Functional Imaging Pain And Depression

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Advances in neuroimaging techniques, including functional magnetic resonance imaging and positron emission tomography, have revealed brain regions involved in the experience of acute pain. In a seminal study, investigators using functional imaging techniques demonstrated release of endogenous opioids and interaction of these opioids with mu-opioid receptors in response to experimentally induced acute pain.13 Activation of the endogenous opioid system was associated with reductions in the sensory and affective intensity of the acute pain experience. In a meta-analysis, six brain structures were found to be consistently activated by acute pain stimuli including the primary and secondary somatosensory cortices, insular cortex, anterior cigulate cortex, prefrontal cortex, and the thalamus.14 In general, the primary and secondary somatosensory cortices have been implicated in the sensory-discriminative processes of pain, whereas the thalamus, insula, anterior cigulate, and prefrontal cortices have been associated with the affective-motivational dimension of pain. Sensory-discriminative processes involve recognition of the quality and intensity of pain stimuli, including spatial and temporal characteristics. The affective-motivational dimension of pain refers to the negative emotions associated with pain experiences, including the innate sense of unpleasantness. Other brain structures, including the amygdala and periaqueductal gray matter, can be activated to a lesser extent by acute pain stimuli.15 Furthermore, significant interindividual variation exists in the level to which various brain structures can be activated by acute pain stimuli. Variations in these observed effects can be explained, in part, by interindividual differences in peripheral neurotransmission. For example, polymorphisms of catechol-O-methyl transferase have been shown to alter activation of the endogenous opioid system.16 Other factors which could account for variations in the activation of brain structures include gender and interindividual differences in how anticipation alters the response to nociceptive stimuli.17'18

Activation of brain structures by acute pain stimuli is different among individuals with chronic pain. In general, the primary and secondary somatosensory, anterior cin-gulate, insula, and thalamus are activated significantly less compared to normal subjects. In the aforementioned meta-analysis, the average incidence of activation of these brain regions in normal controls was 82 percent compared to 42 percent for individuals with chronic pain.14 Alternatively, among adults with chronic pain, the incidence of prefrontal cortex activation was 81 percent compared to 55 percent in normal subjects.14 The observation that activity in brain structures associated with the affective-motivational dimension of pain are accentuated in patients with chronic pain is consistent with clinical observations that these patients experience more pain-related emotions and affective distress. This postulate is also consistent with neuroimaging findings from patients with comorbid depression and chronic pain. In a cohort of patients with fibromyalgia, which represented a homogenous group of patients with chronic pain, symptoms of depression were not correlated with the magnitude of experimentally induced pain.19 Furthermore, no correlation was found between the severity of pain or depressive symptoms and activation of brain structures implicated in processing the sensory-discriminative dimensions of pain. However, a significant correlation was found between measures of depression and activation of brain structures responsible for processing the affective-motivational qualities of pain, including the prefrontal cortices. Whereas these findings require further study and replication by other investigators, they provide the impetus for the assertion that chronic pain, with or without comorbid depressive symptoms, is associated with dysregulation in an entire network of brain regions subserving both the sensory and affective components of pain.15 Findings from functional neuroimaging studies could also provide the basis for further understanding the analgesic mechanisms of anti-depressant medications.

TRICYCLIC ANTIDEPRESSANTS

Tricyclic antidepressants (TCA) were the first class of drugs widely used for the treatment of depression. These compounds were also the first class of antidepressants used to treat pain.

Structure and mechanism of action

Tricyclic antidepressants have a central three-ring structure with a single side chain. Tertiary amine tricyclics, including amitriptyline and imipramine, have two methyl groups at the end of the side chain while secondary amines, such as desipramine and nortriptyline, have one methyl group. Tetracyclic antidepressants, such as maprotiline and mianserin, are a related group of drugs that are not as widely used as the tricyclic compounds.

The analgesic effects of TCAs are mediated in part by activation of the descending inhibitory pathways that project from supraspinal centers and terminate in the dorsal horn of the spinal cord.20 The principal mechanism of action appears to be related to blockade of serotonin and norepinephrine transport by the side chain and not the central three-ring structure. Tertiary tricyclics are more potent in blocking serotonin transport, whereas the secondary amines have greater affinity for blocking norepinephrine transport.21 As a result of reuptake inhibition, serotonin levels rise. Inhibitory presynapic autoreceptors are desensitized while postsynapic receptors are up-regulated. The overall effect of these pre- and postsynaptic changes enhances the transmission of serotonin. Reuptake inhibition of norepinephrine enhances transmission by desensitizing inhibitory presynaptic autoreceptors in a process mediated by a2-adrenergic receptors. Other proposed mechanisms of action include blockade of voltage-gated sodium channels,22 inhibition of N-methyl-D-asparate receptors23 and interaction with opioid receptors.24 Major secondary effects include blockade of muscarinic, histamine (H1), and a1-receptors, which are responsible for many adverse side effects (Table 18.1).

Pharmacology and adverse effects

Absorption of tricyclics occur in the small intestine where, following first-pass metabolism, peak levels are achieved in two to eight hours. The principal method of clearance is hepatic metabolism via demethylation of the side chain and hydroxylation of the central ring structure. Tertiary amines are demethylated to the secondary amines which are conjugated to inactive forms. Several cytochrome P450 enzymes are responsible for the metabolism of TCAs including the 1A2, 3A4, 2C19, and 2D6 pathways.25 Drugs or other substances that either inhibit or induce these enzymatic pathways can alter serum TCA levels.

In general, undesirable effects related to TCA use stem from blockade of various receptor systems (Table 18.1). Secondary amines are associated with fewer side effects compared to tertiary amines. Anticholinergic effects can

Table 18.1 Profile of antidepressant dosages, reuptake activity, and receptor affinities.

Dose range

Serotonin

Norepinephrine

Adrenergic

Histaminergic

Cholinergic

Sodium

reuptake

reuptake

blockade

blockade

blockade

channel

Tricyclics

Amitriptyline

25-200

+ +

++

++

++

+++

++

Imipramine

25-200

+ +

++

++

++

++

++

Nortriptyline

30-150

+

+ +

+

+

+

+

Desipramine

50-200

+

+++

+

-

+

+

Selective serotonin reuptake inhibitors

Fluoxetine

20-60

+ +

-

-

-

-

+

Paroxetine

20-60

+ + +

+

-

+

+

-

Citalopram

20-60

+ + +

-

-

-

-

-

Serotonin-norepinephrine reuptake inhibitors

Duloxetine

60-120

+++

+++

-

-

-

-

Venlafaxinea

75-225

++

++

-

-

-

-

Milnacipran

100-200

+

+ +

-

-

-

-

Norepinephrine reuptake is dose dependent.

Norepinephrine reuptake is dose dependent.

lead to urinary retention, constipation, tachycardia, blurred vision, and delirium. Antihistaminergic effects include sedation, increased appetite, and weight gain. Orthostatic hypotension results from blockade of a1-receptors and could contribute to the increased risk of fall-related hip fractures among patients receiving TCAs.26,27,28 Tricyclics also have type 1 antiarrhythmic properties in that cardiac conduction is prolonged by inhibition of sodium channels. These antiarrhythmic effects could, in part, account for the increased risk of sudden cardiac death and myocardial infarction in patients treated with TCAs.29,30 The use of TCAs in combination with methadone, which increases the QTc interval, has been associated with an increased risk of death related to accidental overdose.31,32 Tricyclics also increase the risk of seizure by inhibiting chloride channels.

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