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).