Antidepressant Agents for the Treatment of Chronic Pain and Depression

Michael W. Jann, Pharm.D.; Julian H. Slade, Pharm.D.

Disclosures

Pharmacotherapy. 2007;27(11):1571-1587. 

In This Article

Biologic Link Between Chronic Pain and Depression

Chronic Pain Model

As previously stated, pain can be grouped into three basic categories. It is beyond the scope of this article to review extensively its complex peripheral and central mechanisms. However, the basic pathophysiology of pain is provided to establish a foundation for its treatment with antidepressant agents.

For pain to occur, an organic or environmental stimulus must be converted into an electrochemical signal, and then transmitted to higher brain centers for interpretation. At that point, it is determined whether the signal is innocuous or noxious in nature. Pain has been described as a complex emotional experience involving not only the transduction of noxious stimuli, but also cognitive and emotional processing by the brain.[4] Pain is not homogeneous and involves multiple genetic and biochemical mechanisms, nervous system pathways, and neuronal plasticity.[4–7] We briefly review only nociceptive and neuropathic pain mechanisms.

For nociceptive pain that originates from a noxious stimulus, the process is initiated at the nociceptor. The two main nociceptor classes include the lightly myelinated, medium-diameter, rapidly conducting Ad fibers, and the unmyelinated, small-diameter, more slowly conducting C fibers.[4] Thereby, Aδ fibers mediate rapid, acute, sharp pain, and C fibers mediate delayed, more diffuse, dull pain. A wide range of stimuli triggers the pain sequence, which could involve a rapid and/or delayed response. Each stimulus has a corresponding receptor that triggers the pain process ( Table 1 ). For example, heat or thermal exposure elicits a rapid response through activation of vanilloid receptor subtype 1 and vanilloid-like receptor subtype 1 on Aδ fibers, launching the pain process. Tissue damage from other mechanisms (e.g., medical disease) can release various biochemical stimuli (e.g., glutamate), which act through their corresponding receptors to commence the delayed pain process by way of the C fibers.[4]

Neuropathic pain is associated with disease or injury of the peripheral or central nervous system and presents difficult therapeutic paradigms for clinicians. Diabetes mellitus, immune disorders, cancer, and ischemic disorders are examples of disease processes that can lead to neuropathic pain. Classification of neuropathic pain can be based on its location in the periphery, spinal cord, or brain ( Table 2 ). Some disorders could have multiple locations (e.g., multiple sclerosis).[8] An essential aspect of neuropathic pain is a partial or complete loss of afferent sensory function and paradoxic hypersensitivities (i.e., hyperalgesia and allodynia). Hyperalgesia is the lowering of the pain threshold and an increased response to noxious stimuli, whereas allodynia is the evocation of pain by nonnoxious stimuli. Mechanical hyperalgesia can be divided into three groups: static, punctuate, and dynamic. These groups are easily distinguishable, as static hyperalgesia begins from gentle pressure, punctate starts with a pinprick, and dynamic comes from a light brush that evokes a painful sensation. Allodynia is characterized by sensations or stimuli that are not considered painful, such as touch, warmth, cold, or simple movements eliciting a painful response. Like nociceptive pain, similar biochemical and molecular mechanisms occur in neuropathic pain with the involvement of Aδ and C fibers.[4,8]

Both nociceptive and neuropathic pain stem from the primary sensory neurons and terminate in the dorsal horn of the spinal cord. The dorsal horn is the first site of synaptic transfer to the brain and can be influenced by neuronal plasticity or modulation integral to pain generation and pain hypersensitivity.[5] Neural pathways from the spinal cord dorsal horn activate many brain structures through an ascending pathway that involves the autonomic, perceptual, and cognitive systems, which elicit the pain response displayed clinically.[4]

Depression Model

Clinical symptoms of depression can be grouped into three basic categories: emotional (depressed mood, lack of motivation, disinterest in social activity, anxiety), cognitive (inability to concentrate, poor memory), and physical (insomnia, headache, fatigue, and stomach, back, and neck pain). The physical pain aspects of depression are well recognized among clinicians. For example, the Hamilton Rating Scale for Depression (HAM-D), a clinical rating scale developed in 1960 to assess depression, contains 21 items, eight of which are questions that ask patients about their physical symptoms.

Theories about the biologic basis for depression have evolved over more than 25 years. The principal biochemical basis for depression has focused on two neurotransmitters: serotonin and norepinephrine.[9,10] These two neurotransmitters have also been implicated in the underlying pathophysiology of chronic pain.[4–7] Serotonergic and norepinephrine neurons overlap in the brain, and these two systems interact biochemically and neuroanatomically. In patients with depression, alterations or reductions of these two neurotransmitters and their respective receptors become dysfunctional over time, leading to a dysregulated system. The following six criteria for dysregulation have been proposed: the system is impaired in one or more regulatory or homeostatic mechanisms; basal output of the system is erratic; normal periods of functioning are disrupted; the system is less responsive to environmental stimuli; a slow return to basal activity occurs after the disturbance; and effective agents restore or reregulate the system.[11] Basically, norepinephrine and serotonin concentrations and output become erratic in patients with depression, and antidepressants attempt to restore a "normal" firing rate in neuronal areas and neurotransmitter activity at the synaptic cleft.

Both the serotonin and norepinephrine pathways in the brain and their associated symptoms have been determined. Both pathways originate in the brain stem and project to various brain regions (Figure 1). Serotonin pathways originate at the raphe nucleus and project to the frontal cortex, basal ganglia, hypothalamus, and limbic areas. Norepinephrine pathways originate in the locus ceruleus and project to the frontal cortex, limbic areas, hypothalamus, and cerebellum. The clinical symptoms for mood disturbance can be associated with the frontal cortex and limbic regions. Loss of appetite, weight loss or gain, and loss of pleasure can be connected to the hypothalamus. Therefore, depressive symptoms originate from various brain areas that result in a complex set of clinical presentations to the health care professional. Each symptom can vary over time in intensity and duration, challenging the role of pharmacotherapeutic interventions.

Figure 1.

Origins and projections of the serotonin and norepinephrine pathways, and interactions between the brain stem and other higher brain areas, with their clinical manifestations.

Interrelationship Between Chronic Pain and Depression

The link between the higher brain centers involved with depression and pain and the peripheral body regions occurs in the brain stem, with neurotransmission relayed through the spinal cord. Abnormal body activity and functions (e.g., musculoskeletal) are suppressed from the consciousness by the serotonin and norepinephrine descending pathways in the spinal cord that originate in the brain stem.[12,13] This suppression is not always constant and functions as a homeostatic regulator. For example, these descending pathways suppress the body's input from minor discomforts such as aching muscles and joints.

As the descending serotonin and norepinephrine neurons arise from the brain stem, two areas within the brain stem have been identified as the source of these neurons (Figure 1). As previously mentioned, the dorsal raphe nucleus serves as a basis for serotonin neurons, and the locus ceruleus serves as a foundation for norepinephrine neurons.[14] In fact, specific norepinephrine cell groups A5 and A7 in the locus ceruleus have been identified and provide anatomic evidence of neuronal projections from the brain stem to the spinal cord.[15–17]

A dysfunctional serotonin and norepinephrine system that promotes emotional and vegetative depressive symptoms is likely to also have dysfunctional descending serotonin and norepinephrine pathways, which provides the explanation for depressed patients who also complain of headache, abdominal pain, and musculoskeletal pain in the lower back, joints, and neck, as well as fatigue and energy loss. The serotonin and norepinephrine descending neurons project from the brain stem into the spinal cord's dorsal horn. Within this area, a complex set of biochemical actions takes place involving other types of neurotransmitters (e.g., γ-aminobutyric acid) and peptides (substance P) modulating the pain stimuli that originates in the peripheral neurons (Figure 2).[18]

Figure 2.

Peripheral pathways and descending projections from the brain stem to the spinal cord. The serotonin and norepinephrine descending neurons project from the brain stem into the spinal cord's dorsal horn, where a complex set of biochemical actions takes place involving other types of neurotransmitters (e.g., γ-aminobutyric acid [GABA]) and peptides (substance P), modulating the pain stimuli that originate in the peripheral neurons. A host of peptides that includes substance P characterize one primary afferent nociceptor pathway, and the other pathway is identified as IB4 for its binding action to the peptide IB4 lectin. Another peripheral pathway that involves norepinephrine neurons contains sympathetic postganglionic neurons (SPGN) and also includes neuropeptide Y.

There are two main primary afferent nociceptor pathways that lead into the spinal cord from the periphery (Figure 2).[19] One pathway is characterized by a host of peptides that includes substance P, and the other pathway has binding action to the peptide IB4 lectin. Both pathways are composed of Aδ and C fibers and terminate in the superficial region of the dorsal horn. Another peripheral pathway that involves norepinephrine neurons contains sympathetic postganglionic neurons, as well as neuropeptide Y. A painful stimulus from the periphery can affect multiple pathways, eliciting the complex set of mechanisms leading to and found within the central nervous system.

As stated earlier, numerous receptor systems located on these two nociceptor pathways exist that form the starting point of pain and its interactions with depression. Glutamate, a major excitatory neurotransmitter, affects both pathways and could serve as one common pharmacologic model for the rapid action of the Ad fibers and the slower actions of C fibers.[5] Many other receptor systems and their corresponding stimuli complete this discussion of the circuitry of pain modulation that incorporates depressive symptomatology. This discussion focuses only on serotonin and norepinephrine pathways. Other models are certainly involved, most notably, enkephalin and opioid peptide links.[18]

Many questions remain, such as, what are the functional consequences of coexistent neurotransmitters and other neuromodulator receptor systems in a single neuron? Are there presynaptic influences on descending pathways? What types of interactions occur between serotonin and norepinephrine terminals in the spinal cord? Regardless of these many unanswered questions, depression and pain possess a physiologically linked basis with a discrete central nervous system network involving opioid-like peptides, biogenic amines, glutamate, and other transmitters.

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