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.