Amitriptyline or Pregabalin to Treat Neuropathic Pain in Incurable Cancer

A Randomised Controlled Trial in the Palliative Setting Regarding Off-Label Medication: Investigating the Efficiency of Amitriptyline Versus Pregabalin From a Societal Perspective

Rationale: Often, incurable cancer patients suffer from severe symptoms as (neuropathic) pain and fatigue with polypharmaceutic interventions as a consequence. Regarding neuropathic pain in incurable cancer patients, pregabalin has been registered for neuropathic non-cancer pain, and amitriptyline is not registered for neuropathic pain, but is recommended as the drug of first choice in the Dutch handbooks of palliative care. As a consequence of an adaptation of a Dutch law (July 2007) about off-label medication prescription, off-label medication is not allowed anymore unless a standard or protocol exists. No clinical trials for this patient group have been published before.

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

Study design: An open label, randomised non-inferiority trial Study population: Incurable cancer patients with neuropathic pain Intervention: When a patient decides to take part in the study, he will be allocated randomly to one of the two study groups. A minimisation algorithm will be used, that balances for the cause of neuropathic pain (tumour related versus treatment related), type of treatment (ongoing chemo- or radiotherapy versus not ongoing chemo- or radiotherapy) and institution. Each drug will be prescribed in a step up procedure. Patients will be followed during 8 weeks.

Main study parameters/endpoints: Neuropathic pain, as measured with the mean VAS and McGill questionnaire, strategy success, costs per strategy, side effects, quality of life and concomitant analgesic drugs.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: There are hardly any risks for the patients. The drugs in both arms already are usual care for the target population. If there is no or a too small effect, the drug of the other arm will be added, which strategy also is already usual care. All other medication, except for Tricyclic Antidepressants Drugs (TADs) and Anti Epileptic Drugs (AEDs), as well as radiotherapy and chemotherapy are allowed. The patient has to visit the hospital 2 times during the study period. The patient had to fill in a pain diary daily (5 min), cost diary and EQ-5D every other week (10 min), related questionnaires as HADS, McGill and EORTC-QLQ-C30 monthly (20 min).

Inclusion Criteria:

• Age 18+
• Incurable cancer
• Life expectancy three months or longer
• NRS ≥ 4
• Neuropathic pain
• Adequate renal function with cockroft ≥ 60 ml/min
• Signed informed consent
• Expected adequacy of follow up

Exclusion Criteria:

• Previous use of TAD or AED for neuropathic pain within 30 days prior to screening
• Unstable regime of analgetica for 1 week prior to screening
• Use of cannabis
• Radiotherapy aimed at the source of the neuropathic pain 2 weeks before screening
• Chemotherapy with known neurotoxic effect (taxanes, thalidomide, vinca alkaloids, cytarabine,fluoropyrimidines, oxaliplatin) 2 weeks before screening
• Unstable regime of corticosteroids for 1 week prior to screening
• Pregnancy
• Any condition preventing the intake or absorption of oral drugs
• Participation in any other studies involving investigational products within the 30 days prior to screening