Duloxetine for chronic osteoarthritis pain; an important alternative?

Osteoarthritis (OA) is a highly prevalent chronic condition of the
musculoskeletal system. In the Dutch population it is the single largest
contributing factor to a decreased physical wellbeing. The vast majority of
patients suffering from OA are treated in a primary care setting. The general
practitioner (GP) plays a key role in the treatment of pain, the most
debilitating symptom of this condition. Currently, usual care by GP*s consists
of education, exercise training and pain medication in the form of paracetamol,
NSAID*s or opioids. Thus far, however, the effectiveness of symptomatic
treatment has proven to be limited. Improved analgesic treatment is therefore
needed, especially since there are no treatment options available aimed at
delaying or halting progression of the disease, with the exception of surgical
joint-replacement, an intervention not only costly but also of limited
durability.
Until now, the effectiveness of analgesia in OA has only been studied for the
total population of OA patients. However, there are strong indications of
specific subgroups, especially with regard to pain symptomatology. Pain in OA
consists of nociceptive pain in the joint itself, peripheral sensitized pain
from locally generated inflammatory factors, and centrally sensitized pain.
Central sensitization, sometimes called neuropathic pain, leads to
hypersensitivity to pain. Inhibition of descending input from the brain stem
operates through norepinephrine and serotonin. Disinhibition of this descending
input contributes to central sensitization. This type of pain, or sensitized
pain mechanism, is present in a large percentage of OA patients with chronic
pain (37%) and is probably responding particularly poorly to currently
available analgesia, as it requires medication with a centrally acting effect.
A common given analgesic for non-OA neuropathic pain is amitriptyline in the
Netherlands. However, there are no randomized placebo controlled trials about
the efficacy of amitriptyline for chronic pain in knee or hip OA. Moreover, in
the recent guidelines of the Osteoarthritis Research Society International
(OARSI) for non-surgical management of knee OA, duloxetine is recommended for
individuals. Duloxetine is traditionally an antidepressant, which in the
Netherlands is also indicated for the treatment of diabetic peripheral
neuropathy. Duloxetine and amitriptyline belong to a different medication
group. Duloxetine is a serotonin norepinephrine reuptake inhibitor (SNRI) and
the mechanism is that it strengthens the inhibition of the descending input,
while amitriptyline is a tricyclic antidepressant (TCA) of which the actual
mechanism is not completely clear; hypothesized is that it inhibits the
reuptake of serotonin and norepinephrine, but less selectively than an SNRI.
Several randomized placebo-controlled trials have now demonstrated the efficacy
of low dose duloxetine versus placebo in the treatment of pain in OA
(clinically relevant effect sizes of 0.5 for pain of OA, 0.6 for disability of
OA and 0.4 of average pain of OA). These trials are short-term (10-16 weeks)
randomized placebo-controlled trials in a highly controlled secondary care
setting. Not known is the effectiveness of duloxetine as third choice analgesia
in a pragmatic and primary care setting. Neither is clear, whether the efficacy
of duloxetine is predominantly found in those patients suffering from
neuropathic pain, or whether duloxetine as a third choice analgesia in primary
care is cost-effective. Measurements of neuropathic pain traditionally required
sophisticated quantitative measurements not suited for use in clinical
practice. However, a simple questionnaire modified for OA (modified painDETECT)
which can be applied in a GP setting, has recently been demonstrated to
correspond well with such traditional, more extensive measurements. Knees with
higher modified painDETECT scores (>12.0) had higher odds of having signs of
central sensitization.
Currently, besides education, lifestyle advice, physiotherapy and dietary
therapy, the usual care of the GP follows a stepped approach when prescribing
analgesics in patients with chronic OA pain. Paracetamol is the first treatment
option, as it is relatively safe and has few contraindications. If the
analgesic effect of paracetamol proves to be insufficient, GP*s have the option
of prescribing non-steroidal anti-inflammatory drugs (NSAID*s), and
subsequently tramadol or other opioids. However, these medications are often
contraindicated, particularly in elderly patients, and they are associated with
the occurrence of serious adverse reactions. The availability of well
indicated, effective and relatively safe medicine, to be used when current
analgesic options fail, would help to improve the quality of life in these
chronic pain patients and would allow GP*s to deliver better and more targeted
care. In the long term, this could potentially help postpone the need for a
joint-replacement and revision surgery, whilst retaining quality of life.

The objective of this proposal is to investigate if duloxetine is effective as
a third choice pain medication for treating chronic pain in OA compared to
usual care. Furthermore, we will assess the cost-effectiveness of duloxetine
treatment and if the presence of neuropathic pain will be necessary for
(cost)-effectiveness.

Open-labeled cluster randomized controlled trial with a follow-up period of one
year.

Patients in the intervention group will be treated with duloxetine 60mg once a
day during one year in addition to usual care. Patients in the control group
will receive care as usual.
Usual care consists of analgesics (according to the NHG farmacotherapeutische
richlijn pijnbestrijding), education, lifestyle advice, physiotherapy and
dietary therapy.

Patients receiving duloxetine may benefit from the analgesic effect of
duloxetine. Patients in the intervention arm may experience side-effects of
duloxetine. Duloxetine is a registered drug in the Netherlands and side-effects
are well known. In addition, is studies with duloxetine in OA patients no
unexpected side-effects occurred.
The control group receives usual care according to the guidelines; there is no
additional burden expected in this group.
In both groups patients have to answer questionnaires during six moments in the
study; patients may experience this as a burden.