Journal of Pain & Relief
Open Access

Peripheral pain; Central pain; Pharmacological treatment; Nociception; Central sensitization

Introduction

Pain management remains one of the most challenging areas in clinical medicine due to its subjective nature, multifactorial origin, and variability in response to treatment. While acute pain typically arises from identifiable tissue damage, chronic pain often persists beyond the resolution of injury and is driven by complex neuroplastic changes within the central nervous system.

A fundamental concept in understanding and managing pain is differentiating peripheral from central pain mechanisms. Peripheral pain is initiated by activation of nociceptors in response to noxious stimuli such as heat, chemical injury, or mechanical damage. This type of pain is typically acute, localized, and serves a protective function. In contrast, central pain refers to pain that originates from or is maintained by abnormal processing in the brain and spinal cord, often continuing even after peripheral injury has healed. Pharmacological interventions are more effective when aligned with the underlying pain mechanism. However, misclassification of pain can lead to inappropriate treatment, resulting in poor outcomes and increased risk of drug side effects or dependency. This article examines the pathophysiology of peripheral and central pain, reviews pharmacological agents that target each system, and highlights clinical strategies to optimize treatment [1, 2].

Description

Peripheral Pain Mechanisms

Peripheral pain is mediated by nociceptors—specialized sensory neurons that detect harmful stimuli. These receptors respond to mechanical, thermal, and chemical insults, triggering an action potential that travels via Aδ and C fibers to the spinal cord and brain. Inflammation and injury release substances such as prostaglandins, bradykinin, and cytokines that sensitize these receptors and lower the threshold for pain activation—a process known as peripheral sensitization [3].

Central Pain Mechanisms

Central pain arises when the CNS undergoes maladaptive changes in response to persistent or repeated nociceptive input. This includes:

• Central sensitization: Increased excitability of neurons in the spinal cord and brain, amplifying pain signals.
• Loss of descending inhibition: Impaired ability of the brain to suppress pain signals.
• Neuroplasticity: Long-term changes in pain pathways and cortical reorganization.
• Glial activation: Release of inflammatory mediators within the CNS [4].

Discussion

Pharmacological agents targeting peripheral mechanisms

The primary goal in peripheral pain management is to reduce inflammation, inhibit nociceptor activation, and prevent peripheral sensitization.

1. Nonsteroidal anti-inflammatory drugs (NSAIDs): NSAIDs such as ibuprofen, naproxen, and diclofenac inhibit cyclooxygenase (COX) enzymes, reducing prostaglandin synthesis. This decreases inflammation and nociceptor sensitization. NSAIDs are effective for acute pain, arthritis, and post-operative pain, but their long-term use can cause gastrointestinal, renal, and cardiovascular side effects.
2. Acetaminophen (Paracetamol): Although its precise mechanism remains unclear, acetaminophen appears to act both centrally and peripherally by inhibiting prostaglandin synthesis and activating descending serotonergic pathways. It is widely used for mild to moderate pain and is generally safe when used appropriately [5].
3. Local anesthetics: Agents like lidocaine block sodium channels on peripheral nerves, inhibiting the initiation and transmission of pain signals. They are used in localized procedures, nerve blocks, and topical formulations for musculoskeletal or neuropathic pain.
4. Corticosteroids: These potent anti-inflammatory agents inhibit multiple pathways involved in inflammation and immune activation. They are effective in inflammatory joint diseases, radiculopathies, and acute injuries, but systemic side effects limit their chronic use.

Pharmacological agents targeting central mechanisms

Managing central pain requires agents that alter neurotransmission, modulate excitatory pathways, and enhance descending inhibitory systems.

1. Opioids: Opioids such as morphine, oxycodone, and fentanyl act on mu-opioid receptors in the brain and spinal cord, reducing pain perception and emotional response to pain. While effective for both acute and some forms of chronic pain, long-term opioid use is associated with tolerance, dependence, opioid-induced hyperalgesia, and overdose risk. Their efficacy in central sensitization-driven pain (e.g., fibromyalgia) is limited and controversial [6].
2. Gabapentinoids (Gabapentin, Pregabalin): Originally developed as antiepileptic drugs, gabapentinoids bind to the alpha-2-delta subunit of voltage-gated calcium channels, reducing excitatory neurotransmitter release. They are particularly effective in neuropathic pain and fibromyalgia. Side effects include sedation, dizziness, and cognitive slowing.
3. Antidepressants (TCAs and SNRIs): Tricyclic antidepressants (e.g., amitriptyline) and serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine, venlafaxine) modulate pain through enhancement of descending inhibitory pathways. These drugs are commonly used in chronic centralized pain conditions and have the added benefit of treating comorbid depression and anxiety.
4. NMDA receptor antagonists: Drugs like ketamine block N-methyl-D-aspartate (NMDA) receptors, which are involved in central sensitization. Low-dose ketamine infusions have been used in refractory pain states such as CRPS and post-surgical hyperalgesia. Their use requires careful monitoring due to dissociative and psychotropic effects [7].
5. Cannabinoids: Cannabinoids exert analgesic effects through the endocannabinoid system, modulating both central and peripheral pain. While evidence is still emerging, some formulations (e.g., nabiximols) have shown promise in neuropathic and cancer pain.

Clinical implications and challenges

Distinguishing between peripheral and central mechanisms is essential for guiding pharmacological treatment. Misidentifying centralized pain as peripheral can lead to over-reliance on NSAIDs or opioids, resulting in poor efficacy and increased side effects. Conversely, applying central-acting agents to purely peripheral pain may be unnecessary. Clinical tools such as the PainDETECT questionnaire, quantitative sensory testing, and careful history-taking can aid in identifying features of central sensitization (e.g., widespread pain, pain disproportionate to injury, poor response to NSAIDs) [8].

Treatment should be individualized:

• Acute, localized pain: Emphasis on NSAIDs, acetaminophen, or local anesthetics.
• Inflammatory conditions: May require corticosteroids or DMARDs.
• Neuropathic or centralized pain: Benefit from gabapentinoids, antidepressants, and education-based approaches.

Combination therapy or multimodal analgesia is often more effective than monotherapy. For example, combining acetaminophen with an SNRI may offer both peripheral and central modulation of pain, particularly in patients with mixed pain mechanisms. Furthermore, non-pharmacological interventions—such as cognitive-behavioral therapy, physical therapy, and patient education—are crucial for central pain conditions, where psychological and social factors amplify pain perception. Biomarker-driven pain profiling and precision medicine approaches will likely revolutionize pain management by allowing clinicians to tailor treatments to each patient’s underlying pain mechanism [9, 10].

Conclusion

Effective pain management depends on understanding the mechanisms driving an individual’s pain experience. The distinction between peripheral and central pain is critical in guiding pharmacological choices. While peripheral pain typically responds well to anti-inflammatory agents, local anesthetics, and short-term opioids, centralized pain requires more complex management involving gabapentinoids, antidepressants, NMDA antagonists, and psychological support. Recognizing the limitations of single-agent approaches, clinicians should embrace multimodal and multidisciplinary strategies that address both peripheral and central contributors to pain. Future therapies that more precisely target molecular pathways in pain processing hold promise for improving outcomes and reducing the burden of chronic pain worldwide. By integrating mechanism-based assessment and treatment into routine practice, healthcare professionals can provide more effective, individualized, and safer care for patients suffering from a wide spectrum of pain disorders.