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11 Articles in Volume 13, Issue #2
Spinal Cord Stimulation: Fundamentals
Assessment of Psychological Screeners for Spinal Cord Stimulation Success
Educating Patients About Pain Medications
Central Sensitization: Common Etiology In Somatoform Disorders
Demystifying Pain Pathways
Vibroacoustic Harp Therapy in Pain Management
Erythrocyte Sedimentation Rate and C-Reactive Protein: Old But Useful Biomarkers for Pain Treatment
Editor's Memo: Inflammatory Disease—Time to Refine Our Diagnoses
Ask the Expert: Pain Persists in Spite of High-dose Opioids
Ask the Expert: Rectally Administered Morphine
Letters to the Editor: Mistaken Hormone, Lab Values

Demystifying Pain Pathways

Understanding pain pathways can help clinicians better manage chronic pain syndromes.
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Pain is one of the most common medical complaints, takes many forms, and remains incompletely understood. Despite our growing knowledge of pain mechanisms and a burgeoning armamentarium of pain medications, many questions remain. There have been many theories of pain through history. A prevailing theory is that pain is a message relayed from the periphery to the brain with no intervening modulation.1 Today we understand that pain signals travel along a complex neural network.1,2 Pain is indeed a signal, but its transmission through the neural system is regulated by a complex biochemical interplay that can deliver the pain signal with fidelity or can amplify or inhibit it.

Normal Signaling

To understand pain pathways, we must first understand normosensitivity, or the normal and appropriate transmission of a pain signal. Inputs or signals travel from neuron to neuron; as the signal traverses synapses, it is affected by a variety of neurotransmitters and neuromodulators. It is beyond the scope of this article to discuss the biochemistry involved and, indeed, it is not completely elucidated. For our purposes, we recognize that inputs coming from one neuron are relayed to appropriate receptors on the next neuron. In the case of normal pain signals, the presynaptic action potentials are exactly equivalent to the postsynaptic action potentials. In other words, the pain signal is not modulated, inhibited, or amplified (Figure 1).


Hyperalgesia occurs when the patient has a heightened experience of pain. A good example of hyperalgesia in clinical context might be the pain associated with an infected digit. Pain signals travel along the neural network and may be transmitted with good fidelity up until the point at which the neuron encounters the point of infection. The signals are transmitted but the presynaptic inputs are vastly magnified by the neuron at the infection (Figure 2).

Thus, the pain encountered with pressure put on an area of infected tissue is magnified by the neuronal amplification of that signal. Hyperalgesia can be a beneficial adaptive mechanism to help the body protect wounds as they heal.

Thus, the pain encountered with pressure put on an area of infected tissue is magnified by the neuronal amplification of that signal. Hyperalgesia can be a beneficial adaptive mechanism to help the body protect wounds as they heal.

Central Sensitization

Sensitization can occur at the peripheral level or in the central nervous system (CNS). In peripheral sensitization, peripheral nociceptors become increasingly excitable and magnify pain signals being transmitted to the CNS. Central sensitization is essentially the same thing except it is the neurons in the CNS that are overly excitable. The result is that a normal stimulus or a mild pain becomes amplified within the neural network to the point that the subject perceives moderate or even severe pain. Peripheral and central sensitization can coexist in the same patient.

Through biochemical interplay of various neurotransmitters and neuromodulators (which again are incompletely understood), the presynaptic signal becomes amplified across the synapse. This amplification eventually crescendos in a vast multiplication of the original signal postsynaptically (Figure 3). This also activates voltage-gated sodium channels and other processes.

The remarkable thing about sensitization is that there need not be pathophysiological damage to the neurons themselves. In many ways, sensitization resembles normal sensitivity in that incoming signals cross the synapse, modified by neurotransmitters and neuromodulators, to their appropriate postsynaptic receptors. The change is biochemical, leading to a ramping up of the signal. Thus, while peripheral and central sensitization often present clinically as long-lasting conditions, they are usually reversible—at least insofar as the neural network is concerned.

Acute pain typically travels on the normal pain pathway; the pain experienced is equivalent to the pain signals transmitted. At some point, acute pain can become chronic pain (chronification). The exact transition from acute to chronic pain is incompletely understood and involves central sensitization.3 While our current definitions of chronic pain are quite simplistic (and probably over simplistic if only based on duration), chronic pain is often quite different from acute pain. For one thing, sensitization is often involved, which means the pain is magnified. Patients with chronic pain often describe it as more diffuse than acute pain. While a person can usually precisely identify the location of acute pain, that is not always the case with chronic pain, which can be more vague and move around. Over time, chronic pain becomes dissociated with its original cause.


Allodynia is a particularly distressing clinical condition in which a person experiences normal stimuli as painful. Patients with allodynia may experience even a light touch or a gentle nudge as severe pain (Figure 4). Allodynia may be compared to hyperalgesia in that signals travel across the neural network with relatively good fidelity until they encounter a particular neuron that massively amplifies the pain signals. The main difference between allodynia and hyperalgesia is that the inputs in allodynia are innocuous (touch, nudge, moderate temperature) while hyperalgesia involves noxious stimuli.

Types of Pain and Pain Pathways

It is currently understood that there are multiple mechanisms of pain: for example, pain may be nociceptive, neuropathic, or mixed.4 It is sometimes thought that these different pain mechanisms might have different pathways, but that is not always the case. Neuropathic pain is pain that can arise from a lesion or disease in the somatosensory system, and that signal is maintained ectopically by a dysfunction in the nociceptors in the relevant tissue or by abnormal pain signaling to the CNS.5 Because neuropathic pain involves aberrant neural behavior, it typically manifests in ways similar to the hyperalgesic model, but there is no single distinctly "neuropathic" pain pathway. Most often, what makes neuropathic pain different from nociceptive pain is the physiology or neurotransmitters involved.

Neuropathic pain typically presents as shooting pain, sharp jabbing pain, electrical shocks, "pins and needles," numbness, or extreme cold. The pain can be diffuse and may migrate around the body. Neuropathic pain can occur commonly with postherpetic neuralgia, secondary to diabetes, or as the result of chemotherapy that can cause peripheral nerve damage. Managing neuropathic pain is challenging.5,6

Mixed pain syndromes are common and generally involve nociceptive pain with a neuropathic component. Many chronic pain patients have nociceptive pain with a neuropathic component; both components require treatment.7

Last updated on: October 28, 2014