Treatment of Complex Regional Pain Syndrome type I;A randomised, double-blind, placebo-controlled study with multiple rounds of S(+)-ketamine infusions (The Ket Ket Study)

Treatment of CRPS-1 has proven to be extremely difficult. Since the cause of
CRPS-1 is unknown there is no direct action against the causative agent
possible. Many treatment modalities have been proposed, alone or in
combination, such as physiotherapy, oral medication (incl. analgesics,
antidepressants, antioxidants), sympathetic block, and epidural analgesia.
Treatment remains largely empirical and symptomatic, with frequently only
marginal effectiveness. Recently investigations focused on the use of ketamine
in CRPS-1.

Primary aim:
The primary aim of this study is to evaluate the effect of two consecutive
infusions of S(+)-ketamine in patients with CRPS-I on pain relief. The design
of the study is prospective, randomised, double-blind and placebo-controlled.


Secondary aims of this study are:
• To establish the effect of S(+)-ketamine on sensory, autonomic and motor
disturbances in
CRPS-1 patients.
• To establish the side effect profile of multiple S(+)-ketamine infusions.

5.1 Design of the pilot study (see also Table 1)
The pilot study will consist of 5 groups:
• Group 1: patients will be admitted in week 1 and week 4 and will receive
S(+)-ketamine on
both occasions. The total study duration will be 52 weeks.
• Group 2: patients will be admitted in week 1 and week 13 and will receive
S(+)-ketamine
on both occasions. The total study duration will be 52 weeks.
• Group 3: patients will be admitted in week 1 and week 13. In week 1 patients
will receive
an active placebo and in week 13 S(+)-ketamine. The total study duration
will be 52 weeks.
• Group 4: historical control-patients who participated in the previous
clinical trial (P05.100).
They received a single S(+)-ketamine infusion at week 1. The study duration
was in total
12 weeks.
• Group 5: historical control-patients who participated in the previous
clinical trial (P05.100).
They received a single placebo (saline) infusion at week 1. The study
duration was in total
12 weeks.
Patients in Groups 1 to 3 will be admitted twice for 5 days, during which a
continuous intravenous infusion will take place with S(+)-ketamine or active
placebo.
Because of different weeks of admission, the study will be performed
single-blinded.
Table 1 shows the schematic overview of the pilot design.


5.2 Clinical trial design (see also Table 2)
Patients will be recruited and randomized into 2 groups. Both groups will be
admitted twice for 5 days, during which intravenous continuous infusions will
take place with S(+)-ketamine or (active) placebo.

• Group 1 will be admitted in week 1 and week x (week x will be determined from
the pilot
study) and will receive S(+)-ketamine on both occasions.
• Group 2 will be admitted in week 1 and week x and will receive S(+)-ketamine
in week 1
and (active) placebo in week x.

The first infusion will be performed single-blinded and the second infusion
will be performed double-blinded. Because we expect longstanding positive
effects of S(+)-ketamine on pain scores, the total duration of the study will
be 52 weeks.

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