A randomised controlled trial in the palliative setting regarding off-label medication: investigating the efficiency of amitriptyline versus pregabalin from a societal perspective

As a consequence of recent changes in the Dutch law about prescribing
medication, off-label use of drugs is allowed only based upon evidence, or
using standards or protocol. This study deals with neuropathic pain in
incurable cancer patients. The drug pregabalin has been registered for
neuropathic non-cancer pain. Amitriptyline is not registered for neuropathic
pain but is recommended as the drug of first choice in the Dutch handbooks of
palliative care. So far clinical trials for this patient group are lacking.
This study will show what stategy is appropriate for this patientpopulation.

To compare efficiency, side effects and costs of a strategy with amitriptyline
as drug of first choice versus a strategy with pregabalin as drug of first
choice.

An open-label, randomised non-inferiority trial

When a patient agrees to take part in the study and has given informed consent,
he will be allocated randomly to one of the two treatment groups. Each drug
will be dosed in a step up titration procedure. Patients will be followed
during 8 weeks.
Arm 1: amitriptyline will be prescribed in a step-up procedure. Starting dose
25 mg before the night, if not effective enough (less than 2 points improvement
on a NRS compared to the previous titration or NRS>3) and acceptable or no
side-effects, step up every 48 hours (till a maximum of 75 mg).
Arm 2: pregabalin will be prescribed, also in a step-up procedure. Starting
dose 2 dd 75 mg, if not effective enough (less than 2 points improvement on a
NRS compared to the previous titration or NRS>3) and acceptable or no side
effects, step up every 48 hours until a maximum dose of 2 dd 300 mg. If the
prescribed drug does not have the desierd effect:
- too less pain reduction on maximum daily dose: add drug of other arm in step
up procedure as described in protocol;
- major side-effects (meaning that the patient wants to stop the drug as a
result of the side-effects): stop drug that causes side-effects and start drug
of other arm in step up procedure as described above.
Additional drugs (e.g. PCM, opioids, NSAID, benzodiazepines) that the patient
already used or needs to start during the study period are allowed, except for
other TADs and AEDs. Palliative chemotherapy and radiotherapy are also allowed.
All medication will be recorded, including daily dose and route of
administration. All drug us is recorded.

Burden:
To distinguish neuropathic pain from other sorts of pain, the assessment of 2
assessors will be used. Next, patients suffering from neuropathic pain will be
asked to score a NRS.
When included, they will be asked to fill in a pain diary (NRS once a day,
number of episodes of break through pain once a day). The oncologist will be
asked to write down an overview of all medications and alternations at T0, T4
and T8. The research nurse keeps this information with him.
At T0, four weeks and eight weeks, the patient will be asked to fill in the
QLQc30, the Euroqol, BDI-PC and the McGill pain questionnaire, as well at the
moment he changes to the other arm of the study. At 4 and 8 weeks, the patient
will be asked to fill in the PGIC, and the oncologist to fill in the CGIC.

Risks:
We have chosen a design with hardly any or no risks for the patient. The drugs
in both arms already are usual care for the target population. If there is no
or just a too small effect, the drug of the other arm will be added, which
strategy also is already usual care. If the drug of the first arm causes to
many or to large side-effects, the drug will be stopped and we wil offer the
drug of the other arm. Finally, all other medication, except for TADs and AEDs,
as well as radiotherapy and chemotherapy are allowed.