Influence of S(+)-ketamine on Diffuse Noxious Inhibitory Control (DNIC) and offset analgesia (OA) in chronic pain patients (neuropathic pain, complex regional pain syndrome type 1, fibromyalgia) and healthy volunteers

DNIC and offset analgesia. Pain perception is modulated via facilitatory and
inhibitory control systems. Inhibitory control is most important to chronic
pain patients as there are strong indications that failed inhibition
constitutes a predisposition to acquired chronic pain. Various systems involved
in inhibitory control have been demonstrated over the years. Two systems seem
important: (1) top-down inhibition of afferent noxious information by
endogenous analgesia originating in the periaquaductal grey (PAG) and affecting
pain perception via descending pathways; (2) bottom-up activation of pain
modulatory systems via activation of spino-bulbo-spinal loops originating in
the dorsal horn of the spinal cord. The effect that the latter system has on
pain perception is called Diffuse Noxious Inhibitory Control (DNIC). The two
systems are interconnected and DNIC is considered a bottom-up activation of the
pain modulatory mechanism, as part of the descending endogenous analgesia
system. DNIC dysfunctions or is less efficacious in various complex chronic
pain states, such as irritable bowel syndrome, chronic headache, fibromyalgia
and temporomandibular disorder. Little is known on DNIC in other evenly complex
chronic pain states such as neuropathic pain and Complex Regional Pain Syndrome
type 1 (CRPS-1).

Offset analgesia is another expression of the endogenous opioid system and is
evoked by noxious stimulation, in order to reduce (or control) the perception
of the noxious event. Offset analgesia becomes apart when an even more painful
stimulus occurs briefly during prolonged painful stimulation. Due to activation
of the endogenous opioid system the prolonged stimulation is perceived less
painful after the intense noxious stimulus than therefore. In day-to-day life
this exemplified by putting ones hand or foot in a warm bath. The heat
perception is reduced when taking out the extremity for just a short moment.
The activation of the endogenous opioid system now reduces pain perception.

CRPS-1 and neuropathic pain. Complex Regional Pain Syndrome Type-1 (CRPS-1) is
a chronic pain syndrome typically affecting an extremity after a local trauma
or surgical intervention. The initial phase of the syndrome is characterized by
pain, edema, changes in skin temperature and color, and hyperhydrosis. Although
the recovery rate of CRPS is unknown, a substantial number of patients develop
chronic disease with severe pain, disability, and loss of quality of life. In
the Netherlands the incidence of CRPS-1 is 26 per 100,000 person years, with
predominance in women. At present, the pathophysiology of CRPS-1 remains
largely unknown. In contrast to neuropathic chronic pain syndromes there is no
proof of a clinically evident nerve lesion as a causative factor in CRPS-1.
Neuropathic pain is due to an evident nerve lesion from trauma (incl. surgical
trauma), diabetes (small fiber neuropathy), infection (incl. HIV),
chemotherapy, etc. The primary sensation is a burning pain coinciding with
areas of hyperalgesia and allodynia.
S(+)-ketamine. We recently showed significant and long-lasting pain relief in
CRPS-1 patients using low-dose S(+)-ketamine treatment (Protocol P05.100).
Ketamine is an antagonist of the N-methyl-D-aspartate receptor (NMDAR). The
NMDAR is implicated in the development and maintenance of chronic pain states.
In several chronic pain states the NMDAR is activated and upregulated in the
spinal cord (central sensitization). This results in enhanced signal
transmission in the pain circuitry from the spinal cord to the cortex leading
to spontaneous pain, allodynia (pain perception from a non-noxious stimulus)
and hyperalgesia (increased pain sensitivity). Our observation in CRPS-1
patients suggests that ketamine*s beneficiary effect (that is, dechronification
of pain) is caused by desensitization of the NMDAR. How this relates to DNIC
and offset analgesia is unknown. While it has been suggested that DNIC and
offset analgesia are involved in the endogenous opioid-receptor system, a role
for the NMDAR is not excluded. In fact, the close relation between chronic pain
(with a causal role for an activated/upregulated NMDAR) and a reduced DNIC
implicitly suggests a role for the NMDAR in DNIC/offset analgesia.

1. Measure DNIC and offset analgesia in CRPS-1 patients, fibromyalgia patients
and neuropathic pain patients;

2. Compare DNIC and offset analgesia in chronic pain patients with DNIC and
offset analgesia in healthy volunteers;

3. Assess the effect of low-dose S(+)-ketamine on DNIC and offset analgesia.

Open-label, observational study design

A 1-h infusion with low dose S(+)-ketamine

Nausea. There is a chance that the subjects become nauseated. In that case they
will receive 4 mg iv ondansentron (Zofran), a potent antiemetic. This will not
end the study.

Psychomimetic side effects (ketamine). S(+)-ketamine may cause psychedelic side
effects such as hallucinations, vivid dreams, feeling of inebriation,
confusion, drowsiness, and dizziness. All of these side effects are temporarily
and will disappear spontaneously or after discontinuation of the S(+)-ketamine
infusion. We are currently performing a S(+)-ketamine study (08.075) and have
now some additional knowledge on the psychomimetic effects of the S(+)-variant
of ketamine. The psychomimetic effects of S(+)-ketamine are minimal with some
dizziness as most pronounced side effect. If side effects occur they do so only
after prolonged infusion. Hence we do not expect serious problems from
S(+)-ketamine with respect to psychomimetic side effects in our current study.
We cannot exclude, however, that some hallucinations or vivid dreams during the
ketamine infusion occur. They will dissappear upon the termination of the
infusion. In case such side effect does occur in our study, the infusion of
ketamine will immediately be terminated and the study will continue without
further drug infusion.