Effectiveness of Ketamine in Malignant Neuropathic Pain Relief

To see whether the addition of low-dose ketamine to a subcutaneous morphine infusion improves analgesia in patients with neuropathic cancer pain.

Patients with cancer pain judged to have a neuropathic component and receiving pain treatment with a subcutaneous infusion of morphine will be included in a randomized, double blind, placebo-controlled, crossover study. All patients will be recruited from hospital wards (Haukeland University Hospital, Bergen). In the case of patient withdrawal or dropout, new patients will be recruited so that the total number of patients completing the study will be 20. Data from patients not completing the study will solely be used to provide information about adverse effects.

The basic treatment with subcutaneous morphine infusion will be supplemented with a separate subcutaneous infusion of ketamine 1 mg/kg/ 24 hours or NaCl 9 mg/ml (placebo).

After 48 hours (phase 1) there will be a "wash-out" period of minimum 10 hours to minimize carryover effects before the treatment is replaced by the alternative treatment for a further 48 hours (phase 2) in a standard crossover design. The treatment duration is based on ketamine's short plasma half-life which is less than 2 hours after initial equilibration.

Pain intensity (using NRS) will be recorded at rest and on movement x 4 daily. Rescue medication in the form of morphine subcutaneous bolus may be given to the patient as required. There will be a" lockout" time of 1 hour which means that the rescue dose of morphine can be repeated every 60 minutes if necessary, providing the patient is awake and has a respiratory rate of 8 or more per minute.Randomization will be performed by Haukeland University Hospital Pharmacy. The study drug/ placebo will also be prepared by the hospital pharmacy according to a standard instruction.

Eligibility Criteria:
Inclusion Criteria:

Age 18-70 years. In-patient. Cancer pain judged to have a neuropathic component. Clinically normal renal and hepatic function. Able to cooperate and understand information. Worst pain at rest or on movement 5 or more (NRS 0-10). Pain currently treated with continuous subcutaneous morphine infusion. The daily morphine dose is 48mg or more per 24 hours and a 30% increase in the daily dose has not provided sufficient pain relief.

Not treated with ketamine during the last 48 hours prior to inclusion.

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Exclusion Criteria:

Reduced renal or hepatic function. Suspicion of morphine toxicity (sedation, hallucination, myoclonus, increasing pain).

Increased intracranial pressure (suspicion of cerebral metastases) or cerebral metastases.

Unable to cooperate/ understand information. Worst pain at rest or on movement less than 5 on NRS. Current treatment with other opioids than morphine. The patient is undergoing radiotherapy in the pain area, or has received radiotherapy in the pain area within the last four weeks.

Changes in the use of analgesics (paracetamol, NSAIDS), adjuvant drugs (antidepressants, antiepileptic, corticosteroids, muscle relaxants) or their dosages less than 2 days prior to inclusion or during the study period.

Pregnant and lactating women. Any situation in which an increase in blood pressure would constitute a hazard. Acute intermittent porphyria. Psychiatric illness, epilepsy, alcoholism, glaucoma. Hypersensitivity to any of the drugs ingredients. Current treatment with ketamine.

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