Iontophoretic administration of S(+)-ketamine in patients with neuropathic pain

The effective treatment of patients suffering from peripheral neuropathic pain
remains a clinical challenge (Mersey and Bogduk, 1994). Despite a standard
pharmacological approach (stepwise escalation of the WHO analgesic ladder
including opioids) in combination with first and second-line drugs such as
anticonvulsants, antidepressants, baclofen, α-adrenergic agonists, and oral
anesthetic antiarrhythmic agents, some of these patients experience severe
neuropathic pain.
In these patients, iontophoretic administration of S(+)-ketamine has to be
considered to decrease the neuropathic pain

At this time, iontophoretic administration of S(+)-ketamine is a already in use
as a treatment of peripheral neuropathic pain in several pain clinics In the
Netherlands (including the pain clinic at the Medical Center in Alkmaar).
Although this treatment is considered to be a valuable alternative, no
scientific evaluation has been performed regarding its efficacy. Additionally,
there is no knowledge available regarding a dose response curve.
The purpose of this randomized, double-blind, placebo controlled, crossover
study is to investigate the benefits regarding pain relief, health status, and
quality of life after administration of S(+)- ketamine by an
iontophoresis-assisted transdermal drug delivery system in patients with
peripheral neuropathic pain. In this study several doses of S(+)-ketamine (i.e.
placebo or 0 mg, 50 mg , 75 mg, and 100 mg S(+)-ketamine) will be evaluated.

Moncenter investigation
Randomized, double-blind, placebo controlled, crossover study

This trial will be conducted following a complete counterbalancing design.
Each patient will be treated with four different doses of S(+)-ketamine (0, 50,
75, and 100 mg) in a random treatment sequence. All possible treatment
sequences will be present within the study group.
Because 4 different doses will be evaluated, a total of 24 treatment sequences
are possible (4*3*2=24). In this view, 24 patients are necessary to perform
this study. With an estimated dropout of 15%, a total of 28 patients will be
randomized.
In this trial design, complete counterbalancing design, each patient will
function as his own control. The main advantage of this trial design is that
possible influences coming from suggestion or expectations by the patient will
be neutralized. Between treatments, a washout period of minimal two weeks will
be established.

Burden
Four treatments with different doses of S(+)-ketamine with 2 weeks interval
between two treatments. The trial will take 8 weeks. Before start of treatment,
patients will be evaluated using several questionnaires (30-45 minutes). Pain
intensity using a Pain diary: 5 minutes per day
Questionnaires and a neurological clinical examination of the patients before
each treatment: 30 minutes.
After each treatment: questionnaire (5 min) and a neurological clinical
examination (10 min).
One day following each treatment< three questionnaires: 20 min.

Risks

Ketamine is primarily in use as an anestheticum. The parenteral use of ketamine
may induce an increase in blood pressure and heart rhythm. In this trail
S(+)-ketamine will be given to treat neuropathic pain. In this context, the
dose is much lower and given through the skin using iontophoresis. The risks of
side effects are very low. It is, however, always possible that side effects,
as mentioned, may occur.
Possible side effects of S(+)-ketamine following parenteral administration are
decline in mood, conscious perception,
and intellectual performance, nightmares, and dizziness. No side effects,
however, occur following iontophoretic administration of S(+)-ketamine in
patients with central neuropathic pain.
Side effects are reversible and disappear after ending treatment with
S(+)-ketamine

Benefit
Iontophoretic administration of S(+)-ketamine may relief neuropathic pain. In
this view, patients may experience less pain following this treatment.