Magnesium Oral Supplementation to Reduce Pain Inpatients With Severe Peripheral Arterial Occlusive Disease

Study Overview
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Brief Summary
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Magnesium exerts analgesic effects in several animal pain models and in patients affected by acute postoperative pain and chronic pain of neuropathic origin. There is no evidence that magnesium can modulate pain in patients with peripheral arterial occlusive disease (PAOD). We describe the protocol of a single-center randomized double-blind clinical trial aimed at assessing the efficacy of oral magnesium supplementation in controlling severe pain in patients with advanced PAOD.

Detailed Description
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Adult patients admitted to our Acute Pain Service for intractable pain will be eligible if they are affected by PAOD at stages III and IV of Lèriche-Fontaine classification, and are opioid-naïve. Patients enrolled will be randomized to the control group, treated with standard therapy, consisting of an oral administration of oxycodone 5 mg and pregabalin 25 mg per day plus placebo (fructose 10 g) twice a day for two weeks, or to the experimental group, treated with magnesium oxide 300 mg twice a day. Randomization will be computer-generated, with allocation concealment obtained using opaque, sequentially numbered and sealed envelopes. Trials participants, care providers, data collectors, outcome assessors and data analysts will be blinded to treatment allocation. Patients will be evaluated on the day of hospital admission (day 0) and on days 2, 4, 6, 8, 12, and 14 with the following information being collected: daily oxycodone dose received; patient's perceived average and maximum pain using the Numerical Rating Scale (NRS: 0=no pain to 10=worst possible pain); pain relief using Pain Relief Scale (PRS: 0% no pain relief to 100% complete pain relief); characteristics of the pain, using the Neuropathic Pain Scale (NPS: 10 items); impact of pain on the patient's daily activities, using the Brief Pain Inventory (BPI; 9 items). A sample size calculation performed for the primary outcome showed that 150 patients (75 per group) are needed to achieve 90% power to detect a minimum reduction of 30% in oxycodone dosage in the experimental group, after allowing for a drop-out rate of around 20%. Ethical approval of the study protocol has been obtained from Comitato Etico Provinciale di Brescia, Brescia, Italy.

Official Title
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Magnesium Oral Supplementation to Reduce Pain in Patients With Severe Peripheral Arterial Occlusive Disease: The MAG-PAPER Randomized Clinical Trial

Conditions
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Peripheral Arterial Disease

Intervention / Treatment
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* Dietary Supplement: Magnesium oxide
* Dietary Supplement: Fructose
* Drug: Oxycodone
* Drug: Pregabalin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult patients (18 years or above) PAOD at stages III and IV according to the Lèriche-Fontaine classification no treatment with opioids at the time of recruitment Exclusion Criteria: renal failure (serum creatinine ≥ 2.0 mg/dl); congestive heart failure (New York Heart Association, NYHA > 3); treatment with digoxin and/or calcium channel blockers; pre-existing neuromuscular diseases; chronic diarrhea; acute limb ischemia successfully treated with interventional angiography, Fogarty embolectomy and/or surgical revascularization.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mg-group<br>Standard therapy plus magnesium oxide. Standard therapy: oxycodone 5 mg and pregabalin 25 mg per day for two weeks. Starting by day 2, the opioid dose will be titrated every 48 hours in order to reach the maximum therapeutic goal and to minimize side effects. A rescue dose: paracetamol 1g (maximum dose 3 g per day). | Dietary Supplement: Magnesium oxide<br>* Oral magnesium oxide 300 mg twice a day<br>Drug: Oxycodone<br>* Oxycodone hydrochloride 5 mg at 8 am<br>* Other names: Oxycontin, Mundipharma Pharmaceutic;Drug: Pregabalin<br>* Pregabalin 25 mg at 8 pm<br>* Other names: Lyrica, Pfizer Italia;|
| Placebo Comparator: C-group<br>Standard therapy plus fructose. Standard therapy: oxycodone 5 mg and pregabalin 25 mg per day for two weeks. Starting by day 2, the opioid dose will be titrated every 48 hours in order to reach the maximum therapeutic goal and to minimize side effects. A rescue dose: paracetamol 1g (maximum dose 3 g per day). | Dietary Supplement: Fructose<br>* Oral fructose 10 g twice a day<br>Drug: Oxycodone<br>* Oxycodone hydrochloride 5 mg at 8 am<br>* Other names: Oxycontin, Mundipharma Pharmaceutic;Drug: Pregabalin<br>* Pregabalin 25 mg at 8 pm<br>* Other names: Lyrica, Pfizer Italia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The oxycodone dosage needed to achieve satisfactory analgesia | Patient's satisfactory analgesia is defined as NRS ≤4 | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Level of pain relief | The level of pain relief is measured using Pain Relief Scale | 2 days | 
| Time to satisfactory analgesia | The time needed to achieve satisfactory analgesia (NRS≤4) | from 2 to 14 days | 
| Time to 50% reduction of pain | The time needed to achieve a reduction of pain of 50% using Pain Relief Scale(PRS = 50%) | from 2 to 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pain, Peripheral Arterial Disease, Magnesium Oxide