What causes pain?

What Causes Pain

Pain is primarily caused by tissue injury that triggers an inflammatory response, activating nociceptors through various inflammatory mediators including cytokines, neuropeptides, growth factors, and neurotransmitters. 1 This inflammatory origin applies to all types of pain, whether acute or chronic, peripheral or central, nociceptive or neuropathic.

Mechanisms of Pain

Nociceptive Pain

Pain begins with the detection of noxious stimuli by specialized receptors called nociceptors. The process involves:

• Tissue injury leads to release of inflammatory mediators at the injury site 2

• Inflammatory mediators activate nociceptors, including:

  • Monoamines
  • Cytokines
  • Prostanoids
  • Peptides
  • Neurotransmitters (glutamate, substance P, CGRP)
  • ATP
  • Nitric oxide
  • Neurotrophins 2

• Signal transmission: Activated C and Aδ fibers transmit signals to the dorsal horn of the spinal cord 2

• Central processing: Information ascends to thalamic, limbic, and cortical structures for pain discrimination 2

Neuroinflammation and Chronic Pain

When pain persists beyond normal healing time (>3 months), it becomes chronic pain, which involves:

• Central sensitization: Prolonged noxious stimulation sensitizes peripheral nerve endings and enhances neuronal firing 2
• Glial cell activation: Microglia and astrocytes become activated, releasing pro-inflammatory mediators 3
• Loss of inhibitory control: Death of inhibitory interneurons and enhancement of descending pain facilitation 2
• Neuroplastic changes: Structural and functional changes in pain processing pathways 1

Types of Pain

Neuropathic Pain

• Caused by injury to central or peripheral nervous systems 2
• Common in HIV patients (nearly half of pain is neuropathic) 2
• Can result from direct viral infection, secondary pathogens, medication side effects 2
• Other causes include syphilis, alcohol use disorders, nutritional deficiencies, diabetes mellitus, thyroid dysfunction, kidney disease, and multiple myeloma 2

Nociceptive Pain

• Results from tissue injury due to inflammation, infection, or neoplasia 2
• Examples include osteoarthritis and muscular back pain 2

Chronic Pain Syndromes

Chronic pain may be:

• Primary: Pain as a disease in itself (e.g., fibromyalgia, nonspecific low back pain) 4
• Secondary: Pain as a symptom of underlying disease (e.g., cancer-related, neuropathic, visceral, post-traumatic) 4

Specific Pain Conditions

Breast Pain

• Cyclical mastalgia: Hormonal in origin, bilateral, diffuse 2
• Noncyclical breast pain: Inflammatory in nature, often unilateral and focal 2
• Extramammary causes: Account for 10-15% of "breast pain" cases, including:
  • Musculoskeletal conditions (costochondritis, pectoral strains)
  • Nerve entrapment
  • Spinal conditions
  • Cardiac issues (coronary ischemia)
  • Gastrointestinal problems (reflux, peptic ulcer)
  • Pulmonary conditions (pleurisy, embolus)
  • Shingles 2

Pain in Neurological Conditions

• Affects 20-40% of patients with primary neurological diseases 5
• Particularly prevalent in spinal cord trauma (significantly elevated odds) 6
• Often becomes centralized through maladaptive CNS responses 5
• Should be considered a brain disease affecting neural networks 5

Pain in Inflammatory Bowel Disease

• Often multifactorial and not always linked to disease activity 2
• Can be inflammatory (stricturing disease, fistulae) or non-inflammatory (adhesions, functional symptoms) 2
• Extra-intestinal factors may include gallstones, renal calculi, pancreatitis, or joint/skin complications 2

Treatment Considerations

Medication Approaches

• NSAIDs: Effective for nociceptive pain exacerbations but carry risks including:

  • Cardiovascular events (heart attack, stroke)
  • GI bleeding and ulceration
  • Renal complications 7
  • Should be used at lowest effective dose for shortest time needed 7

• Other medications:

  • Tricyclic antidepressants, selected anticonvulsants, or transdermal lidocaine for neuropathic pain 2
  • Opioids should not be first-line for chronic non-cancer pain due to limited evidence of long-term benefit and risk of serious harms 2

Non-pharmacological Approaches

• Physical therapy to address posture, muscle weakness, or repetitive motions 2
• Cognitive and behavioral psychotherapy to help cope with pain 2
• Environmental enrichment has shown benefits in neuropathic and chronic pain models 2

Important Considerations

• Pain is both a sensory and emotional experience, influenced by biological, psychological, and social factors 2
• The same pain signal may produce different sensations in different individuals based on their biopsychosocial context 2
• Pain assessment should include evaluation of both sensory and affective components 2
• Chronic pain should be recognized as a health condition in its own right, particularly when it persists beyond 3 months 4

Understanding the inflammatory profile of specific pain syndromes is key to effective treatment, with the goal of inhibiting or suppressing inflammatory mediators and modulating neuronal transmission 1.