Efficacy of Metamizole Versus Ibuprofen and a Short Educational Intervention Versus Standard Care in Acute Low Back Pain
Efficacy of Metamizole Versus Ibuprofen and a Short Educational Intervention Versus Standard Care in Acute Low Back Pain
The EMISI trial is a randomized, double blind, controlled trial (RCT) using a factorial
 design in patients with a new low back pain episode. The study aims to assess (A) whether
 metamizole, a non-opioid drug approved in Switzerland for pain treatment, is non-inferior to
 ibuprofen in a new episode of acute or subacute LBP and (B) whether a short educational
 intervention including evidence-based patient information is superior to usual care alone.
 Despite its increased use, the role of metamizole for the treatment of LBP is unclear and has
 so far not been systematically studied.
Purpose Low back pain (LBP) is among the top three most common diseases worldwide resulting
 in a life with pain-related disability. In patients with persistent LBP over 3 months, the
 risk for chronic pain increases dramatically and effective interventions should aim to
 prevent pain persistence without overtreatment. Therefore, during an acute LBP episode, the
 most common recommendations are to use pain medication to alleviate pain and to keep patients
 physically active. Non-opioid and opioid pain medication is increasingly used to control
 pain. Despite the frequency of LBP, only few high-quality studies assessed the efficacy of
 pain medication. Since the 1990s, the use of opioid pain medication for non-cancer pain has
 soared and resulted in an epidemic of opioid dependence and abuse in the U.S. This, despite
 the fact that randomized clinical trials found little or no additional efficacy of opioids
 compared to non-opioid medication in LBP. Moreover, opioids are associated with potentially
 severe side-effects, including confusion, sedation, respiratory depression and dependence.
 Therefore, non-opioid pain medications that are safe and effective are urgently needed to
 control pain.

 Non-steroidal anti-inflammatory drugs (NSAIDs) are considered to be effective for LBP and
 recommended by guidelines. However, adverse events including kidney injury and
 gastrointestinal bleeding, limit the use of NSAIDs in many patients. Metamizole is an
 effective non-opioid analgesic and antipyretic with a favorable gastrointestinal and renal
 safety profile and therefore, a valuable treatment option in many LBP patients with
 contraindications for NSAIDs. Metamizole has been increasingly used in many countries such as
 Germany, France, Spain, and Switzerland. Despite its increased use, the role of metamizole
 for the treatment of LBP is unclear and has so far not been systematically studied. This
 surprising lack of efficacy data may be due to an ongoing controversy over the risk of
 metamizole-associated agranulocytosis, a serious hematological adverse event. Even though the
 overall risk of agranulocytosis is increased compared to other drugs, it only occurs in a
 small proportion of susceptible patients and the overall safety profile of metamizole is
 still favorable compared to other analgesics such as NSAIDs or opioids, which carry their own
 specific risks.

 Many patients have reservations against regular intake of pain medication and limit physical
 activity to keep pain manageable without medication, which is against the guidelines'
 recommendation. However, education to encourage activity may help to improve pain control and
 function as well. In a busy primary care practice extended educational sessions that have
 been shown to be effective are not feasible. A short educational intervention that provides
 evidence-based information on the nature of LBP and promotes physical activity may also
 improve outcome.

 Objectives This study aims to assess (A) whether metamizole is non-inferior to ibuprofen in a
 new episode of acute or subacute LBP and (B) whether a short educational intervention
 including evidence-based patient information is superior to usual care alone.

 Methods The EMISI trial is a randomized, double-blind, controlled trial (RCT) using a
 factorial design recruiting patients consulting general practitioners (GP) practices and the
 outpatient Division of the Department of General Internal Medicine at the University Hospital
 Bern, Switzerland. Patients are randomized into one of four groups (1:1:1:1): metamizole +
 educational intervention vs. metamizole + standard care vs. ibuprofen + educational
 intervention vs. ibuprofen + standard care. Patients assigned to the educational information
 will receive an information leaflet and a phone call by a member of the research team to
 discuss evidence based information on LBP. All patients will receive usual care provided by
 their GPs that includes additional pain medications and non-pharmacological measures at the
 GPs discretion.

 The primary outcome (A) Comparison of ibuprofen vs. metamizole: change from baseline pain on
 the numeric rating scale (NRS) to day 14 (non-inferiority).

 B) Comparison of the short intervention vs. usual care: change from baseline Core Outcome
 Measures Index (COMI) sum-score to 42 days follow-up (superiority).

 Statistical analysis Analysis will include an intention-to-treat (ITT) and a per-protocol
 (PP) analysis for the comparison of the primary between metamizole and ibuprofen outcome (NRS
 change from baseline to follow-up at 14 days). Both analyses need to meet non-inferiority in
 order to claim success. The comparison of the primary outcome between the intervention and
 the usual care group (COMI change from baseline to day 42) will be performed according to
 intention-to-treat principle. Based on the sample size calculation for both interventions,
 120 patients will be included into the study.
Inclusion Criteria:

 -  Informed consent as documented by signature

 -  Age 18 years or older

 -  Seeking care for new onset of non-specific or specific LBP (pain duration of less than
 12 weeks LBP prior to the baseline visit)

 -  The GP plans to prescribe a non-opioid pain medication for pain control

 Exclusion Criteria:

 -  Presence of red flags (serious neurological deficit requiring surgery, infection,
 vertebral fracture)

 -  Active malignancy and / or history of a (previous) hematologic disorder (anemia
 (hemoglobin < 10.0 g/L), neutropenia or agranulocytosis, thrombocytopenia),

 -  Known contraindications against the study medications: heart failure (NYHA III-IV),
 liver failure (liver cirrhosis, ascites), renal insufficiency (estimated glomerular
 filtration rate (eGFR) < 60 ml/min/1,73 m2) or previous acute kidney injury (AKI stage
 2 according to the KDIGO definition), previous gastrointestinal ulcer, inflammatory
 bowel disease.

 -  Immune deficiency or under immunosuppressant treatment

 -  Current use of opioids

 -  Known intolerance to the study medication (i.e. previous acute allergic reaction to
 the study medication)

 -  Patients unable or unwilling to follow instructions or do not speak and are unable to
 read / understand German

 -  Patients unable to provide informed consent themselves

 -  Known or suspected non-compliance, drug or alcohol abuse

 -  Inability to follow study procedures, e.g. due to language problems, psychological
 disorders, dementia, etc.

 -  Participation in another study within the 30 days preceding the randomization and
 during the present study or previous enrolment into the current study

 -  Enrolment of the investigator, his/her family members, employees and other dependent
 persons

 -  Pregnancy: In women in the child bearing age a negative pregnancy test (urine or blood
 test as available in the primary care practice) before inclusion is required. Women
 who are not willing to use safe contraception (condom or birth control pill) during
 the course of the trial, intention to become pregnant during the trial, pregnancy, or
 breast feeding