mg/kg (magnesium 0.06 mmol/kg) IV infusion over 30 min (1-wk washout) Magnesium, 7; placebo, 7
Unclear number of dropouts
Chronic neuropathic pain Felsby et al,29 1996 3-period crossover, n = 10 Not reported Magnesium chloride (MgCl2), IV infusion Magnesium: 10 min bolus infusion (0.16 mmol/kg), followed by a continuous infusion (0.16 mmol·kg−1·h−1) Total infusion time did not exceed 1 h Magnesium, 10 (3 cancer participants); ketamine, 10 (3 cancer participants); placebo, 10 (3 cancer participants)
Ketamine: 10 min bolus infusion (0.2 mg/kg), followed by a continuous infusion (0.3 mg·kg−1·h−1) Unclear number of dropouts
CRPS-1 Fischer et al,30 2013 Parallel, n = 56 Magnesium: 23.0 (8.5–64.8); placebo: 10.5 (5.0–26.8)a Magnesium sulfate, IV infusion 70 mg/kg via IV infusion of 25 mL/h over 4 h, daily 5 consecutive days, fixed dose Magnesium, 29/25; placebo, 27/24
Migraine without aura Köseoglu et al,31 2008 Parallel, n = 40 Not reported Magnesium citrate, water-soluble granule sachet 300 mg/sachet, given twice a day 3-mo fixed dose Magnesium, 30; placebo, 10
Unclear number of dropouts
Migraine with or without aura Peikert et al,33 1996 Parallel, n = 81 Magnesium: 203.2 (130.8); placebo: 181.6 (125.5)b Trimagnesium dicitrate, water-soluble granular powder 600 mg daily 12-wk fixed dose Magnesium, 43/39; placebo, 38/34
Migraine without aura Pfaffenrath et al,32 1996 Parallel, n = 69 Not reported Magnesium-aspartate-hydrochloride-trihydrate, granulate in sachets 5 mmol magnesium (121.5 mg) per sachet, 2 sachets twice a day 12-wk fixed dose Magnesium, 35/31; placebo, 34/30
Neuropathic pain Pickering et al,34 2011 Parallel, n = 45 Unclear Trihydrated magnesium chloride, oral 419 mg per capsule (equivalent to 55 mg Mg2+ per capsule), 6 tablets a day 4-wk fixed dose Magnesium, 22/22; placebo, 23/23
CRPS-1 van der Plas et al,35 2013 2-period crossover, n = 30 Participants completing the study: 11.5 (6.0–16.0)a Magnesium sulfate, IM injection 100 mg/mL solution; Treatment started at a daily volume of 5 mL twice a day and was increased in weeks 2 and 3 to twice-daily volumes of 7.5 and 10 mL, respectively 3-wks (1-wk washout) Magnesium, 28/23; placebo, 27/24
Chronic low back pain with a neuropathic component Yousef et al,36 2011 Parallel, n = 80 Magnesium: 7.9 (1.9); placebo: 8.5 (2.1)b Magnesium sulfate, IV infusion; followed by magnesium oxide and magnesium gluconate, oral capsules Magnesium sulfate: 1 g in 250 mL saline 0.9% daily IV infusion: Given over 4 h every day for 2 wk Magnesium, 40; placebo, 40
Oral capsules contained 400 mg magnesium oxide and 100 mg magnesium gluconate, given twice a day Oral therapy: 4 wk (after 2 wk of IV infusion) Unclear number of dropouts
Abbreviations: CRPS, complex regional pain syndrome; IM, intramuscular; IV, intravenous.
aMedian (interquartile range).
bMean (standard deviation).

Table 2. - Main Results of Pain Outcomes From Included Trials of Magnesium for Chronic Pain
Chronic Pain Condition First Author, Year Primary Outcome and Pain Measure Time/Duration of Follow-up Analgesic Efficacy: Treatment Versus Placebo Adverse Events
Chronic postherpetic neuralgia Brill et al,28 2002 Pain intensity (0–10 VAS) and pain relief Pain intensity: 10, 20, and 30 min during infusion Magnesium treatment superior to placebo 20 (P = .016) and 30 min (P = .016). However, all participants had their pain return the same evening. Adverse events were inconsistently reported
Pain relief at time of discharge, 1 h later, and the following morning No adverse events were reported during the magnesium sulfate infusion except for a mild feeling of warmth at the injection site
Chronic neuropathic pain Felsby et al,29 1996 Pain intensity (10 cm VAS) During bolus infusion, 3 times during continuous infusion, and 15 min after termination of the drug (pain intensity) Magnesium failed to show a significant reduction in VAS score Side effects (7 participants) in the magnesium group included heat sensation (7), injection pain (2), and sedation (1)
Allodynia
Before infusion, immediately after bolus, and at infusion (allodynia) Side effects in the placebo group were not reported
Complex regional pain syndrome type 1 Fischer et al,30 2013 Pain intensity (0–10 NRS and McGill Pain Questionnaire) During administration of trial medication, 3, 6, and 12 wk No significant differences found throughout the duration of follow-up Adverse events were inconsistently reported
Common side effects in the magnesium group were flushing and dizziness; other side effects reported were a vasovagal reaction (1), palpitations (1), and phlebitis from IV insertion (1)
Side effects in the placebo group included palpitations (2) and spreading pain around IV cannula (1)
Migraine without aura Köseoglu et al,31 2008 Migraine frequency 3 mo Median post/pretreatment ratios of migraine attack frequency and severity were found to be lower in the Mg group compared to the placebo group; insufficient data provided to estimate effect size Adverse events were inconsistently reported
Migraine severity (10 cm VAS) Side effects in the magnesium group included diarrhea or soft stools (4) and gastric irritation (2)
Migraine with or without aura Peikert et al,33 1996 Migraine frequency 12 wk Magnesium superior to placebo in reducing migraine attack frequency at weeks 9–12 compared to baseline (P = .0303) Adverse events were inconsistently reported
Pain intensity (0–10 VAS) No significant differences found for pain intensity In total, 17 adverse events in 15 participants were reported, where 5 events were unrelated to the medication
Side effects in the magnesium group included diarrhea or soft stools (8) and gastric irritation (2)
Side effects in the placebo group included moderate diarrhea (2)
Migraine without aura Pfaffenrath et al,32 1996 Percentage of participants with a reduction of 50% or greater in the duration of migraine in hours or pain intensity (100 mm VAS) 12 wk No significant differences found throughout the duration of follow-up Adverse events were inconsistently reported
16 of 35 participants in the magnesium group reported 35 adverse events including soft stools (5), diarrhea (5), and palpitations (3)
8 of 34 participants in the placebo group reported 17 adverse events. The nature of these adverse events was not described
Neuropathic pain Pickering et al,34 2011 NPSI 4 wk No significant differences found throughout the duration of follow-up Not reported
Pain intensity (0–10 numerical scale)
CRPS-related dystonia van der Plas et al,35 2013 Pain intensity (0–10 numerical scale) 3 wk Magnesium treatment statistically but not clinically superior to placebo at 3 wk (P = .01) Side effects in the magnesium group included injection pain (19), subcutaneous hematoma (7), mild allergy (3), itchy sensation at the site of injection (1), edema (1), flushing (1), headache (1), nausea (1), impaired cardiac conduction (1), sleepiness (1), return of injection fluid (1), and hyperhidrosis (1)
McGill number of words chosen and McGill pain rating index No significant differences found for McGill number of words chosen and McGill pain rating index Side effects in the placebo group included injection pain (9), mild allergy (2), flushing (1), headache (3), nausea (2), exacerbation of CRPS (1), gingivitis (1), hyperexcitation (1), lightheadedness (1), and painful breasts (1)
Chronic low back pain with a neuropathic component Yousef et al,36 2011 Pain intensity (0–10 numerical scale) 2 wk, 6 wk, 3 mo, and 6 mo Applying a Bonferroni correction for comparing groups at 4 time points (P < .05/4 = .0125 significant), pain score was reduced in the magnesium group compared to the placebo group at 6 wk (P = .003), but not at 2 wk (P value not reported), 3 mo (P = 0.045), or 6 mo (P = .027). Adverse events were inconsistently reported
Side effects in the magnesium group included mild diarrhea during their oral treatment (4)
Abbreviations: CRPS-1, complex regional pain syndrome type 1; IV, intravenous; NPSI, Neuropathic Pain Symptom Inventory; NRS, numerical rating scale; VAS, visual analog scale.

The summary of findings is shown in Tables 1 and 2.

Effects of Intervention: Neuropathic Pain

Three studies included participants with neuropathic pain.28,29,34 Two studies investigated a single IV infusion of magnesium compared to placebo. A beneficial effect of magnesium compared to placebo was not found in one study and a temporary beneficial effect was found in the other. The third study investigated 4 weeks of oral magnesium treatment compared to placebo and found no difference in pain intensity between the 2 groups.

A single-dose, 2-period crossover RCT by Brill et al28 investigated magnesium sulfate administered as an IV infusion over 30 minutes. A total of 7 participants with postherpetic neuralgia were included. Pain scores were significantly lower for magnesium compared to placebo at 20 (P = .016) and 30 minutes (P = .016). The median difference (95% CI) between magnesium and placebo was 2 (1–5) at 20 minutes and (1–7) at 30 minutes. However, all the participants reported that their pain returned the same evening.

A single-dose, 3-period crossover RCT by Felsby et al29 investigated magnesium chloride administered as an IV loading dose for 10 minutes followed by a continuous infusion that did not exceed 1 hour. A total of 10 chronic pain participants were included. Magnesium failed to show a significant reduction in VAS score compared to placebo (P = .084). There were insufficient data to calculate estimated treatment effect and its 95% CI.

A parallel, 2-arm design RCT by Pickering et al34 investigated trihydrated magnesium chloride capsules, given orally, for 4 weeks. A total of 45 participants with neuropathic pain were included. Changes in mean pain intensity before and after treatment were not statistically different between magnesium and placebo (P = .630). The baseline mean (standard deviation [SD]) pain intensity in both groups was 5 (3) on the numerical pain scale. After 4 weeks of treatment, the mean pain intensity was 4 (3) in the magnesium group and 4 (2) in the placebo group. There were insufficient data to calculate estimated treatment effect and its 95% CI.

Effects of Intervention: CRPS-1

Two studies included participants with CRPS.30,35 One study investigated IV magnesium and the other investigated intramuscular magnesium compared to placebo. Both studies found no clinically significant difference between magnesium and placebo in reducing pain intensity.

A parallel, 2-arm design RCT by Fischer et al30 investigated IV magnesium sulfate administered intravenously for 4 hours every day for 5 consecutive days. A total of 56 participants diagnosed with CRPS-1 were included. No significant differences in pain intensity were found between the magnesium and placebo group at 3, 6, and 12 weeks (P values not provided). In the magnesium group, the mean (SD) pain intensity scores were 6.1 (1.8) at baseline, 5.3 (2.8) at 3 weeks, 5.2 (3.1) at 6 weeks, and 5.1 (3.0) at 12 weeks. In the placebo group, the mean (SD) pain intensity scores were 6.3 (1.6) at baseline, 5.5 (2.4) at 3 weeks, 5.3 (2.5) at 6 weeks, and 5.4 (2.3) at 12 weeks.

A 2-period crossover RCT by van der Plas et al35 investigated magnesium sulfate administered intramuscularly, twice a day, for 3 weeks. A total of 30 participants with CRPS-related dystonia were included. There was a small but statistically significant improvement in pain intensity after 3 weeks of magnesium treatment when compared to placebo (P = .01). After magnesium treatment, the mean (SD) pain pretreatment value went from 7.3 (1.6) to 6.7 (2.1) at 3 weeks, whereas after placebo treatment, the mean pain (SD) pretreatment value went from 7.2 (1.5) to 7.3 (1.6) at 3 weeks. There were insufficient data to calculate estimated treatment effect and its 95% CI.

Effects of Intervention: Chronic Low Back Pain

One study included participants with chronic low back pain.36

A parallel, 2-arm design RCT by Yousef et al36 investigated IV magnesium sulfate given over 4 hours every day for 2 weeks, followed by oral magnesium capsules containing magnesium oxide and magnesium gluconate given twice a day for 4 weeks. A total of 80 participants with chronic low back pain with a neuropathic component were included.36 Pain scores were evaluated at 2 weeks, 6 weeks, 3 months, and 6 months. Applying a Bonferroni correction for comparing groups at 4 time points (P < .05/4 = .0125 significant), pain score was reduced in the magnesium group compared to the placebo group at 6 weeks (P = .003), but not at 2 weeks (P value not reported), 3 months (P = .045), or 6 months (P = .027). In the magnesium group, the mean (SD) pain intensity scores were 7.5 (2.2) at baseline, 3.4 (1.15) at 2 weeks, 3.9 (1.4) at 6 weeks, 4.4 (1.6) at 3 months, and 4.7 (1.8) at 6 months. In the placebo group, the mean (SD) pain intensity scores were 7.4 (2.4) at baseline, 3.6 (1.4) at 2 weeks, 6.6 (1.7) at 6 weeks, 6.8 (2.2) at 3 months, and 7.2 (2.45) at 6 months. There were insufficient data to calculate estimated treatment effect and its 95% CI.

Effects of Intervention: Migraine

Three studies studied participants with migraine.31–33 All 3 studies investigated oral magnesium administered for 3 months compared to placebo. One study found some benefit, where magnesium demonstrated a lower median post/pretreatment ratio for migraine severity compared to placebo. Two studies found no significant difference between magnesium and placebo in reducing pain intensity.

A parallel, 2-arm design RCT by Köseoglu et al31 investigated oral magnesium citrate twice a day for 3 months. A total of 40 participants with migraine without aura were included. The median (range) post/pretreatment ratio of migraine severity was 0.57 (0.00–0.71) in the magnesium group compared to 1.00 (0.83–1.17) in the placebo group (P < .001). There were insufficient data to calculate estimated treatment effect and its 95% CI.

A parallel, 2-arm design RCT by Pfaffenrath et al32 investigated oral magnesium twice a day for 3 months. A total of 69 participants with migraine without aura were included. A beneficial effect of magnesium over placebo in terms of migraine intensity at the end of the 3-month period was not observed (P value not provided). A reduction of ≥50% in migraine intensity was found in 20.0% of patients in the magnesium group and 14.7% in the placebo group. Due to uncertainty of how many participants were included in the analysis, there were insufficient data to calculate the estimated treatment effect and its 95% CI.

A parallel, 2-arm design RCT by Peikert et al33 investigated oral magnesium once a day for 12 weeks. A total of 81 participants with migraine were included. A beneficial effect of magnesium over placebo in terms of migraine intensity was not observed (P = .320). In the magnesium group, the mean reduction (SD, 95% CI) of pain intensity was 2.06 (2.77, 1.21–2.1) compared to 1.25 (2.29, 0.50–2.00) in the placebo group. However, in the last 4 weeks of trial (weeks 9–12), magnesium was superior to placebo in reducing migraine attack frequency (P = .0303). In the magnesium group, the mean reduction (SD, 95% CI) in frequency of attacks was 1.51 (2.07, 0.87–2.15) compared to 0.58 (2.30, −0.18 to 1.33) in the placebo group. Of note, however, this study did not mention whether they corrected for multiple comparisons.

Withdrawals due to Lack of Efficacy, Adverse Events, or for any Cause

Only 6 of the 9 included studies explicitly reported the number of withdrawals.30,32–35

Three studies provided information on reasons for withdrawals. van der Plas et al35 reported 8 withdrawals in total: 3 participants withdrew during intramuscular magnesium treatment due to injection pain, 1 participant withdrew during intramuscular magnesium treatment due to a broadened QRS complex, 3 participants withdrew during placebo treatment due to other adverse events (headache, severe dystonia, and exacerbation of CRPS), and an additional 1 participant withdrew from the study after completing the first placebo treatment period due to injection pain.35 Pfaffenrath et al32 reported 4 withdrawals in each of the magnesium and placebo treatment arms. However, only one of the dropouts from the magnesium group was due to a lack of efficacy compared to all 4 from the placebo group. Three participants from the magnesium group and 1 participant from the placebo group withdrew early due to adverse events. Peikert et al33 reported 4 withdrawals in each of the magnesium and placebo groups. Three withdrawals in the magnesium group were due to unwanted side effects and 1 in the placebo group was due to a lack of effectiveness. The remaining 4 participants were lost to follow-up.

Adverse Events

The adverse events that participants experienced between those who received magnesium compared to those who received placebo were inconsistently reported and any meaningful statistical analyses could not be done. Details regarding adverse events are shown in Table 2.

DISCUSSION

Summary of Main Results

This systematic review of 9 RCTs evaluated the efficacy and safety of magnesium versus placebo for the management of chronic pain. There was mixed or no evidence of benefit in most chronic pain conditions. However, there was some evidence that magnesium may provide some benefit to people with chronic low back pain with a neuropathic component following 6 weeks of magnesium treatment.36 These results should be interpreted with some caution because most studies did not report individual responder outcomes of clinically useful benefit in regard to pain intensity and pain relief. The underlying distribution of individual data for pain intensity and pain relief is often skewed, and using group means values for pain intensity or pain relief can generate misleading results.26,53,54 In terms of adverse events, due to the small size of included studies and the inconsistent and incomplete reporting of adverse events, no useful information on harms was obtained.

Our review agrees with a previously published report by The Canadian Agency for Drugs and Technologies in Health that there is little high-quality evidence for the efficacy and safety of magnesium for chronic pain conditions.55 The 3 studies in our review investigating neuropathic pain28,29,34 were not included in the Canadian report due to its limited literature search and publication date inclusion criteria. Our review also agrees with a systematic review published by Collins et al56 in 2010 that evaluated the effects of NMDA receptor antagonists on neuropathic pain, which could not make any conclusions about the efficacy of NMDA receptor antagonists on neuropathic pain. One study34 in our review was published after the review by Collins et al,56 but this study also found no difference between magnesium and placebo in reducing pain. Collins et al56 calculated summary effect sizes for IV ketamine in postamputation pain and CRPS and found IV ketamine to be only beneficial in postamputation pain. A similar, updated review was conducted by Aiyer et al57 in 2018. However, this review did not include studies with magnesium. This review found IV ketamine to be the most investigated and beneficial NMDA receptor antagonist in neuropathic pain.57 All of the 13 included RCTs that investigated IV ketamine found some analgesic benefit in neuropathic pain.57 Nevertheless, further studies need to be undertaken to gain more knowledge on the clinical use of NMDA receptor antagonists in chronic pain.

Future Directions

One area of interest for future research is the evaluation of magnesium for the prevention of chronic postoperative pain. Given the potential benefits of NMDA antagonists such as ketamine in preventing chronic pain after surgery,58 magnesium is another worthy candidate to study. Relevant to this, a recent prospective observational study of 100 participants found that perioperative magnesium sulfate may be effective in preventing chronic neuropathic postthoracotomy pain measured by The Leeds Assessment of Neuropathic Symptoms and Signs pain scale.59 However, a double-blind RCT found that compared to control, intraoperative magnesium sulfate did not reduce the intensity of chronic postmastectomy pain in 126 patients.60 There is also an ongoing double-blind RCT with 100 women investigating the effect of perioperative oral magnesium chloride on pain intensity 1-month postmastectomy.61 Thus, further research on the preventive effects of magnesium is anticipated.

Overall Completeness of Evidence and Limitations

Several limitations must be acknowledged. First, as per our criteria, all studies were randomized and double blind. However, most studies were of short duration (treatment period of <6 weeks), and all were at a high risk of bias due to small sample size (<50 participants per treatment arm), increasing the risk of random chance effects and small study bias. Second, most of the studies had variable chronic pain conditions, treatment and follow-up periods, and magnesium formulations. This heterogeneity made it difficult to compare the findings of the studies with each other, and therefore, our analysis was descriptive in nature. Third, although most studies excluded patients with renal insufficiency and failure, most studies did not control for other patient factors that may affect magnesium levels such as the use of thiazide and loop diuretics.62 Fourth, the included studies utilized a variety of different magnesium formulations and most did not measure or report magnesium levels in participants during treatment. Oral magnesium absorption occurs primarily in the small intestines via the paracellular pathway and is affected by several endogenous (eg, magnesium status) and exogenous (eg, magnesium dosing) factors.63 Magnesium absorption reaches a plateau after 2–5 hours of ingestion and is approximately 80% complete by 6 hours.63 Although the absolute absorption increases with increasing dose, the relative bioavailability of magnesium is higher when it is taken up in multiple, frequent, low doses.63 Studies suggest that magnesium supplementation with organic magnesium compounds, such as magnesium citrate, generally has higher bioavailability than inorganic magnesium compounds, such as magnesium oxide.63–66 Due to differing bioavailabilities, without measuring magnesium levels, it is difficult to determine whether lack of efficacy is due to inadequate dosing or that magnesium is indeed not efficacious. Similarly, it is not possible to determine whether an observed therapeutic effect of magnesium is from treating existing hypomagnesemia or inducing hypermagnesemia or both. Thus, there may be a role for clinical trials of magnesium that more specifically evaluate the analgesic effects of certain target blood levels of magnesium, by titrating the administered magnesium dose to a specific blood level, as has been done in other therapeutic areas.67

CONCLUSIONS

For the purposes of routine patient care, there is insufficient evidence to support or refute the hypothesis that magnesium is efficacious and safe in chronic pain. However, although currently available evidence is equivocal, there were some trial signals to suggest the potential for analgesic efficacy in chronic pain conditions. Larger, double-blind, RCTs for a variety of chronic pain conditions conducted over longer periods would be required to understand the role of magnesium in the management of chronic pain. These trials would ideally be stratified by baseline body magnesium and magnesium formulations.

ACKNOWLEDGMENTS

The authors wish to thank Sandra Halliday for her assistance in building the search strategy.

DISCLOSURES

Name: Rex Park, BHSc.

Contribution: This author led the writing of the manuscript and co-led the preparation of the systematic review.

Conflicts of Interest: None.

Name: Anthony M.-H. Ho, MD, FRCPC, FCCP.

Contribution: This author assisted in manuscript preparation and review.

Conflicts of Interest: None.

Name: Gisele Pickering, MD, PhD, DPharm.

Contribution: This author assisted in manuscript preparation and review.

Conflicts of Interest: None.

Name: Lars Arendt-Nielsen, PhD.

Contribution: This author assisted in manuscript preparation and review.

Conflicts of Interest: None.

Name: Mohammed Mohiuddin, BSc.

Contribution: This author was the second reviewer in study selection, data extraction, and risk of bias assessment. This author also assisted in manuscript preparation and review.

Conflicts of Interest: None.

Name: Ian Gilron, MD, MSc, FRCPC.

Contribution: This author was the senior reviewer in study selection, data extraction, and risk of bias assessment. This author co-led the preparation of the systematic review as well as assisted in manuscript review.

Conflicts of Interest: I. Gilron has received support from Biogen, Adynxx, TARIS Biomedical, AstraZeneca, Pfizer, and Johnson and Johnson and has received grants from the Canadian Institutes of Health Research, Physicians’ Services Incorporated Foundation, and Queen’s University.

This manuscript was handled by: Honorio T. Benzon, MD.

FOOTNOTES

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