Efficacy of Low Analgesic Doses of Ketamine Associated With Opioids in Refractory Cancer Pain Treatment (KEPAL)

• Patient Global Impression of Change/ Clinical Global Impression of Change [ Time Frame: 4 days ] [ Designated as safety issue: No ]
• Daily sleep interference score [ Time Frame: 4 days ] [ Designated as safety issue: No ]
• Patient satisfaction of pain relief [ Time Frame: 4 days ] [ Designated as safety issue: No ]
• Opioids consumption [ Time Frame: 4 days ] [ Designated as safety issue: No ]
• Evaluate the adverse effects of opioids-ketamine association versus opioids-placebo [ Time Frame: 4 days ] [ Designated as safety issue: Yes ]
  Number of Participants with Adverse Events as a Measure of Safety and Tolerability

Long-term opioid therapy is commonly administered for the management of severe cancer pain. Increasing doses of opioids are titrated against effects until analgesia is achieved or intolerable adverse effects occur. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been reported to improve analgesia in patients with uncontrolled pain receiving high doses of opioids. This study aims at determining the effectiveness of ketamine as an adjuvant to opioids in relieving cancer pain.

Main objective:

To show that low analgesic doses of ketamine in intravenous infusion during 4 days associated with opioids better relieve refractory cancer pain than opioids without ketamine.

This study is a prospective study, multicenter (11 centres), consisting of 3 phases:

• a randomized controlled double blind phase of 5 days with 2 parallel groups of 38 patients each : ketamine (in association with high opioids), in intravenous injection during 4 days, versus placebo (in association with high opioids), in intravenous injection during 4 days ;
• an open-label phase of maximum 4 days, during which the ketamine Panpharma® is administered in intravenous infusion to the hospitalized patients who are still having uncontrolled pain persisting or recurrent ;

• an observational phase : starting at the discharge of the patient, of a maximal period of 6 months.The inclusion period is during 18 months, the total duration of the study is 2 years.

  76 patients are expected: 38 will be treated with opioids and ketamine; 38 will be treated with opioids and a placebo.

Success is defined by a decrease of the daily pain score of 50 % after 4 days. The expected rate of success in the placebo group is 10 % whereas the expected rate of success in the ketamine group is 30 %.

Primary outcome (pain score on a 11-point numerical scale) will be evaluated everyday as well as secondary outcomes (patient and clinician global impression of change, opioid consumption, adverse reactions, patient satisfaction on pain relief, sleep interference score).

Vital parameters (cardiac frequency, respiratory frequency and arterial blood pressure) will be checked everyday, many times a day : every hour for the four hours after the beginning of the treatment and then, every four hours ; every hour for the two hours following a dose shift).

• Drug: Ketamine
  Drip continues of ketamine in intravenous injection included posology enters 0,5mg/kg /day and 2mg/kg/day during 4 days
  Other Name: Ketamine
• Drug: NaCl
  Drip continues of NaCl 0,9% in intravenous injection during 4 days
  Other Name: NaCl

• Experimental: Ketamine
  Ketamine PANFARMA
  Intervention: Drug: Ketamine
• Placebo Comparator: Not Ketamine
  NaCl
  Intervention: Drug: NaCl

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Inclusion Criteria:

• Hospitalized cancer patients (informed and conscious of the cancer diagnostic)
• Undergoing opioid treatment for 15 days at least
• Refractory pain (score higher than 5 on an 10-point numerical pain rating scale)
• Ability to score pain on a numerical pain rating scale
• Patient written agreement

Exclusion Criteria:

• Ketamine contraindications
• Methadone or other NMDA-antagonist treatment
• Karnofsky index under 10
• Pregnancy