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Special report – War on Pain: Understanding pain and pain mechanisms


By Kevin T. Galloway, BSN, MHA; Chester C. Buckenmaier III, MD; and Rosemary C. Polomano, PhD, RN, FAAN

Pain is a significant challenge both for those who experience it and those who treat it. A highly personal and subjective experience, it can be difficult to quantify and measure objectively. What’s more, the peripheral and central complexity of pain necessitates a targeted approach to ensure effective pain management.

The International Association for the Study of Pain defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” Pain may be acute or of short duration (3 months or less) or chronic, generally defined as a duration exceeding 3 months. Acute pain acts as a self-limiting physiologic warning after tissue injury. Generally, acute pain is easier to treat than chronic pain, responding well to short-term analgesic therapy. But unless treated effectively in a timely manner, acute pain may evolve into chronic pain—a relentless pathologic condition.

Chronic or persistent pain commonly requires long-term management with various pharmacologic and nonpharmacologic strategies. Affecting more than 75 million Americans, it’s the primary reason why people seek medical attention. Its consequences include lost work productivity, disability, and increased healthcare costs. Unrelieved and persistent chronic pain contributes to depression, anxiety, poor sleep patterns, and decreased quality of life.

Pain in the military

Pain is a significant problem among military personnel, including those injured during combat operations or training exercises and veterans with long-lasting effects from service-related injuries. As of 2007, more than 21,000 deployed military service members had sustained wounds to multiple body regions while serving in Operation Enduring Freedom (OEF) or Operation Iraqi Freedom (OIF). Blast-related injuries accounted for 65% of combat injuries; 50% to 79% of combat injuries were traumatic extremity injuries, including trauma to one or both legs or arms, amputation, and mangled leg or arm injuries. Among service members and OEF and OIF veterans who’ve sustained major traumatic limb loss, 62.5% have residual limb pain and 76% have phantom limb pain.

Approximately 60% of injured military service members also experience signs and symptoms of traumatic brain injury. Military service members with polytrauma commonly must undergo multiple surgical procedures—an average of 5.5 per person. This places them at increased risk for developing unremitting pain, given that 10% to 50% of patients who have general surgery develop persistent pain. Preventing pain and reducing its severity early are critical to mitigating the lasting effects of chronic pain associated with injury.

Many military service members with polytrauma require inpatient rehabilitation; nearly all (96%) experience at least one pain problem during their stay. Although pain from combat-related polytrauma is significant, the most common type of pain among military service members from OIF is low back pain (53%). In about 24% of these cases, a precipitating event isn’t identified.

Chronic pain in veterans

Research demonstrates a high prevalence of chronic pain among veterans. A limited cohort study (n = 340) of OEF and OIF veterans found 81.5% experienced chronic pain. Many other studies show that a concerning number of veterans from previous conflicts have chronic noncancer pain. Severe chronic pain is associated with increased suicide risk, which prompted the incorporation of suicide assessment and suicide prevention interventions into routine plans of care at Veterans Administration medical centers and primary-care settings that treat veterans.

Classifying pain

In addition to the broad classification of pain as either acute or chronic, pain may be classified based on its characteristics, cause, or the mechanisms involved in sustaining it. One classification system divides pain into nociceptive and non-nociceptive. (See Classification of pain by clicking the PDF icon above.)

Nociceptive pain results from activation of ongoing pain receptors (nociceptors) in either the surface or deep tissues of the body. Two types of nociceptive pain exist:

  • Somatic pain is caused by injury to the skin, muscle, bone, joint, or connective tissue. It’s generally sharp or burning (as with injury to the skin or tissue just below the skin) or dull, aching, and localized (as with injury to deeper tissues).
  • Visceral pain results from ongoing injury to internal organs or the tissues that support them. Generally, it’s poorly localized and described as cramping (as with injury to a hollow structure, such as the gallbladder or intestine) or pressure-like and stabbing (as with injury to a solid organ).

Non-nociceptive pain stems from nerve-cell damage in the peripheral nervous system (PNS) and central nervous system (CNS, termed neuropathic pain); or from overactivity in the sympathetic nervous system with CNS and PNS mechanisms (sympathetic pain).

  • Neuropathic pain occurs when injury to a nerve causes it to become electrically unstable and fire signals randomly in a disordered pattern. A person with this type of pain is hypersensitive to stimuli (such as hot, cold, and touch), and the injury elicits such
    sensations as numbness, electric shock like or tingling, burning, “pins and needles,” sharp pain, or lancinating pain. Also, pain may be referred to an area that the injured nerve normally supplies (for example, sciatica from a herniated intervertebral disc).
  • Sympathetic pain follows fractures and soft-tissue injuries. It’s marked by extreme hypersensitivity in the skin surrounding the injury and peripherally in the limb, which may be so painful the person refuses to use it.

Goals of pain management

The most important goal of pain management is to restore the patient’s function to its original or optimal state. The traditional approach of treating pain as a symptom of some other disease process fails because it doesn’t consider pain mechanisms or recognize that pain fundamentally alters the PNS and CNS, leading to sustained and amplified pain.

Current research focuses instead on understanding pain mechanisms, the transition from acute to chronic pain, and rational pain therapy. Consequently, the primary goals of effective pain care are to target specific pain mechanisms in the PNS and CNS, prevent development of
chronic pain, and improve overall patient outcomes. Many pain specialists believe the best approach to managing pain is to consider pain a disease process. A holistic, evidence based approach to understanding pain and its management is crucial to designing and administering the most successful pain therapies.

Pain mechanisms

Scientists have identified the mechanisms and mediators of pain. The ascending (excitatory) systems of pain processing facilitate pain through increases in substance P and other excitatory neurotransmitters, nerve growth factor, and cytokines. Balancing the excitatory systems are descending (inhibitory) pathways from the brain that modulate nociceptive signals from being sent upward to the brain.

Ultimately, the perception of pain is affected by interactions between these excitatory and inhibitory systems. Pain can occur when these systems are disrupted or incapable of modulating sensory input. Pain therapies are directed toward reducing excitatory processes and maximizing inhibitory mechanisms within these systems. (See Targeting drug therapy to the pain mechanism and Pain pathways and the drugs that affect them by clicking the PDF icon above.)

Nociceptive pain is initiated by a stimulus (such as a burn or an injury) that activates primary nociceptors. The nociceptors convert mechanical, electrical, chemical, or thermal energy into an action potential, transmitted to the dorsal horn of the spinal cord by A-delta and C nerve fibers. Thin, myelinated A-delta fibers provide rapid transmission and are responsible for the immediate pain sensation (“fast pain”). Unmyelinated C fibers provide slower conduction that leads to a delayed secondarypain sensation. These fibers synapse in the dorsal horn, where spinal transmission is mediated by the release of glutamate and other excitatory neurotransmitters. Then the nociceptive signal is transmitted through ascending spinal-cortical pathways to the brain, which generates the sensory, emotional, and evaluative aspects of pain.

Inflammatory pain follows cellular or tissue damage, resulting in release of chemical mediators that induce an inflammatory response and sensitize and provoke nociceptors. This leads to sensitization of somatosensory components of the PNS.

Transition from acute to chronic pain

Undertreated acute pain has many clinical consequences, including psychosocial distress, physiologic responses that impair tissue healing and lead to hemodynamic and metabolic disturbances, limitations of mechanical function, and delayed ambulation. What’s more, undertreated acute pain can lead to chronic pain, which results from complex changes in the CNS and PNS.

The transition from acute to chronic pain is marked by sensitization, which may be primary (occurring at the injury site and known as peripheral sensitization) or secondary (occurring in the CNS). After injury, peripheral sensitization occurs when inflammatory mediators bind to Gprotein–coupled receptors and activate protein kinases (such as A or C), which phosphorylate nociceptor ion channels and receptors. This reduces the threshold required for nociceptor activation, in turn amplifying or prolonging subsequent responses to pain. The result may be abnormal pain conditions, such as:

  • hyperalgesia—extreme sensitivity to painful stimuli; this condition of neuronal hyperexcitability at the injury site may extend into surrounding uninjured tissue
  • allodynia—pain from typically non-noxious stimuli.

Within the CNS, changes occur that alter processing of sensory impulses by the dorsal horn, which has become sensitized. While multiple mechanisms explain how central sensitization occurs, all of them lead to increased dorsal-horn neuronal excitability and responsiveness, due to a barrage of pain signals from C fibers. This increases the likelihood that painful signals will be transmitted upward to the brain, reducing the capability for pain inhibition. Long-term central sensitization causes expansion of the area of perceived pain and increases the response to noxious stimuli. Protracted central sensitization also may cause long-term changes in the expression of neurotransmitters or receptors, or in neuronal structure and survival; as a result, the CNS becomes overresponsive to sensory input and pain. This chain of neurochemical and neurophysiologic changes leads to rapid, independent firing of spinal neurons in response to excessive input from the PNS without a stimulus—a process called wind up. Such changes alter normal stimulus-response characteristics and play an important role in the transition from acute to chronic pain and the development of chronic pain syndromes. Many patients with chronic pain syndromes have severe persistent pain that continues beyond the expected recovery time and is disproportionate to their tissue injuries. Protracted central sensitization also may lead to neuroplasticity—the brain’s natural ability to form new connections to compensate for injury or environmental changes. Neuroplasticity can be adaptive, as when one learns new skills to cope with pain, or pathologic. With pathologic neuroplasticity, changes in neuronal structure and pain messaging and processing become permanent. The result: spinal cord sensitization and disinhibition, which contribute to many chronic pain conditions, including complex regional pain syndromes, phantom limb pain, and chronic low back pain. Examples of wind up, these painful conditions commonly are less responsive to analgesics because the underlying pathophysiologic abnormalities are complex. The complexity of the underlying mechanisms underscores the need for alternative pain-management approaches.

Cognitive and affective dimensions of pain

Over the last decade, scientists have gained a greater appreciation of the brain’s role in the perception of pain and factors relevant to this perception. (See Factors involved in pain perception by clicking the PDF icon above.) Use of imaging techniques during application of various nociceptive stimuli (such as heat, cold, and electrical impulses) has led to a clearer understanding and mapping of the brain areas involved in pain. These techniques show marked variability in brain activation in response to pain among individuals, and suggest that the lateral area of the brain is involved with sensory components of pain (for instance, location, intensity, and quality), whereas the limbic forebrain is involved with emotional and cognitive dimensions.

Attention/distraction is one of the factors that influence pain perception. The influence of distraction on pain perception occurs in wounded soldiers who don’t feel pain during the heat of combat. Studies support distraction as a feasible pain-modulating technique; this provides a therapeutic basis for advising patients with pain to take a walk, read a book, or listen to music. Activities that focus attention on achieving goals are particularly effective in distracting from pain and form a basic component of pain rehabilitation programs. Distraction as a pain- modulating technique also can be used as an adjunct to other pain-treatment modalities, such as medications.

Anticipation or expectation of pain also plays a role in pain perception. Anticipating pain is an adaptive response in acute pain but a maladaptive one in chronic pain. For example, a healed lower-back injury is no longer an obvious source of nociception, but fear of previously experienced pain may cause a person to stiffen or become guarded—triggering a cycle of more fear and pain, which in turn may cause significant disability. Anticipating pain increases pain and activates brain regions linked to the processing of pain perception. Multiple factors, including existing fear and anxiety, gender, ethnicity, and psychological state, contribute to the vast differences in how individuals perceive pain in response to a given stimulus or injury. In fact, pain perception may have more to do with how much pain a person expects to experience than the actual intensity of the stimulus itself.

Better understanding, better treatments

Acute pain is common and often selflimiting. But acute pain that goes untreated or undertreated can progress to chronic pain. Our understanding of pain, its mechanisms, and the development of chronic pain is evolving. The idea that chronic pain is best viewed as a disease entity in its own right rather than simply a symptom of a condition has gained wider acceptance. Neuroimaging studies show chronic pain is a degenerative condition promoting central sensitization and abnormal neuroplasticity. Insight into the complexity of pain mechanisms has led to more rational and targeted approaches to pain therapies and to safer and more effective pain treatments.

Selected references

Belmont PJ, Goodman GP, Zacchilli M, et al. Incidence and epidemiology of combat injuries sustained during “the surge” portion of Operation Iraqi Freedom by a U.S. Army brigade combat team. J Trauma. 2010; 68(1):204-210.

Clark ME, Bair MJ, Buckenmaier CC 3rd, et al. Pain and combat injuries in soldiers returning from Operations Enduring Freedom and Iraqi Freedom: implications for research and practice. J Rehabil Res Dev. 2007;44(2):

Clark ME, Scholten JD, Walker RL, et al. Assessment and treatment of pain associated with combat-related polytrauma. Pain Med. 2009;10(3):456-469.

Cohen SP, Griffith S, Larkin TM, et al. Presentation, diagnoses, mechanisms of injury, and treatment of soldiers injured in Operation Iraqi Freedom: an epidemiological study conducted at two military pain management centers. Anesth Analg. 2005;101(4):1098-1103.

Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009; 10(9):895-926.

Lew HL, Otis JD, Tun C, et al. Prevalence of chronic pain, posttraumatic stress disorder, and persistent postconcussive symptoms in OIF/OEF veterans: polytrauma clinical triad. J Rehabil Res Dev. 2009;46(6):697-702.

Neugebauer V, Galhardo V, Maione S, et al. Forebrain pain mechanisms. Brain Res Rev. 2009;60(1):226-242.

Owens BD, Kragh JF, Wenke JC, et al. Combat wounds in Operation Iraqi Freedom and Operation Enduring Freedom. J Trauma. 2008;64(2):295-299.

Polomano RC. Concepts in Acute Pain Management: A Nurse’s Guide to Multimodal Approaches to Drug Therapy: INROADS into Pain Management Initiative. Accessed July 22, 2011.

Reiber GE, McFarland LV, Hubbard S, et al. Servicemembers and veterans with major traumatic limb loss from Vietnam war and OIF/OEF conflicts: survey methods, participants, and summary findings. J Rehabil Res Dev. 2010;47(4):275-297.

Scholz J, Woolf CJ. Can we conquer pain? Nat Neurosci. 2002;(suppl 5):1062-1067.

Vadivelu N, Mitra S, Narayan D. Recent advances in postoperative pain management. Yale J Biol Med. 2010;83:11-25.

Voscopoulos C, Lema M. When does acute pain become chronic? Br J Anaesth. 2010;105(suppl 1):i69-85.

Zouris JM, Walker GJ, Dye J, Galarneau M. Wounding patterns for U.S. Marines and sailors during Operation Iraqi Freedom, major combat phase. Mil Med. 2006;171(3):246-252.

Kevin T. Galloway, is Chief of Staff of the Army Pain Management Task Force of the Office of the Army Surgeon General in Alexandria, Virginia. Chester C. Buckenmaier III is director of the Defense and Veterans Center for Integrative Pain Management and an associate professor at the Uniformed Services University of the Health Sciences in Rockville, Maryland. Rosemary C. Polomano is an associate professor of pain practice at the University of Pennsylvania School of Nursing and an associate professor of anesthesiology and critical care (secondary) at the University of Pennsylvania School of Medicine in Philadelphia.

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