What is hyperalgesia

Hyperalgesia is increased sensitivity to pain or increased pain from a stimulus that normally provokes pain ¹. Hyperalgesia reflects increased pain on suprathreshold stimulation. This is a clinical term that does not imply a mechanism. For pain evoked by stimuli that usually are not painful, the term allodynia is preferred, while hyperalgesia is more appropriately used for cases with an increased response at a normal threshold, or at an increased threshold, e.g., in patients with neuropathy. It should also be recognized that with allodynia the stimulus and the response are in different modes, whereas with hyperalgesia they are in the same mode. Current evidence suggests that hyperalgesia is a consequence of perturbation of the nociceptive system with peripheral or central sensitization, or both, but it is important to distinguish between the clinical phenomena, which this definition emphasizes, and the interpretation, which may well change as knowledge advances. Hyperalgesia may be seen after different types of somatosensory stimulation applied to different tissues.

Noxious stimulation of the skin with either chemical, electrical or heat stimuli leads to the development of primary hyperalgesia at the site of injury and to secondary hyperalgesia in normal skin surrounding the injury ². Secondary hyperalgesia is inducible in most individuals and is attributed to central neuronal sensitization. Some individuals develop large areas of secondary hyperalgesia (high-sensitization responders), while others develop small areas (low-sensitization responders). The magnitude of each area is reproducible within individuals, and can be regarded as a phenotypic characteristic.

Hyperalgesia vs Allodynia

The official International Association for the Study of Pain definition of allodynia is “pain due to a stimulus that does not normally provoke pain” ³. An example would be a light feather touch (that should only produce sensation) causing pain. Allodynia is different from hyperalgesia, which is an exaggerated response from a normally painful stimulus, although both can and often do co-exist. Both are types of neuropathic pain ⁴.

An example of the difference between allodynia and hyperalgesia on the physical exam would be softly rubbing a cotton-tipped swab against a patient’s skin. Lightly brushing a swab against the skin would cause a low-level stimulus, but should not elicit a pain response. A patient who experiences pain with a stimulus that should only cause sensation may have allodynia. If the clinician significantly increases the degree of pressure, some pain would be part of a normal response. A patient who feels an excessive amount of pain would be noted to have hyperalgesia. Thus, on physical exam, allodynia presents as a lowering of the pain threshold, while hyperalgesia presents as a heightening of response ⁴. While this often means that allodynia and hyperalgesia seem to exist along the same continuum of stimuli on physical exam, there is still a clear difference in modalities. With allodynia, the response to the stimulus differs from those who have normal sensation, while in hyperalgesia, the response to the stimulus is the same as those who have normal sensation, but it is an exaggerated response.

Allodynia can be due to an underlying disease such as diabetes-induced neuropathic tactile allodynia or can be the primary disease process itself, such as in postherpetic neuralgia. It is often further classified by the type of stimulus causing the nociception, such as tactile, thermal, dynamic or static allodynia, or by the principal site of nociception, such as cutaneous allodynia ⁵.

Hyperalgesia and allodynia classification

• Allodynia and hyperalgesia are classified according to the sensory modality that elicits pain, i.e. thermal (cold and heat) or mechanical (dynamic touch, punctuate, and pressure).
• Dynamic mechanical allodynia is pain evoked by light brushing or stroking of the skin.
• Pressure (static and deep pressure) allodynia and hyperalgesia are elicited by pressure to skin and deep tissue).
• Punctate allodynia and hyperalgesia are evoked by punctate skin stimulation by a pin or a monofilament.
• Cold and warm allodynia and hyperalgesia are provoked by cold or warm stimuli applied to the skin.

What causes allodynia?

Allodynia is a symptom, not a disease. The exact cause behind allodynia is unknown ⁴. 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 ⁶. 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.

Hyperalgesia clinical assessment

• Simple bedside tests include response (pain intensity and character) to cotton swab, finger pressure, pinprick, cold and warm stimuli, e.g., metal thermo rollers at 20 °C and 40 °C, as well as mapping of the area of abnormality.
• Quantitative sensory testing can be used to determine pain thresholds (decreased pain threshold indicates allodynia) and stimulus/response functions (increased pain response indicate hyperalgesia). Dynamic mechanical allodynia can be assessed using a cotton swab or a brush. A pressure algometer and standardized monofilaments or weighted pinprick stimuli are used for assessing pressure and punctate allodynia and hyperalgesia and a thermal tester is used for thermal testing.

Hyperalgesia treatment

Neuropathic pain is difficult to treat. Currently, International Association for the Study of Pain guideline recommendations “first-line treatment in neuropathic pain are tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors (SNRIs), 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” ⁷.

Visceral hyperalgesia

Visceral hypersensitivity is the most definitive and unifying theory explaining the pathophysiology of all functional gastrointestinal disorders ⁸. This theory is based on the strong association between the enteric nervous system and central nervous system (CNS) and their common embryonic origin ⁹. Patients with functional gastrointestinal disorders have a low threshold for nociceptive stimuli. A variety of ill-defined factors including genetic, environmental, psychosocial (early stressors in life) etc predispose an individual to visceral hyperalgesia. Postulated mechanisms for visceral hyperalgesia include sensitization of primary sensory neurons and central spinal neurons, altered descending inhibitory control, and impaired stress response. This in turn causes alteration of bowel–gut axis and causes abnormal secretion of excitatory neurotransmitters such as serotonin. Serotonin plays a key role in the regulation of gastrointestinal (GI) motility, secretion, and sensation. The bidirectional communication between the brain–gut neurons through various neural and hormonal circuits may lead to changes in the CNS and cause other associated symptoms such as headache. Stimulation of the autonomic nervous system and sympathetic hyperactivity may account for symptoms such as pallor. Novel imaging techniques such as functional magnetic resonance imaging have shown defective visceral pain processing pathways in patients with functional gastrointestinal disorder.

Although, the theory of visceral hyperalgesia has not been specifically proven in patients with abdominal migraine, it is the most evidence-based explanation for all functional gastrointestinal disorders ⁹. A 2017 study found evidence suggesting Y2 receptor antagonism and YY gene deletion may be related to visceral hyperalgesia ¹⁰. The contribution of genetic factors to abdominal migraine is further supported by the presence of family history of migraine or chronic abdominal pain in most of the patients ¹¹. However, more research is needed to identify these factors.

Opioid induced hyperalgesia

Opioid induced hyperalgesia (increased sensitivity to pain) occurs in many different patients, depending on the dose given and the pattern of administration. Most work has reported opioid induced hyperalgesia if you are receiving continuing treatment with opioids or stop taking opioids.

Opioids are a class of drugs commonly used to treat moderate to severe pain. They can be used over prolonged periods to relieve chronic pain. Opioid induced hyperalgesia is a clinical picture which involves increasing pain in patients who are receiving increasing doses of opioids. Opioids are substances such as opium, morphine, heroin, codeine and methadone.

Clinical observation suggests that the degree of opioid-induced hyperalgesia may vary with different opioids ¹². For example, morphine is more likely to produce opioid-induced hyperalgesia than is methadone.

While the exact temporal relationship between the time course of opioid therapy and the development of opioid-induced hyperalgesia is unclear, it is conceivable that opioid-induced hyperalgesia would be more likely to develop in patients receiving high opioid doses with a prolonged treatment course, although it has also arisen in patients receiving a short course of highly potent opioid analgesics ¹³. Patients who are receiving opioid therapy for neuropathic pain may be more susceptible to developing opioid-induced hyperalgesia because of the shared cellular mechanisms involved ¹⁴.

During opioid treatment of pain, a decline in analgesic efficacy has traditionally been thought to result from the development of pharmacological tolerance (or disease progression), best overcome by dose escalation. More recently, it has been recognized that opioids can also activate a pronociceptive mechanism resulting in heightened pain sensitivity or opioid-induced hyperalgesia ¹⁵. Although hyperalgesia had previously been observed during opioid withdrawal, new evidence suggests that increased pain sensitivity can also occur during opioid administration, in the absence of an overt, precipitated withdrawal. This paradoxical opioid-induced pain sensitivity may contribute to reduced opioid analgesic efficacy. Therefore, it is possible that a decrease in opioid analgesic efficacy may be a result of opioid induced hyperalgesia (a pronociceptive mechanism), not simply of pharmacological tolerance. Both a sensitization and a desensitization process are taking place.

Opioid-induced hyperalgesia is mediated through distinct cellular mechanisms, including endogenous dynorphin, the glutamatergic system, and descending
facilitation ¹⁶. Interestingly, the cellular mechanisms of opioid induced hyperalgesia have much in common with those of neuropathic pain and opioid tolerance ¹⁶. For example, both peripheral nerve injury and repeated opioid administration can activate a similar cellular pathway involving activation of the central glutamatergic system ¹⁷. NMDA antagonists such as ketamine have been used clinically to reverse the glutamatergic component of pain sensitivity.

Risk factors for developing opioid induced hyperalgesia

• If you are taking high doses of opioids, you may be more likely to experience increasing pain and sensitivity.
• If you have medical conditions such as kidney failure or liver failure, the effects of opioid medications may be affected. Opioid drugs are broken down by the liver and excreted by the kidney. One of the after products of morphine is much more potent than morphine itself. It is undecided whether a build up of this after product is linked to being more sensitive to pain.
• When you are on opioids and suddenly stop taking the medication, evidence has shown that hyperalgesia has been one of the many symptoms associated with stopping opioid medications.

Opioid induced hyperalgesia signs and symptoms

Opioid induced hyperalgesia symptoms

Doctors may consider this condition in patients who have a history of;

• increasing sensitivity to pain,
• pain that worsens despite high doses of opioids and
• pain that becomes more wide-spread around the body.

Signs of opioid induced hyperalgesia

When the doctor is examining you, some of the following signs may be found. On examination, you may complain of pain from non-painful stimuli, such as soft touching of the skin with cotton wool.

There may be increased activity in your nervous system. These signs include;

• myoclonus (uncontrollable twitching and jerking of muscles or muscle groups),
• seizures (due to abnormal electrical activity in the brain causing things such as abnormal movements, spasms, or changes in behavior).

1. Opioid-induced hyperalgesia may differ from preexisting pain in its quality, location, and distribution pattern. The clinical hallmark of pathological pain is hyperalgesia in a dermatomal or generalized distribution. Quantitative sensory testing may reveal abnormalities in the threshold, tolerability, and distribution patterns of pain. A difference between neuropathic pain and opioid-induced hyperalgesia might be that for many neuropathic pain conditions,
   hyperalgesia arises in a distinct anatomical distribution, whereas opioid-induced hyperalgesia could be generalized in its distribution. This type of testing is in its infancy, but it may eventually reveal whether opioid-induced hyperalgesia is a completely separate phenomenon or can worsen existing neuropathic pain.
2. Opioid-induced hyperalgesia may intensify with opioid dose escalation but improve after supervised opioid tapering. In contrast, undertreatment of preexisting pain and pharmacological opioid tolerance may be overcome by a trial of opioid dose escalation.

Opioid induced hyperalgesia treatment

Research has shown that opioid induced hyperalgesia is a significant consequence of taking opioid medications. If you are taking such medications and are experiencing increasing pain, the use of alternative pain killers and stopping opioids may need to be considered.

In most cases, the first step is to look at reducing or discontinuing the current opioid. Alternatively, the doctor can look at changing your opioid to one with less risk of toxic effects to your nervous system: e.g., – fentanyl or methadone.

Low doses of drugs which have an opposing mechanism of action to opioids (called opioid antagonists), or specific NMDA (N-methyl-D-aspartate; a special amino acid implicated in opioid sensitivity) antagonists (such as ketamine) may be appropriate in some cases. Your doctor will be able to provide you with more information about this.

High levels of water intake is also recommended for your well-being.

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