Page 60 - AN-3-1

Advanced Neurology Dementia with Lewy bodies and substance misuse

metabolism of other drugs, and concurrent use of new warning added risks of abuse, misuse, and addiction,
multiple antidepressants can potentiate benzodiazepines. which could lead to overdose and death. They added
95
Combinations of serotonergic drugs, such as duloxetine that it is frequently abused with alcohol and other drugs,
and imipramine, can result in serotonin syndrome, with continued use can lead to physical dependence, and abrupt
resulting tremors, sweating, myoclonus and tachycardia, withdrawal can precipitate life-threatening withdrawal
delirium, muscle rigidity, seizures, rhabdomyolysis, reactions. The American Addiction Centers placed
109
metabolic acidosis, coma, and death. Imipramine alone benzodiazepines as the fourth hardest drug to quit, right
96
110
is known to impair cognition due to its anticholinergic after crystal methamphetamine. Tapering can take several
side effects. Others potentiate the hypotensive and weeks to years and must be done cautiously both to avoid
90
anticholinergic effects, increasing complaints of withdrawal effects and mitigate the risk of substitutional
dizziness. 97,98 alcohol misuse. Long-acting benzodiazepines may need to
be substituted for short-acting ones for a period of time and
Prescription drug misuse is common, occurring in
6% of Americans a year. Of those, 30% or 4.8 million patient databanks must be monitored for prescriptions by
111
individuals succumb to the misuse of benzodiazepines, other providers. Supportive therapies such as cognitive
second only to opioids. Benzodiazepines are widely behavioral therapy, sleep hygiene assistance, medication
99
prescribed for a broad range of ailments ranging from reconciliation, and psychological support are essential for
101
insomnia to pain; over 12% of American adults were successful treatment.
given prescriptions in 2019. They are recommended The co-misuse of alcohol and benzodiazepines is not
100
for use for only up to 2 – <4 weeks due to their high coincidental. Benzodiazepine ligands bind to gamma-
risk for tolerance, addiction, and misuse. Tolerance may aminobutyric acid (GABA) receptors, opening ligand-
develop after 3 – 4 weeks, with symptoms of withdrawal gated chloride channels and decreasing the firing rates of
and psychological dependence soon following, even in nerve cells. Over a brief period of time (<4 weeks), 101,102
112
those taking the medication as prescribed. 101,102 These tolerance occurs where natural GABA and benzodiazepines
effects are thought to be worse with the short-acting are less effective. This takes place when there is a
benzodiazepines. Some clinical observations have in fact decrease of GABA receptors, as seen in the substantia
suggested that once-daily administration of short-acting nigra, 52,113 or when there is a change in the configuration
benzodiazepines might produce repeated episodes of of the receptor, making it more difficult to bind. 102,114-120
acute dependence and withdrawal. This can contribute Concurrent with increased GABAergic inhibition is
102
to anxiogenic effects after long-term benzodiazepine increased excitatory glutamatergic activity. 17,107,114,121,122 As
use in some patients. Tolerance develops in part due to benzodiazepines are removed, unchecked glutamatergic
17
impaired dopamine reception during benzodiazepine use; excitatory activity results in kindling and the side effects
it takes more stimulation over time to get the benefits of of withdrawal. 7,81,123-125 Alcohol binds to GABA receptors
dopamine. The dopamine impairment can diminish the and so can act as a substitute for benzodiazepines during
ability to experience the drug’s effect as well as the normal withdrawal 126,127 (Figure 5). These substances can act on the
pleasures of everyday life. Repeated drug exposure LC, a common site of synucleinopathy in DLB. The LC
103
48
will give rise to a short-term increase in dopamine levels is involved in the sleep–wake cycle, cognition, attention,
to alleviate the anxiogenic effects but make the next and executive function 128,129 and is a key part of the stress
withdrawal worse. 103-105 The excess free systolic dopamine response, releasing norepinephrine and stimulating the
can contribute to ROS, mitochondrial dysfunction, hypo-adrenal axis. It also sends noradrenergic output
130
protein modifications, and cell death. 68,106 There is clinical to the ventral tegmental area, which is the origin of
evidence that in patients with no history of sedative dopaminergic cell bodies and is involved in motivation,
131
or hypnotic drug misuse, benzodiazepine dependence cognition, and drug addiction. 132
occurs to avoid the severe symptoms of withdrawal rather When glutamatergic activity exceeds normal levels,
than for any pleasurable effects of the drug. 103,107 whether through cumulative small changes to the
The withdrawal symptoms for benzodiazepines can GABAergic/glutamatergic balance or through more severe
be severe, including panic attacks, headache, seizures, increases and kindling from the periodic withdrawals
psychotic reactions, and delirium tremens. 91,101,108 In which are a part of addiction, there is an increased risk of
2020, the FDA updated the black box warning on all glutamate-induced cytotoxic response. 134,135 This results in
benzodiazepines. In addition to the previous warning, increased calcium influx through N-methyl D-aspartate
which advised against mixing benzodiazepines with opioids receptors and the generation of neuroinflammation and
due to the risk of respiratory depression and death, the ROS. 134,136-138 Neuroprotective neurotrophic factors, such

Volume 3 Issue 1 (2024) 8 https://doi.org/10.36922/an.2232