D-Cycloserine in Chronic
Pain
: Preclinical Studies
Millecamps et al. showed that d-cycloserine (DCS), a partial agonist at
the NMDA receptor and a component of NRX-101, dose-dependently reduced
mechanical sensitivity in rats with spared nerve
injury.43 Infusions of DCS directly into the medial
prefrontal cortex or amygdala (but not into other brain regions) induced
antinociception in rats subjected to spared nerve injury. This
antinociceptive effect was mimicked by a combination of NMDA and glycine
and blocked by a selective antagonist of the glycine site of the NMDA
receptor, HA-966. Moreover, spared nerve injury caused a down-regulation
of NR2B subunit expression in the medial prefrontal cortex, which was
reversed with repeated oral administration of DCS. In addition, repeated
oral DCS administration also reduced cancer chemotherapy drug-induced
neuropathic pain behavior.43 Importantly, infusions of
DCS into mPFC reversed place avoidance behavior induced by mechanical
stimulation of the injured paw rats with spared nerve injury. DCS
reduced pain-like symptoms by about 50%, but the rats behaved as if the
remaining pain does not bother them, suggesting that DCS reduced the
emotional impact of the neuropathic pain.43,44
In separate work, Walker et al. showed that DCS facilitates extinction
of conditioned fear (fear-potentiated startle) after either systemic
injections or intra-amygdala infusions.45 This
facilitation was blocked by HA-966. The criticality of NMDA receptors in
the prelimbic cortex for the maintenance of neuropathic pain has been
confirmed through the use of a selective NMDA receptor antagonist,
LY235959.46 These findings have been confirmed by
intraperitoneal administration of DCS in the Wistar Kyoto (WKY) rodent
model of conditioned fear (NRx Pharmaceuticals, data on file).
D-cycloserine potentially decreases opioid
cravings
Opioid withdrawal involves both physical and psychological components,
similar to other substance use disorders. Patients may be able to
overcome physiological effects of withdrawal, only to relapse after
being exposed to drug-taking triggers.47Naloxone-induced conditioned place aversion is an animal model of this
form of opioid craving.48 When the opioid antagonist,
naloxone, is given to opioid-dependent rats, it triggers an immediate
withdrawal syndrome. If rats are confined to a specific area on the test
apparatus during acute withdrawal, they develop an aversion to that
location. When allowed to move freely in the test apparatus, they will
avoid the area that is now associated with withdrawal. Extinction is a
means of reducing conditioned responses and involves exposure to the
conditioned stimulus in the absence of the unconditioned stimulus with
which it was paired previously. Using this model, Myers and Carlezon
showed that opioid-dependent animals were slow to extinguish their
memory of the conditioned stimulus; however, administration of DCS
accelerated this extinction. The authors conclude that DCS facilitates
extinction of morphine withdrawal-associated place
aversion.49
Clinical Experience with DCS and Chronic
Pain
Schnitzer et al. performed randomized, double-blind, placebo-controlled
pilot study of the efficacy and safety of D-cycloserine in 41 people
with chronic back pain.44 Patients in the active arm
received daily oral doses of D-cycloserine. Participants sequentially
received 100 mg, 200 mg, and 400 mg for two weeks. Various pain scales
were assessed before and after the six-week study. The primary endpoint
(Numeric Rating Scale) improved by 1.05±3.1 units in the DCS group than
in placebo. The results failed to reach statistical significance
(p=0.14) overall, though the effect size was 0.4. However, at the
highest administered dose of DCS (400mg/day), a
statistically-significant (P=0.02) reduction in pain was seen compared
to placebo (Figure 2). This threshold dosage corresponds to the 25µg/ml
blood level identified by Javitt as the threshold at which DCS saturates
the glycine modulatory sites on the NMDA receptor and begins functioning
as an NMDA antagonist. Based on these results, the Schnitzer group has
embarked on a larger clinical trial using the 400 mg dose of DCS in over
200 patients with chronic pain (NCT03535688).