Allodynia

Etiology

The exact etiology behind allodynia is unknown. Allodynia is the phenomenon of a non-painful stimulus producing a sharp pain response, which implies an error in neuronal conduction. The mechanism behind this error is unclear. The strongest existing evidence suggests that sensory neuronal fibers may stimulate pain pathways, possibly due to an error in long-term potentiation. However, studies exist that suggest that superficial sensory components may also have involvement, as well as evidence that different mental states can affect the perception of allodynia. If we use the analogy of crisscrossed fibers, the actual location of the crisscrossing can vary and may be located almost anywhere along the peripheral to the central nervous system tract. Allodynia can involve both the peripheral nervous system and central nervous system via sensitization, and the mechanism behind the inappropriate pain sensations can evolve over time; this might partially explain the existing contradictory studies - they may all be measuring allodynia with neuronal confusion at different locations.

A non-painful stimulus such as light skin touch should only activate the low threshold A-beta fibers. In cutaneous allodynia, these A-beta fibers then also communicate with and activate pain pathways, through different sodium channel types than the Nav1.7 sodium channels usually associated with pain, as well as through the modification of dorsal ganglia.[2] However, allodynic pain is multifactorial, and as people suffering from post-thalamic stroke pain can attest, the crisscrossing of neurons can happen as high as in the cerebellum.

In summary, many types of peripheral nerve fibers communicate with and travel via different central nervous system pathways. Type A nerve fibers are myelinated. They further categorize into alpha fibers, which are mostly responsible for proprioception, beta fibers, which transmit light touch, and delta fibers, which carry both pain and temperature sensations. There are also unmyelinated type C nerve fibers, which carry sensations of aching pain, as well as temperature and pruritus.

Epidemiology

Neuropathic pain affects 0.9% to 17.9% of the general population, depending on the study and the exact inclusion criteria for neuropathic pain, with the best estimate between 6.9% and 10% of the population.[3] Allodynia is estimated to affect 15% to 50% of people with neuropathic pain.[4] The exact prevalence and epidemiology of allodynia are difficult to determine, as it is a symptom associated with many diseases. Listed below is the epidemiology of the most common diseases associated with allodynia:

Fibromyalgia

Fibromyalgia affects 0.5% to 5% of people in the general public, with varying ranges across different countries. Known risk factors for fibromyalgia include age, lupus, and rheumatoid arthritis. Studies report that women appear to be 2-9 times more likely to be diagnosed with fibromyalgia than men; however, this may be due more to clinical bias than merely meeting fibromyalgia criteria.[5] A recent study of rheumatoid patients which used a strict criteria-based scoring system to diagnose fibromyalgia found that women composed 58% of the sufferers. Some research also supports stress, obesity, and family history as risk factors; however, the literature is not conclusive.[6]

Trigeminal Neuralgia

Trigeminal neuralgia affects 0.01% to 0.02% of the general population. Women are 1.5-3 times more likely to carry a diagnosis of trigeminal neuralgia than men. Age is a strong factor, with most cases of trigeminal neuralgia occurring at over 40 years of age.[7][8]

Diabetic Neuropathic Pain

Diabetes affects roughly 10% of people in the US, and this rate is increasing by about 5% each year. At least 10% (and some sources estimate 100%) of people who have diabetes will develop neuropathic pain. The neuropathic pain can include allodynia, hyperalgesia, or other kinds of pain like feelings of electric shocks or burning. The severity of neuropathic pain often does not correlate with the degree of sensory deficit, making this a primary illness, and not a secondary symptom due to neuronal damage. There does not appear to be a sex-specific difference in the development of diabetic neuropathic pain.[9]

Migraine Associated Allodynia

The prevalence of cutaneous allodynia among migraine sufferers is around 65%, although some estimate it to be higher. Severe cutaneous allodynia may occur in roughly 20% of migraine sufferers.[10][11]

History and Physical

HPI

Allodynia is a symptom, not a disease. It may be a patient’s chief complaint, but it is important to investigate further to determine the disease process causing the allodynia.

First, one should inquire when and how the allodynia started. Often, there is an instigating event, e.g., chemotherapy, herpes, or trauma. Sources suggest allodynia can develop more abruptly, as in trigeminal neuralgia, or may develop more insidiously, as in allodynia associated with diabetes. Other questions to ask the patient: Is the allodynia progressive? Does the pain wax and wane, or is it fairly constant? What is the quality of the pain? What have they tried for the pain? What makes it better, and what makes it worse? Is the pain associated with tactile stimuli, with movement, with temperature, or something else?

A thorough examination of past medical, surgical, and family history is also warranted, particularly for cancer, diabetes, hypertension, strokes, migraines, rheumatological history, trauma, extreme stress, and opioid history. Be sure to have an updated list of medications to spot possible iatrogenic neuropathy. Please refer to the differential diagnosis section for a list of diseases that can cause allodynia. Lastly, the IASP has published an article to assist clinicians in identifying the type and extent of neuropathic pain with which a patient is presenting.[12]

Physical Exam

On physical exam, allodynia is often present with a smaller stimulus than compared to hyperalgesia. Performing a complete neurological exam is essential; this includes isolating light touch vs. temperature vs. proprioception sensory exams, along with motor and strength testing. It is critical to test the “unaffected” side, even if the professed allodynia is only on one side, for comparison. It is also important to test all four extremities, especially if the allodynia seems to be progressive from distal to proximal areas. COverage of EMGs and other neurological tests will be under the “Evaluation" section.

An example of a focused exam on an area of allodynia is below:

General:

First, perform a visual inspection of the area of allodynia. Compare it to the other side for asymmetry. Is muscle wasting present? How is the skin appearance? Are there any rashes, lesions, skin defects, or vesicles? Any scars from prior surgeries?

Light touch:

A cotton-tipped swab is a simple way to deliver a light touch. A monofilament has the added advantage of being able to objectively quantify the amount of pressure the light touch is exerting. Tell the patient to close their eyes while you perform the test, and to tell you when they sense something. Lightly stroke the unaffected side, then the affected side, and then both sides. The patient should be able to articulate which side you stroked. Sometimes patients are so sensitive that even a light breeze will elicit subjective pain. Document if the allodynia follows cutaneous dermatomes, if it is symmetrical and if it is bilateral.

Pain:

A broken wooden cotton-tipped swab is often used to test for the sensation of pain. Use the sharp tip and repeat as above for light touch. The patient should be able to articulate from where the sensation is coming. The distribution of pain sensation and hyperalgesia may be the same or different than the distribution of allodynia.

Temperature:

Some patients experience thermal, rather than tactile, allodynia. You can use the back of any cold metallic device, such as a metal tuning fork, or ice in a glove, to measure sensation to cold. Again, test various cutaneous dermatomes, and examine both sides.

Proprioception and Vibration:

These sensory tests rarely elicit allodynia. However, it is still vital to consider these tests to discern if any other neuronal sensory loss has occurred.

Motor Neurons:

Test bilateral proximal and distal muscles. Testing for coordination will often reveal subtle motor neuron deficits. If the patient is testing poorly on strength, try to ascertain if it is genuinely due to muscle weakness, or if it is due to pain leading to decreased effort.

Reflexes:

Test bilateral reflexes. Make note if the patient is hyper- or hyporeflexive and if reflexes are symmetrical.

Other

Many different diseases can cause allodynia. There should be a further investigation for an underlying cause depending upon history and examination.

Evaluation

Allodynia is a symptom and physical finding. It is imperative to find and diagnose the underlying disease that is associated with or is causing the allodynia. The history and physical should guide clinicians as to whether more invasive (and expensive) evaluations are appropriate.

General Tests

Blood tests:

CBC and BMP are often helpful, with the addition of ESR and CRP if a concurrent rheumatologic condition is suspected. A hemoglobin A1C can be useful to help diagnose diabetes. B12, thiamine, and TSH can also help diagnose other causes of neuropathy.

Imaging:

Imaging is not typically necessary for this diagnosis. CT of the head may be in order in an older patient with a high suspicion for stroke. Similarly, an MRI of the brain may help diagnose MS if the clinical picture suggests high suspicion.

Neuronal Function Tests

Formal neuronal function tests are unnecessary for the diagnosis of allodynia or allodynia related diseases. They are most helpful for quantifying the efficacy of treatment and in research. There are several methods of testing for sensory neuronal conduction. These tests usually require referrals to specialty clinics, but are briefly summarized below:

Quantitative Sensory Testing:

Quantitative sensory testing, or QST, is generally used to test delta and type C fibers. A device applies thermal stimuli to the skin in a graded manner. Plastic monofilaments, needles, and vibrometers can be used to test light touch, pain, and vibration, but those methods are often secondary to its ability to isolate C fiber response to thermal stimuli.

This test creates a graph with an individual's perception and pain thresholds. It also focuses on testing the small unmyelinated C fibers, which are more challenging to isolate during a routine physical exam. However, it still relies on the patient to participate in the measurement of pain and sensation.[13]

Neuron Conduction Studies:

Neuron conduction studies are a type of neurophysiological technique, which measures the time and quality of an electrical impulse as it travels from the stimulation site of a neuron to the recording site of the same neuron. They are often performed on motor neurons along with electromyography (EMG) to assess motor neuron function. The same concept applies to sensory neurons. Note that standard neuron conduction studies usually directly stimulate the nerve. Also, standard neuron conduction studies only test beta fibers, as they have lower thresholds compared to delta fibers; this directly tests the fiber, but only along a short stretch of a neuron.

Somatosensory Evoked Potentials:

Somatosensory evoked potentials measure electrical activity in the brain after a somatosensory stimulus to beta fibers. This test assesses the health of a neuron as a whole and is often useful when possible CNS conduction issues are suspected, such as in patients with multiple sclerosis or spinal cord injury, and in the neurosurgical operating room to prevent injury.

Laser-Generated Heat Pulses and Contact-Heat-Evoked Potentials:

These potentials work similarly to somatosensory evoked potentials. Instead of a sensory stimulus, laser-generated heat pulses and contact-heat evoked potentials use lasers and heated instruments, testing thermal pain perception, thereby measuring delta fibers.

Skin Biopsies:

Punch skin biopsies can quantitatively measure small neurons. After the biopsy, samples are stained to detect intraepidermal nerve fiber (IENF) density, comparing the measured density to a standard.[14]

EMGs:

Electromyography involves placing electrodes on the skin or in muscle fibers to measure muscle activation. EMGs are useful for distinguishing muscular versus neuronal weakness on efferent motor neurons but do not measure sensory neuron deficits. EMG is an option if there is a concern for motor neuron degeneration. Although EMGs do not directly assess nociceptive pathways, they are often helpful in distinguishing locations of neuropathy, and assessing if the neuropathy has a motor neuron component.

Treatment / Management

First, it is important to treat the underlying disease associated with allodynia. Usually, allodynia has an underlying disorder that requires action to slow, stop, or reverse the progression of the disease. However, allodynia by itself is often a progressive disease that worsens, even after the initial insult is over. The effective methods of treating allodynia will differ with each underlying disease state. This article will focus solely on the treatment of general allodynia, from prevention of allodynia’s progression and chronification to medical and other methods of treating allodynia.

Initiation, Progression, and Chronification:

Allodynia appears to be mediated by inflammation. NSAIDs and antiepileptic calcium channel blockers such as gabapentin have helped slow or prevent allodynia in animal models,[15] but more human data is needed. If a preventative component exists, both animal and human research suggest that it would be for the prevention of long-term allodynia, and not to improve immediate post-operative pain relief. Opioids do not seem to prevent allodynia, and in fact can be a cause of allodynia.

Medical Treatment

Oral Medical Pain Management:

Sodium channel blockers, calcium channel antagonists, and anticonvulsants act to increase firing thresholds and are generally effective in treating allodynia and neuropathic pain. Antidepressants such as serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs) also seem to help some types of neuropathic pain, although the evidence is stronger for hyperalgesia than for allodynia. However, selective serotonin reuptake inhibitors (SSRIs) have yielded mixed to disappointing results, and are not a recommendation for the treatment of allodynia. A recent Cochrane review found no good evidence for NSAID use in neuropathic pain.

Opioids are quite effective at treating pain in general; however, they are not as effective in treating neuropathic pain, and there is only very low-quality evidence that oxycodone helps in the treatment of neuropathies. Furthermore, opioids themselves have many potential side effects and can even cause long-term neuropathic pain. There are some strong proponents for cannabis-based medicines. A recent Cochrane review found minimal evidence for benefits and concluded that based on the current research, the potential side effects of cannabis might outweigh its benefits. However, it also acknowledged that there is not much existing research.

Topical Medical Pain Management:

Topical medications seem to help with certain types of allodynia, such as postherpetic neuralgia. Typical over the counter topical medications include lidocaine, menthol, and capsaicin. Lidocaine is a local anesthetic. Topical preparations have high concentrations because it does not easily pass through the skin. Topical menthol asserts its actions through initially activating, then desensitizing nociceptors, and may cause cold allodynia. Recent Cochrane evidence articles found no good-quality randomized controlled trials to support the use of topical lidocaine and topical menthol for neuropathic pain, although many small studies have reported some effectiveness. The strongest capsaicin cream available over the counter is 0.1%. There is also a prescription 8% capsaicin patch that is available, but its use requires close supervision in a hospital setting due to the potential for adverse reactions. A recent Cochrane article did find that high-concentration (8%) capsaicin generated more pain relief compared to control or low dose capsaicin.

Other topical medications include salicylates, fentanyl patches, amitriptyline, gabapentin, and ketamine. Botulinum toxin A (Botox injections) have also been used for peripheral pain. Salicylates may help the underlying inflammation but are generally not used for neuropathic pain. Fentanyl patches have poor data as to their efficacy in neuropathic pain, and their limited topical bioavailability makes high concentrations necessary; this presents a health hazard as patients have been known to ingest their patches instead of just using them topically. Topical amitriptyline and gabapentin present a novel way to deliver systemic medications that are known to be beneficial in a localized way. Again, there is limited data to support their topical use, but they may be useful if patients show negative systemic side effects to the oral preparations. The use of topical ketamine is relatively new. Ketamine has good skin absorption, and this delivery method seems to mitigate most CNS effects caused by IV delivery. It has poor oral bioavailability, which also lessens the chances of overdose.  Botulinum toxin A works by inhibiting muscle contraction, which is thought to decrease biofeedback and muscularly induced pain.

Summary of Medical Pain Management:

Currently, IASP guideline recommendations are "first-line treatment in neuropathic pain for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin. A weak recommendation for use and proposal as the second-line are lidocaine patches, capsaicin high-concentration patches, and tramadol. Lastly, a weak recommendation for use and proposal as the third-line for strong opioids and botulinum toxin A. Topical agents and botulinum toxin A are recommended for peripheral neuropathic pain only."[16](A1)

Non-medical Treatment

Psychological Therapy:

Some level of counseling should accompany the medical management of allodynia. At a minimum, counseling should include the goals and expectations of medical therapy. Patients often hopefully but erroneously believe that medical therapy can completely alleviate their symptoms. Healthcare practitioners need to clearly communicate that the goal of medical therapy is not to completely alleviate allodynia but to decrease the pain to an acceptable level. Weekly or monthly sessions with a trained therapist can often be helpful; therapists can assist patients with learning alternate coping strategies for pain in general and work on cognitive behavioral therapy to address comorbid psychological issues that often accompany pain.

Physical Therapy:

Physical therapy has adopted several psychology techniques to help patients with neurologic pain. Most of these techniques work best on pain without a large underlying medical component, such complex regional pain syndrome (CRPS), post-amputation pain, and trigeminal neuralgia. One technique is desensitization, where a light, innocuous stimulus that does not activate a pain response is gradually increased in intensity, as the patient tolerates. Another physical therapy pain management technique, often used with CRPS and post-amputation pain syndrome is mirror therapy, where a patient sees and interacts with a mirrored image of their “good” side in place of their sensitive side. Biofeedback and exposure therapy are additional ways physical therapists can help with allodynia.

Complementary Alternative Medicine:

There is scant evidence for the efficacy of complementary alternative medicine in neuropathic pain. Cupping and acupuncture have the most study data and may be beneficial in treating different types of neuropathic pain, but additional research is needed.

Interventional Treatment:

Neuropathic pain, including allodynia, is difficult to treat. Interventional treatment may be a consideration if a patient has failed more conservative treatment. One option is the use of nerve blocks. The most common sites for nerve blocks for chronic pain are intercostal nerves and the trigeminal nerve. They can be quite effective but often are of relatively limited duration, in the order of hours to months. Spinal cord stimulators/peripheral nerve stimulators attempt to stimulate sensory and innocuous neurons enough to prevent a strong signal from reaching the thalamus, and can represent a permanent long-term solution to pain; however, they require minor surgery and implantation of an electrical device. Lastly, surgical ligation of nerves is another option and may be a permanent solution to focal allodynia, such as post-vasectomy allodynia.[17]

Differential Diagnosis

Allodynia is a clinical symptom and not a disease. It can occur due to a known medical disorder, be the result of past trauma or injury, or present idiopathically by itself. Anything that causes neuropathy may also have an association with allodynia. Allodynia is often due to diabetes, fibromyalgia, migraine syndromes, or postherpetic neuralgia. Below is a noncomprehensive list with brief descriptions of diseases and traumas that can cause or have known associations with allodynia in alphabetical order:

Alcoholic polyneuropathy: Slow, progressive, associated with past or present alcohol use. Allodynia is often associated with other sensory abnormalities and may be caused mostly by nutritional deficiencies.

Central poststroke pain (also known as thalamic pain syndrome, also known as Dejerine Roussy syndrome): The patient will have a history of stroke. Classically, the stroke is located in the thalamus, although it can also be in other brain locations, such as the spinothalamocortical tract. Onset has been noted anywhere from 1 month to years after the initial stroke. Abnormalities in temperature sensation often accompany this condition.[18]

Complex regional pain syndrome: Often starts with surgery or other trauma, though the instigating trauma may be mild. It can have associations with edema and changes in skin and blood perfusion. Disease progression varies widely.[19]

Diabetes mellitus-associated allodynia (with neuralgia): Patients will have a history of diabetes, and the allodynia may or may present with accompanying sensory deficits.

Envenomation: Some animals, such as snakes and scorpions, have toxins that can cause allodynia. 

Fibromyalgia: Allodynia is a hallmark of fibromyalgia, along with fatigue and nonrestorative sleep. 

Medication toxicity: Chemotherapy drugs are significant contributors to medication toxicity. 

Migraine-associated allodynia: Patients generally will have a history of migraine, with allodynia occurring during their attacks.

Nutritional deficiencies: There is some evidence that vitamin D deficiency can potentiate allodynia.[20] B-vitamin deficiencies also contribute to neuropathy and allodynia and can be a driving cause behind alcoholic polyneuropathy.[21]

Persistent post-surgical pain (also known as chronic post-surgical pain): Pain, including allodynia, persisting for months after surgery. Generally, more extensive surgeries are more likely to cause persistent post-surgical pain. Other risk factors are female gender and age.[22]

Poisoning: Some poisons can cause allodynia. For example, ciguatera fish poisoning can cause a curious cold-induced allodynia, where cold temperature elicits burning and painfully hot sensations. A history of ingesting fish and accompanying gastrointestinal and possible cardiac signs may be present.[23]

Post-amputation stump pain: Occurs after amputation. Unlike phantom limb pain, the pain is proximal to the amputation. Incidence can be as high as 74%, and the pain can persist for years.[24]

Postherpetic neuralgia: Postherpetic neuralgia is a neuropathic pain that occurs after a herpes zoster rash. It can persist for years after the inciting rash.

Post-radiation pain: Patients can develop pain after radiation. The onset of pain can start anywhere between 1 to 10 years after radiation.[25] The differential for such pain must include possible cancer recurrence. 

Trigeminal neuralgia: Patients with trigeminal neuralgia have stimulus-evoked allodynia in the distribution of the trigeminal nerve. Generally, it is sharp and unilateral, although documentation exists of rare cases of bilateral trigeminal neuralgia. The pain can go into remission, or stop, or even change sides of the face with time.[26]

Prognosis

Many different diseases can cause allodynia. It can occur with a past or present insult, be exacerbated or triggered by emotional states, or occur idiopathically. The prognosis of the allodynia will vary dramatically with the associated underlying disease. Please see the differential diagnosis section for a noncomprehensive list of the primary conditions associated with allodynia. 

Complications

The course and complications of allodynia will vary depending upon the cause of allodynia. In general, allodynia often worsens over time as crisscrossed neuronal synapses make stronger connections. Allodynia can have a substantial negative impact on mental and emotional health, due to the distress caused by continual pain. Medical treatments for allodynia also have side effects, especially if the treatment involves opioids.