Can DCS be Clinically Useful in Chronic Pain?

DCS has been used as an antituberculosis agent for at least sixty years. In 2018, the World Health Organization (WHO) recommended DCS as one of the Group B drugs for tuberculosis (TB). In multidrug-resistant TB, the WHO recommends DCS as one of group of antituberculosis drugs to be used in the first-line longer term, treatment regimen.50While DCS has a multi-decade history of safe use in patients, chronic use of higher doses can be associated with neuropsychiatric symptoms51 of which, hallucination and mania are by far the most concerning.52,53 Since DCS would presumably need to be administered sub-acutely or chronically to effectively treat chronic pain, this toxicity could potentially be treatment-limiting.
One approach to minimize neuropsychiatric symptoms is to combine DCS with serotonergic drugs, including SSRI and 5-HT2Aantagonist antidepressants. Both classes of drugs are routinely used on a long-term basis in the treatment of depression and 5-HT2A antagonists at higher doses are used as atypical antipsychotics. Lurasidone has one of the most favorable side-effect profiles among 5-HT2A antagonist drugs, lacking anticholinergic or metabolic side effects that are otherwise common in the drug class.54 However, it must be acknowledged that lurasidone is associated with potential for akathisia.55 Interestingly, DCS and lurasidone appear to mitigate the most common side effects of the other; lurasidone reduces the risk of psychosis and mania while DCS reduces the occurrence of akathisia.56 Thus, when lurasidone and DCS are administered together, the risk of the treatment-limiting toxicities is diminished.

Lurasidone in Chronic Pain

Aside from its role in modulating the hallucinations that may be induced by DCS and other NMDA antagonists, lurasidone may be useful as a treatment for chronic pain in its own right. Lurasidone is a full antagonist at dopamine D2 and serotonin 5-HT2A and 5-HT7 receptors.57 Compared to other antipsychotics, lurasidone has the highest binding affinity for 5-HT7 receptors.54 Peripheral serotonin (5-HT) mediates and potentiates pain58,59whether through direct tissue injection60,61 or through the use of pain models that raise serotonin levels.62,63 Using peripheral 5-HT as a model of pain, Abbott et al. showed 5-HT2A antagonists may be effective as peripherally acting analgesic agents and/or analgesic adjuncts.64 Using chronic constriction injury of the sciatic nerve in rats, Nitada et al. demonstrated that the 5-HT2A receptor antagonist sarpogrelate, specifically ameliorated hyperalgesia without affecting the normal nociception.65 5-HT2A receptors are involved in the sensitization of peripheral nociceptors and spinal nociceptive processing in chemotherapeutic-induced neuropathy, an effect that is blocked by the 5-HT2A receptor antagonist, MDL 11,939.66
The role of 5-HT7 receptors in acute and chronic pain processing is complex.67 Evidence suggests 5-HT7 receptors play a pronociceptive role in chronic pain models and that blocking 5-HT7 receptors may be therapeutic in chronic pain. For example, tactile allodynia induced by L5/L6 spinal nerve ligation could be dose-dependently blocked by the selective 5-HT7 receptor antagonist, SB-269970.68 Peripheral activation of 5-HT7 receptors increases c-Fos levels in rat dorsal horn of spinal cord of rats, a process that is blocked by pre-administration of a selective 5-HT7 antagonist.69 The selective 5-HT7 antagonist SB 269970 reduces nociceptive behavior induced by formalin70 and inhibits mechanical allodynia induced by 5-HT.71 Likewise, 5-HT2A antagonists spiperone, ketanserin and ritanserin effectively blocked the pain response produced by α-methyl-5-HT and prostaglandin E2, suggesting that 5-HT2A antagonists may be effective as analgesics or analgesic adjuncts.64
Growing evidence shows that antipsychotics play a role in chronic pain management. Reports since the 1970s indicate haloperidol can relieve chronic lower back pain72 or refractory chronic facial pain.73 In a review of the published clinical literature, Jimenez et al. reported that various atypical antipsychotics are effective in treating various forms of chronic pain.74

Additional Synergies of DCS and Lurasidone: Chronic Pain and Depression

Chronic pain and depression are frequently comorbid. Studies in psychiatry75 and neurology76 clinics show that the prevalence of pain in depressed patients is 60 to 75%. The mean prevalence for major depression in patients is 52% in pain clinics, 56% in orthopedic clinics, and 85% in dental/facial pain clinics.77 In a review of over 30,000 adults across four continents, patients who have experienced pain for greater than 6 months are more than 4 times as likely to have a depressive disorder than those without chronic pain.78 When pain is moderate or severe or refractory to treatment it is more strongly associated with depression and poorer depression outcomes.77,79 Conversely, the treatment of depression can improve chronic pain outcomes,80,81 an effect that further highlights the close relationship between the two clinical entities.
Not only do pain and depression often co-occur, each tends to exacerbate the other, both subjectively and objectively. Severe depression intensifies the perception of pain82 and makes traditional treatments less effective.83 On the other hand, chronic pain influences the severity and treatment of depression.84 It is often more difficult to treat depression in someone with chronic pain than someone who is without pain.85 Depression is an independent risk factor for poor quality of life in people with chronic musculoskeletal pain.86 Importantly, the risk of suicide is very high in patients with both chronic pain and depression.87
Chronic pain and depression are so strongly linked that it is unclear which process begets the other.79,84,88 Indeed, the two conditions share common neurobiological pathways.77 Higher pain processing centers include the anterior cingulate cortex, prefrontal cortex, insular cortex, amygdala, thalamus, cerebellum, and periaqueductal gray. The emotional aspects of pain are served by these areas along with the ventral tegmental area and nucleus accumbens.89 The amygdala is critical for the processing of stress, depression, and persistent pain.90,91
Given the strong neurobiological and clinical link between depression and chronic pain, several groups have argued that the treatment of depression should be considered part of a comprehensive strategy for the treatment of chronic pain.81,88,92 In light of this, the combination of DCS and lurasidone may not only treat chronic pain at various levels of the peripheral and central nervous systems, but the combination may also reduce symptoms of depression that worsen the course and complicate the treatment of chronic pain. Consider that lurasidone is FDA-approved for the treatment of bipolar depression55 and has been shown to be effective in treating major depressive disorder with mixed features.93 Moreover, the antidepressant effects of high-dose DCS were first noted in the late 1950s, which has been confirmed in several small-scale clinical studies.94-96 Thus, a combination of lurasidone and DCS could be useful as a treatment for chronic pain alone, or in the many patients who have chronic pain comorbid with depression.