Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms

doi:10.1016/S1474-4422(14)70102-4

The Lancet Neurology

Volume 13, Issue 9, September 2014, Pages 924-935

https://doi.org/10.1016/S1474-4422(14)70102-4 Get rights and content

Summary

Allodynia (pain due to a stimulus that does not usually provoke pain) and hyperalgesia (increased pain from a stimulus that usually provokes pain) are prominent symptoms in patients with neuropathic pain. Both are seen in various peripheral neuropathies and central pain disorders, and affect 15–50% of patients with neuropathic pain. Allodynia and hyperalgesia are classified according to the sensory modality (touch, pressure, pinprick, cold, and heat) that is used to elicit the sensation. Peripheral sensitisation and maladaptive central changes contribute to the generation and maintenance of these reactions, with separate mechanisms in different subtypes of allodynia and hyperalgesia. Pain intensity and relief are important measures in clinical pain studies, but might be insufficient to capture the complexity of the pain experience. Better understanding of allodynia and hyperalgesia might provide clues to the underlying pathophysiology of neuropathic pain and, as such, they represent new or additional endpoints in pain trials.

Introduction

Neuropathic pain is an umbrella term for a series of different conditions caused by a lesion or disease of the parts of the nervous system that usually signal somatosensory information.¹ A range of disorders of the peripheral nervous system—such as postherpetic neuralgia, painful nerve lesions, trigeminal neuralgia, postamputation pain—and a series of neuropathies are included under the term. Additionally, CNS disorders such as stroke, spinal cord injury, and multiple sclerosis can have pain as an important symptom. Diseases causing neuropathic pain therefore vary substantially both in terms of anatomical location and cause. Despite this diversity, neuropathic pain disorders have common clinical characteristics, including some, but not necessarily all, of the following: pain in an area with partial or complete sensory loss; different types of evoked pain; specific descriptors such as burning pain; increased pain after repetitive stimulation; and pain persisting after stimulation.1, 2, 3, 4 Two particularly bothersome and prominent symptoms in different types of neuropathic pain are allodynia (ie, pain elicited by a stimulus that normally does not cause pain) and hyperalgesia (ie, an increased pain response produced by a stimulus that normally causes pain; figure 1).⁵

In clinical pain trials, the intensity and degree of pain relief represent important outcome measures. However, these two measures might not capture all aspects of pain, particularly not with the development of new compounds targeting specific occurrences of pain. Current pain treatment is not satisfactory. An elaborate and detailed assessment of neuropathic pain might help to identify subsets of patients who respond to a particular pain treatment.4, 8, 9, 10 Allodynia and hyperalgesia are symptoms and signs that might serve as readouts for pain and thus contribute to improved delineation of neuropathic pain.4, 8, 9, 10

This Review presents an overview of allodynia and hyperalgesia in neuropathic pain conditions, including their clinical manifestations, underlying mechanisms, and potential value as novel outcome measures.

Section snippets

Epidemiology of allodynia and hyperalgesia in neuropathic pain

Allodynia is Greek for other (allo) pain (odynia) according to the International Association for the Study of Pain.⁵ The authors of a systematic review¹¹ showed that the prevalence of pain associated with predominantly neuropathic pain descriptors in questionnaire studies ranged from 7% to 18%, whereas studies based on diagnostic codes reported lower rates of neuropathic pain of 1% to 2%. The authors additionally stressed the variability in the prevalence of neuropathic pain associated with

Clinical assessment and manifestations of allodynia and hyperalgesia

Theoretically, allodynia can be defined as a painful response to a non-nociceptive stimulus—ie, one not encoded by nociceptors¹⁶—but this definition cannot be used in the clinical setting because it would be impossible to establish whether a stimulus is capable of activating nociceptors in the individual patient. Therefore, the clinical terms allodynia and hyperalgesia need to be defined according to the sensation experienced after a stimulus that would normally produce either no pain or pain

Mechanical allodynia and hyperalgesia

Three types of mechanical allodynia and hyperalgesia are usually described: dynamic mechanical allodynia evoked by light touch; punctate allodynia and hyperalgesia evoked by punctate skin stimulation with a pin or monofilament (400 mN); and static allodynia and hyperalgesia provoked by pressure to skin or deep tissue.33, 34 On the basis of experimental studies using capsaicin and freezing lesions, Kilo and colleagues³⁴ described a fourth type, termed impact hyperalgesia, elicited in the primary

Cold perception and allodynia

The authors of early psychophysical studies in human beings showed that the perception of cold can usually be separated into three categories: perception of innocuous cool temperatures when the skin is cooled by between 0·5°C and 1·0°C in the most sensitive areas; cold pain sensation that is perceived in the range of 30–15°C; and a freezing or stinging cold pain sensation at very cold temperatures, usually less than 0°C (separable from cold pain).69, 70, 71 The perception of innocuous and

Pharmacological treatment

Pharmacological treatment is the mainstay of neuropathic pain treatment. A series of compounds has been used to modulate neuropathic allodynia and other manifestations of neuropathic pain. These include drugs acting at voltage-gated and ligand-gated ion channels, metabotropic glutamate receptor ligands, opioids, cannabinoid receptor modulators, and glycine transporter inhibitors.120, 121

Few trials have specifically addressed the treatment of evoked pain. Several randomised, double-blind,

Conclusions and future directions

Allodynia and hyperalgesia in neuropathic conditions, together with sensory loss, represent an important imprint of the activity in the nociceptive system. On the one hand, the extent and degree of sensory loss will show the magnitude of peripheral deafferentation or the CNS structures that have lost their normal patterned input. The areas of allodynia and hyperalgesia in neuropathic pain, on the other hand, provide a measure of those structures within the nervous system where signs of neuronal

Search strategy and selection criteria

We identified papers for this Review through searches of PubMed with the search terms ”allodynia”, “hyperalgesia”, ”neuropathic”, “neuralgia”, and “pain” from 1966 until January, 2014. For treatment, papers from previous systematic reviews were included. Only papers published in English were reviewed. Studies of humans and animals were included. Both original research and review articles were included. The reference lists of the papers, articles from our own files, and relevant book chapters

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ReviewAllodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms

Summary

Introduction

Section snippets

Epidemiology of allodynia and hyperalgesia in neuropathic pain

Clinical assessment and manifestations of allodynia and hyperalgesia

Mechanical allodynia and hyperalgesia

Cold perception and allodynia

Pharmacological treatment

Conclusions and future directions

Search strategy and selection criteria

Pain

Pain

Life Sci

Neuron

Lancet Neurol

Scand J Pain

Pain

Pain

Pain

Pain

Pain

Pain

Pain

Pain

Eur J Pain

Lancet

Handb Clin Neurol

J Pain

Pain

Lancet

Pain

J Pain

Pain

Scand J Pain

Neurosci Lett

Pain

Pain

Pain

Pain

Eur J Pain

Pain

Pain

Pain

J Neurosci Methods

Pain

Pain

Cell

J Pain

Brain Res Brain Res Rev

Exp Neurol

Pain

Neurosci Lett

Pain

Pain

Pain

Pain

Pain

Neurosci Lett

Cell Reports

Pain

Review
Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms