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Magnesium and headache after aneurysmal subarachnoid haemorrhage
  1. S M Dorhout Mees1,
  2. D Bertens1,
  3. H B van der Worp1,
  4. G J E Rinkel1,
  5. W M van den Bergh2
  1. 1Rudolf Magnus Institute of Neuroscience, Department of Neurology, Utrecht, The Netherlands
  2. 2Department of Intensive Care, University Medical Center Utrecht, Utrecht, The Netherlands
  1. Correspondence to Sanne M Dorhout Mees, Department of Neurology, Room G03.228, University Medical Center Utrecht, PO Box 85500, 3508 GA, Utrecht, The Netherlands; s.m.dorhoutmees{at}umcutrecht.nl

Footnotes

  • Funding This study was partly sponsored by the Netherlands Heart Foundation, grant 2005B16.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the METC Utrecht, The Netherlands.

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

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A sudden and severe headache is the most characteristic symptom of subarachnoid haemorrhage (SAH) from a ruptured aneurysm. The headache usually lasts for 1–2 weeks, and often requires treatment with opioids.1 Opioids, however, have a wide range of potential side effects such as drowsiness, respiratory depression, constipation and urinary retention, which may have a negative effect on patient comfort and functional outcome.

Magnesium is a non-competitive antagonist of voltage-dependent calcium channels and the N-methyl-d-aspartic acid (NMDA) receptor.2 Blocking of the NMDA receptor is thought to be involved in pain modulation by preventing the induction of central pain sensitisation.3 Several studies have reported that magnesium reduces perioperative pain or analgesic requirements in coronary artery bypass surgery,4 prostatectomy,5 thoracotomy6 and gynaecological surgery.7 The effect of magnesium on headache after SAH is unknown. Side effects of magnesium therapy are sparse and mild when used in moderate dosages.

There are indications that treatment with intravenous magnesium sulphate improves functional outcome after SAH.8 Headache relief would be an important additional effect of magnesium because this would reduce the need of opioids with their potentially harmful side effects.

We studied if hypermagnesaemia due to magnesium therapy reduces headache and analgesic requirements in patients with aneurysmal SAH.

Methods

Patients

We studied a cohort of patients from the Magnesium in Aneurysmal Subarachnoid Haemorrhage study (MASH-II), an international, randomised, placebo-controlled clinical trial testing the effect of intravenous magnesium sulphate on functional outcome after aneurysmal SAH.9 The study is approved by the local ethics committee. The main criteria for inclusion in MASH-II are aneurysmal SAH, age >18 years and informed consent within 4 days after SAH. Patients with renal failure, defined as a serum creatinine above 150 μmol/l, are excluded. Intravenous magnesium sulphate in a daily dose of 64 mmol or matched placebo (normal saline) is started within 4 days and continued until 20 days after SAH or until discharge when this occurs before day 20.

Patients participating in MASH-II were included in the present study if they had been admitted to the stroke unit of the University Medical Center Utrecht between January 2004 and August 2006 within 2 days of SAH onset, had a score on the Glasgow Coma Scale ≥13, were not aphasic and if the severity of headache had been assessed for at least 2 days. Age, sex and clinical condition at admission as assessed with the World Federation of Neurological Surgeons Scale (WFNS)10 were recorded prospectively. The amount of blood on the admission CT scan was assessed with the Hijdra score.11 Age and Hijdra scores were dichotomised at their median values. A good clinical condition on admission was defined as a WFNS score of 1–3.

All patients were treated according to a standardised protocol on the stroke unit that consisted of absolute bed rest until aneurysm treatment, oral nimodipine in a daily dose of six times 60 mg and intravenous administration of fluids aimed at maintaining normovolaemia. The headache was also treated according to a standardised protocol. All patients received 500 mg of acetaminophen (paracetamol) every 4 h as initial treatment immediately after admission. If this was insufficient, the headache was treated with additional analgesics in the following order and daily doses: codeine four times 10–20 mg, tramadol (a moderately strong synthetic opioid) four times 50–100 mg or piritramide (a strong synthetic opioid) four times 10–20 mg.

Every 6 h until day 10 after SAH, patients were asked to rate their headache on a scale from 0 to 10, with 0 representing no headache at all and 10 representing the worst headache one can imagine. The daily mean headache scores were calculated, as well as the use of analgesic drugs, from the day of the start of MASH-II study medication until day 10 after the SAH. When patients were subsequently transferred to an intensive care unit (ICU) or died, or if there was an inability to assess headache because of a low consciousness before day 10 or if study medication was stopped prematurely, headache scores and analgesic use were no longer recorded. For each patient, a mean headache score of the available days was recorded. We also recorded for each patient the amount of days on the stroke unit and the total amount of days of codeine, tramadol and piritramide use. Magnesium concentrations were measured every other day and recorded until day 10 or death when this occurred before day 10. For each patient, the mean serum magnesium concentration from the day of start of trial medication until day 10 was recorded. Patients were divided into two groups based on their mean serum magnesium levels: levels ≤1.0 mmol/l were considered normal and levels >1.0 mmol/l were considered high.12 Because the MASH-II trial is still ongoing, this division was made based on serum magnesium concentrations and not on actual treatment allocation. Data were analysed anonymously so that individual patients could not be recognised and to ascertain that the MASH-II investigators remained blinded to treatment allocation and serum magnesium concentrations of the individual patients.

Analyses

Differences in mean headache scores between the high and normal magnesium groups were calculated with a Student t test. Odds ratios (ORs) were calculated with regard to codeine, tramadol or piritramide use at any time, for the high magnesium group versus the normal magnesium group, by means of logistic regression. ORs were adjusted for age, sex, clinical condition on admission and the amount of blood on the initial CT scan, if they changed the crude OR by more than 5% in bivariate analysis. In the regression analyses, all variables were introduced dichotomously.

To study differences in the time that patients were using analgesics, we calculated for each medication the difference in proportions of the cumulative amount of days on the medication divided by the cumulative amount of days spent on the stroke unit, between patients with high magnesium levels and those with normal magnesium levels.

Results

During the study period, 422 patients with SAH were admitted to our hospital, of which 210 were included in the MASH-II trial. The headache scores of 102 patients were not available mostly because patients were in too poor a clinical condition during (part of) the study period to provide headache scores. A flow chart of the included patients is shown in figure 1. Baseline characteristics of the 108 included patients are shown in table 1.

Figure 1

Flowchart of the included patients. GCS, Glasgow Coma Scale; ICU, intensive care unit; SAH, subarachnoid haemorrhage.

Table 1

Baseline characteristics of the included patients

All patients used acetaminophen during the first 10 days after the SAH, 69% of patients used codeine at any time during the first 10 days, 59% of patients used tramadol and 36% used piritramide.

There were 61 patients with high magnesium levels, and these patients had a statistically significant lower mean headache score (4.1 (1.8)) than the 47 patients with normal magnesium levels (4.9 (2.2)); mean difference, 0.8 (95% CI 0.1 to 1.6).

The number of patients who used codeine at any time did not differ between the groups (adjusted OR 1.3; 95% CI 0.5 to 3.3). Fewer patients in the high magnesium group than in the normal magnesium group used tramadol at any time (adjusted OR 0.4; 95% CI 0.2 to 0.9) or piritramide (adjusted OR 0.2; 95% CI 0.1 to 0.5) (table 2).

Table 2

ORs for the use of codeine, tramadol and piritramide in patients with high serum magnesium levels compared with patients with normal magnesium levels

For patients with high magnesium levels, the proportion of cumulative days on piritramide was lower and the proportion of cumulative days on codeine was higher. The proportion of amount of days on tramadol did not differ between the two groups (table 3).

Table 3

Differences in the proportion of cumulative days on codeine, tramadol or piritramide between patients with normal magnesium levels and patients with high magnesium levels

Discussion

In this study, the patients with SAH who had high serum magnesium levels less often required treatment with the synthetic opioids tramadol and piritramide than the patients with normal serum magnesium levels. Despite the less frequent use of opioids, the patients with high serum magnesium levels still reported less severe headache.

The observed higher proportion of days on codeine in the patients with high serum magnesium levels is a consequence of the fact that these patients had a non-severe headache and stayed on codeine for a longer period instead of switching to tramadol.

After SAH, activation of NMDA receptors facilitates pain transmission in the central nervous system, which can lead to hyperalgesia.3 The usual analgesics are not effective and may even exaggerate hyperalgesia. This facilitation of the NMDA receptor may be ameliorated by an NMDA-receptor antagonist such as magnesium. Furthermore, the antinociceptic effect of opoids may be potentiated by magnesium.

A limitation of the current study is that we could not assess the effect of magnesium therapy itself but only the association between serum magnesium levels and headache. There were slightly more patients in the high magnesium group than in the normal magnesium group. This may be due to a coincidental imbalance in randomisation in this relatively small group of patients. Other possible explanations are that patients in the normal magnesium group were more often excluded because of early transferral to an ICU or that some patients in the placebo group had physiological serum magnesium levels just above 1.0 mmol/l. Except for the study medication, we did not supplement magnesium in any of our patients.

Patient data were only analysed when patients were able to record their headache. Accordingly, intubated patients and patients with aphasia or with a sustained reduced consciousness were excluded. Thus, we included only a subset of patients who were included in the MASH-II study. Also, when an included patient was transferred to the ICU or died before day 10, only the data before the transferral or death were used. The results of the study thus only hold true for patients admitted early after the onset of symptoms who are in a good clinical condition with no aphasia and who are not intubated. However, we have no reason to assume that the association between serum magnesium levels and headache differs between patients with a normal consciousness and those with a reduced consciousness or between those in a stroke unit and those in an ICU. Also, we used means of the headache scores of all available days per patient, whereas the number of headache scores available differed per patient. However, there were large differences in the time course of headache scores between the patients. Calculating a mean headache score for each day after the SAH separately would have reduced power because headache scores were not known at all days for all patients.

Although several studies have reported that magnesium reduces perioperative pain, previous studies on the effect of magnesium on headache have shown conflicting results. Two small controlled but non-randomised studies have suggested that intravenous magnesium sulphate reduces headache in patients with acute migraine attacks13 and in patients with headache of any type, including migraine, cluster headache and chronic daily hedache.14 However, randomised controlled trials did not show any beneficial effect of intravenous magnesium on migraine15 16 or acute benign headache.17 In most of these studies, magnesium was administered as an intravenous bolus of 1–2 g.15–18 In our study, the patients received the substantially higher daily dose of 16 g (64 mmol) magnesium sulphate for a sustained period, which may be more effective than smaller single doses. We did not administer bolus injections because a bolus injection led to more side effects in a previous study.19 Side effects in the dose we used are sparse and mild.20 21 Diarrhoea, a common side effect of oral magnesium salts that were used in randomised controlled trials of magnesium for migraine prophylaxis,22 does not occur with intravenous administration.

In conclusion, hypermagnesaemia is associated with less severe headache after aneurysmal SAH and decreases the use of analgesics with potentially harmful side effects. These observational data imply that intravenous magnesium therapy provides pain relief for patients with SAH, for whom it might also improve functional outcome.

References

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Footnotes

  • Funding This study was partly sponsored by the Netherlands Heart Foundation, grant 2005B16.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the METC Utrecht, The Netherlands.

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

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