Paracetamol or NSAID's in acute musculoskeletal syndromes

In The Netherlands, each year approximately 3.1 million injuries are treated
medically. This mainly consists of sports related (1.4 million) and private
(1.2 million) injuries. Most of these injuries are musculoskeletal injuries,
without a fracture, often called sprains, contusions or acute musculoskeletal
syndromes. Patients with acute musculoskeletal injuries are distributed
throughout the whole population.
They can have any age, sex or cultural background. They are frequently treated
by a general practitioner or an emergency physician. Pain management is a
crucial part of this treatment. Different drugs can be used for this purpose.
Often used are paracetamol and Non-Steroidal Anti-Inflammatory Drugs (NSAID's).
Which of the drugs (paracetamol or NSAID's) the treating physician prescribes,
often depends on the experience and preference of the physician. To guide staff
treating acute patients, in 2010 the Dutch Institute for Healthcare Improvement
CBO published a guideline on treating pain in trauma patients. The authors of
this guideline mention that there is a preference for paracetamol in treating
pain in minor trauma and acute musculoskeletal syndromes. However, as also
mentioned in the guideline, this is solely based on two studies with a low
level of evidence. In order to fill up this gap in medical literature, there is
need for confirmative evidence that paracetamol works as well as NSAID's in
managing pain after acute musculoskeletal syndromes. By doing the current
project, the research group aims to deliver a high level of evidence (A2) study
answering the question whether patients with acute musculoskeletal syndromes
should be treated with paracetamol or NSAIDs.
Besides the question which drug is most effective in patients with acute
musculoskeletal syndromes, even more important is the fact that the use of both
drugs can have detrimental side effects.
Paracetamol is an analgesic and antipyretic, the exact mechanism of action is
not known, but it should be used wisely, as it is one of the world's main
causes of consecutive liver failure. Paracetamol is used frequently in home
situations and is part of combination preparations without knowledge of many
users.
NSAID's are drugs with analgesic and antipyretic effects and, in higher doses,
they also have anti-inflammatory effects. They inhibit the enzyme
cyclooxygenase (COX), which catalyzes the formation of prostaglandins and
thromboxane. In the process of pain, prostaglandins cause local vasodilation
and increased permeability of capillaries leading to edema. Other effects are
increased sensitivity of local sensible nerves and stimulation of the
temperature centre in the hypothalamus causing fever. The inflammatory
processes can cause damage in cartilage and bone tissue. As described in the
"Farmacotherapeutisch Kompas", a publication of the CVZ (College voor
Zorgverzekeringen), the indications for prescribing NSAID's are, among others,
inflammatory-like and degenerative disorders as well as traumatic disorders as
sprains and contusions. NSAIDs can have several potentially severe side
effects, especially in older patients, such as GI bleeding, renal failure,
bronchospasm and heart failure with additional medical costs. Annually,
according to the HARM study in 21 Dutch hospitals, a considerable proportion of
5.6% of all unplanned admissions in Dutch hospitals is medication related.
Internationally, these numbers are comparable. Half of these admissions are
potentially preventable. The medications most often involved in these
potentially preventable admissions are, besides anticoagulants, the NSAIDs.
Reasons for hospitalization are mainly gastrointestinal tract problems (6.6%
due to gastrointestinal bleeding) and cardiovascular problems. Of the
potentially preventable admissions, 70% of the patients recovered completely,
however 6.3% died and 9.3% experienced a disability after discharge and in 14%
the outcome was uncertain at the time of discharge.
Besides the need for most effective treatment of pain after acute
musculoskeletal syndromes, even more important is the safety profile of both
medications mentioned. The hypothesis of our study is: paracetamol is as
effective as an NSAID, but with a lower incidence of adverse events.
If the current study can point out that paracetamol is as effective as an NSAID
in treating acute musculoskeletal injuries, this could be a very useful
supplement to the guideline of the CBO and an evidence based way of decreasing
additional costs of the use of NSAID's and their adverse events.

The objective of the current study is to compare three different strategies of
pain management in patients presenting to an emergency department and to a
general practice with acute musculoskeletal syndromes (defined as
musculoskeletal complaints after sustaining an injury with exclusion of a
fracture). The strategies of pain management which will be compared are
paracetamol, diclofenac and the combination of paracetamol and diclofenac.

It will be a double-blind, randomized controlled trial with a non-inferiority
and superiority design.

Randomization
Blinded for the recruiter, the physicians and nurses and all other staff and
personnel, as well as the patients themselves, patients are allocated to one of
the three pharmacological treatments in a randomized fashion using a
computerized randomization scheme. In order to ensure equal treatment
allocation in the groups of subjects younger and subjects older then 60 years,
block-randomization is used. All patients are analyzed on an intention-to-treat
basis.

Study medication
The moment of the first pain score and subsequent administration of the study
drugs is marked as T0. All study drugs will be administed orally. All tablets
will have a uniform appearance, prepared in advance by the pharmacy.
Distribution and control of the study medication at the emergency department as
well at Gezondheidscentrum Gein is the responsibility of the pharmacy of the
AMC, experienced with studies involving medication. The patients will receive
two tablets X and one tablet Y. Tablet X will contain paracetamol 500 mg or
paracetamol-like placebo. Tablet Y will contain diclofenac 50 mg or
diclofenac-like placebo. Because the packages containing the study drugs are
prefabricated, possible combinations that the patients can receive will be:
1. paracetamol 1000 mg + diclofenac-like placebo.
2. paracetamol 1000 mg + diclofenac 50 mg.
3. paracetamol-like placebo + diclofenac 50 mg.

By producing the packages in advance in the pharmacy, the combination of
paracetamol-like placebo and diclofenac-like placebo is ruled out, as it is
deemed unethically to withhold patients pain medication in painful injuries.
Besides these drugs, all patients will receive a Proton Pump Inhibitor (PPI);
Omeprazol 20mg orally, this will not be blinded.
The CBO guideline "Use of NSAIDs and prevention of peptic injury" advises
prescribing PPIs in all patients older then 70 years; a past history of peptic
ulcer or untreated H. pylori infection. The guideline also states that a PPI
should be administered when prescribing NSAIDs in patients 60-70 years old; use
of anticoagulants; severe rheumatoid arthritis; heart failure or diabetes; use
of corticosteroids or Selective Serotonine Re-Uptake Inhibitors (SSRIs). As we
aim to treat all patients the same, we choose to administer the PPI to all
study subjects. The alternative would be to exclude all patients with higher
risk of NSAID-related GI-events, however, as we are highly interested in the
group of elderly patients in a subgroup analysis, this is not feasible.
On discharge, patients will receive a package of study drugs. This package will
contain the same combination of (blinded) study medication as they got in the
emergency department or in the general practice, but it will be according to a
schedule during three consecutive days. They will take two capsules X four
times a day and capsule Y three times a day. Possible combinations will be:
1. 4x Paracetamol 1000 mg + 3x Diclofenac-like placebo
2. 4x Paracetamol 1000 mg + 3x Diclofenac 50 mg
3. 4x Paracetamol-like placebo + 3x Diclofenac 50 mg
This means all patients will take home a package of 22 capsules X and 8
capsules Y, which they will be advised to use during three days. Besides this,
the patient will use a PPI (Omeprazol 20mg once daily) during these three days.

Data collection
Besides all baseline characteristics and occurrence of adverse events, the
primary outcome, pain, will be measured using the Numeric Rating Scale (NRS) on
a standardized form by the treating physician, the research or treating nurse
or a research associate, who are all trained in and educated about the study.
Pain will be measured at time of inclusion and at fixed times (30, 60 and 90
minutes after study drug administration). Pain scores will be measured in rest
and with active or passive movement of the extremity involved. When pain relief
is insufficient and the patient / treating physician would like to give
additional pain medication, this is documented. The choice of the additional
pain medication is on the discretion of the treating physician (for example
Tramadol or Morfine orally; or Fentanyl or Morfine IV in the emergency
department). When deemed necessary by the treating physician, the randomization
code can be revealed and the study drugs unblinded. As the alternative pain
medication is frequently used in daily practice, the latter is not expected to
occur.
At the same fixed intervals as the pain scores, the patients will be asked for
potential adverse events. After recording the final set of pain scores and
questions regarding potential adverse events the patients are discharged home,
as soon as regular care is also finished. Patient satisfaction about pain
relief will be documented using a 5-point Likert scale.
All patients will also receive a pain diary. This is a booklet in which the
patients can record their own pain scores using the NRS and potential adverse
events they experience while using the study drugs. All will be on standardized
forms. Patients are instructed on how to use the diary and how to record the
pain scores and potential adverse events. They will also receive information
regarding contacting an independent physician with questions about the study or
termination of participation. They will receive instructions on what to do when
adverse events will happen or when pain management is insufficient. After 1-3
days after discharge the patients will be contacted by a research nurse or
research associate (who are also blinded to the study medication) to evaluate
all recorded data and the diary is obtained by the nurse or associate. After
5-8 days a house visit is planned, or a telephone call is made to evaluate the
clinical course. After one month, the research assistant will have contact with
the patients for the last time to fill in the EQ5D questionnaire. After this
contact, the study ends for the patient. In the economic evaluation, factors
that are analyzed are medication costs, need for additional pain medication,
occurrence of adverse events and incidence of hospitalization due to medication
related adverse events.

The three possible interventions patients can be allocated for are (as
described above under the section 'Study design');
1. Paracetamol 1000mg + Diclofenac-like placebo
2. Paracetamol-like placebo + Diclofenac 50mg
3. Paracetamol 1000mg + Diclofenac 50mg
All study drugs are blinded for the patient, the treating physician and all
other research or clinical staff. Besides this study medication, all patients
will receive Omeprazol 20mg (not blinded). All study drugs will be administered
orally.

After discharge from the Emergency Department or the General Practice, patients
will take the same combination of (blinded) study medication as they already
received, according to a schedule during three consecutive days. The three
different schedules will be:
1. Paracetamol 1000 mg four times daily + Diclofenac-like placebo three times
daily
2. Paracetamol-like placebo four times daily + Diclofenac 50 mg three times
daily
3. Paracetamol 1000 mg four times daily + Diclofenac 50 mg three times daily
All study drugs are blinded, except for the Omeprazol 20 mg, which all patients
take once daily during the three days they take the study medication.

All patients who participate risk the occurrence of known side effects of the
drugs allocated for, as described in the Investigator*s Brochure text. This
risk is the same as in daily practice and probably even smaller, as all
individuals will receive proton pump inhibitors to protect patients from
gastric damage from the NSAID*s.