Numerous compounds alleviate the pain from allodynia. Some are specific for certain types of allodynia while others are general. They include:

- Dynamic mechanical allodynia - compounds targeting different ion channels; opioids

- Mexiletine

- Lidocaine (IV/topical)

- Tramadol

- Morphine (IV)

- Alfentanil (IV)

- Ketamine (IV)

- Methylprednisone (intrathecal)

- Adenosine

- Glycine antagonist

- Desipramine

- Venlafaxine

- Lyrica

- Static mechanical allodynia - sodium channel blockers, opioids

- Lidocaine (IV)

- Alfentanil (IV)

- Adenosine (IV)

- Ketamine (IV)

- Glycine antagonist

- Venlafaxine

- Gabapentin (may also be helpful in cold and dynamic allodynias)

- Cold allodynia

- Lamotrigine

- Lidocaine (IV)

The list of compounds that can be used to treat allodynia is even longer than this. For example, many non-steroidal anti-inflammatory drugs, such as naproxen, can inhibit COX-1 and/or COX-2, thus preventing the sensitization of the central nervous system. Another effect of naproxen is the reduction of the responsiveness of mechano- and thermoreceptors to stimuli.

Other compounds act on molecules important for the transmission of an action potential from one neuron to another. Examples of these include interfering with receptors for neurotransmitters or the enzymes that remove neurotransmitters not bound to receptors.

Endocannabinoids are molecules that can relieve pain by modulating nociceptive neurons. When anandamide, an endocannabinoid, is released, pain sensation is reduced. Anandamide is later transported back to the neurons releasing it using transporter enzymes on the plasma membrane, eventually disinhibiting pain perception. However, this re-uptake can be blocked by AM404, elongating the duration of pain inhibition.

Hyperalgesia is similar to other sorts of pain associated with nerve irritation or damage such as allodynia and neuropathic pain, and consequently may respond to standard treatment for these conditions, using various drugs such as SSRI or tricyclic antidepressants, Nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, gabapentin or pregabalin, NMDA antagonists, or atypical opioids such as tramadol. Where hyperalgesia has been produced by chronic high doses of opioids, reducing the dose may result in improved pain management. However, as with other forms of nerve dysfunction associated pain, treatment of hyperalgesia can be clinically challenging, and finding a suitable drug or drug combination that is effective for a particular patient may require trial and error. The use of a transcutaneous electrical nerve stimulation device has been shown to alleviate hyperalgesia.

Allodynia is a clinical feature of many painful conditions, such as neuropathies, complex regional pain syndrome, postherpetic neuralgia, fibromyalgia, and migraine. Allodynia may also be caused by some populations of stem cells used to treat nerve damage including spinal cord injury. Static mechanical allodynia is a paradoxical painful hypoaesthesia, one etiology of which is lesions of A-beta fibers.

Hyperalgesia ( or ; 'hyper' from Greek ὑπέρ (huper, “over”), '-algesia' from Greek algos, ἄλγος (pain)) is an increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves. Prostaglandins E and F are largely responsible for sensitizing the nociceptors. Temporary increased sensitivity to pain also occurs as part of sickness behavior, the evolved response to infection.

Treatment of opioid tolerance and Opioid-Induced Hyperalgesia (OIH) differs but it may be difficult to differentiate these two conditions in a clinical setting where most pain assessments are done through simple scale scores. The treatment for OIH may be challenging because an inadequate number of quality studies exists possibly due to the complexity in diagnosis of OIH and challenges in working with patients on chronic opioids. Currently there is no single best treatment method for OIH and clinicians are advised to choose an appropriate therapy based on the unique clinical scenario and history of each patient.

One general treatment option is to reduce or discontinue the dose of opioid to see if OIH is improved. Opioid sparing or opioid switching, which is replacing the current opioid with another pharmacological agent such as morphine or methadone, has been reported to be effective in some studies but this may also increase the sensitivity to pain according to some case reports. Ketamine, a NMDA antagonist, has been shown to prevent the extended use of opioid in post-operative hyperalgesia when it is infused in a small amount perioperatively along with the opioid but there are also studies that show ketamine being ineffective in modulating hyperalgesia. Addition of the NSAID, especially some COX-2 inhibitors, or acetaminophen is also suggested as a possible treatment option.

As of 2013 low quality evidence supports the use of bisphosphonates. A 2009 review found "very limited data reviewed showed that bisphosphonates have the potential to reduce pain associated with bone loss in patients with CRPS I, however, at present there is not sufficient evidence to recommend their use in practice".

Physical and occupational therapy have low quality evidence to support their use. Physical therapy interventions may include transcutaneous electrical nerve stimulation, progressive weight bearing, tactile desensitization, massage, and contrast bath therapy.

Hyperpathia is a clinical symptom of certain neurological disorders wherein nociceptive stimuli evoke exaggerated levels of pain. This should not be confused with allodynia, where normally non-painful stimuli evoke pain.

In examining the published studies on opioid-induced hyperalgesia (OIH), Reznikov "et al" criticize the methodologies employed on both humans and animals as being far-removed from the typical regimen and dosages of pain patients in the real world. They also note that some OIH studies were performed on drug addicts in methadone rehabilitation programs, and that such results are very difficult to generalize and apply to medical patients in chronic pain. In contrast, a study of 224 chronic pain patients receiving 'commonly-used' doses of oral opioids, in more typical clinical scenarios, found that the opioid-treated patients actually experienced no difference in pain sensitivity when compared to patients on non-opioid treatments. The authors conclude that opioid-induced hyperalgesia may not be an issue of any significance for normal, medically-treated chronic pain patients at all.

Opioid-induced hyperalgesia has also been criticized as overdiagnosed among chronic pain patients, due to poor differential practice in distinguishing it from the much more common phenomenon of opioid tolerance. The misdiagnosis of common opioid tolerance (OT) as opioid-induced hyperalgesia (OIH) can be problematic as the clinical actions suggested by each condition can be contrary to each other. Patients misdiagnosed with OIH may have their opioid dose mistakenly decreased (in the attempt to counter OIH) at times when it is actually appropriate for their dose to be increased or rotated (as a counter to opioid tolerance).

The suggestion that chronic pain patients who are diagnosed as experiencing opioid-induced hyperalgesia ought to be completely withdrawn from opioid therapy has also been met with criticism. This is not only because of the uncertainties surrounding the diagnosis of OIH in the first place, but because of the viability of rotating the patient between different opioid analgesics over time. Opioid rotation is considered a valid alternative to the reduction or cessation of opioid therapy, and multiple studies demonstrate the rotation of opioids to be a safe and effective protocol.

Anesthesia dolorosa or anaesthesia dolorosa or deafferentation pain is pain felt in an area (usually of the face) which is completely numb to touch. The pain is described as constant, burning, aching or severe. It can be a side effect of surgery involving any part of the trigeminal system, and occurs after 1–4% of peripheral surgery for trigeminal neuralgia. No effective medical therapy has yet been found. Several surgical techniques have been tried, with modest or mixed results. The value of surgical interventions is difficult to assess because published studies involve small numbers of mixed patient types and little long term follow-up.

- Gasserian ganglion stimulation is stimulation of the gasserian ganglion with electric pulses from a small generator implanted beneath the skin. There are mixed reports, including some reports of marked, some of moderate and some of no improvement. Further studies of more patients with longer follow-up are required to determine the efficacy of this treatment.

- Deep brain stimulation was found in one review to produce good results in forty-five percent of 106 cases. Though relief may not be permanent, several years of relief may be achieved with this technique.

- Mesencephalotomy is the damaging of the junction of the trigeminal tract and the periaqueductal gray in the brain, and has produced pain relief in a group of patients with cancer pain; but when applied to six anesthesia dolorosa patients, no pain relief was achieved, and the unpleasant sensation was in fact increased.

- Dorsal root entry zone lesioning, damaging the point where sensory nerve fibers meet spinal cord fibers, produced favorable results in some patients and poor results in others, with incidence of ataxia at 40%. Patient numbers were small, follow-up was short and existing evidence does not indicate long term efficacy.

- One surgeon treated thirty-five patients using trigeminal nucleotomy, damaging the nucleus caudalis, and reported 66% "abolition of allodynia and a marked reduction in or (less frequently) complete abolition of deep background pain."

Hyperpathia describes the neuropathic pain which the pain threshold on one hand is elevated and the other hand is central hyperexcited whenever there is a loss of fibres. Hyperpathia is underlying the peripheral or central deafferentation when the afferent inputs are lost. Hyperpathia only occurs on neuropathic pain patients with the loss of fibres.

The International Association of the Study of Pain’s (IASP) definition of hyperpathia is that: "A painful syndrome characterized by an abnormally painful reaction to a stimulus, "especially a repetitive stimulus, as well as an increased threshold." The definition also complies with a note which is: "It may occur with allodynia, hyperesthesia, hyperalgesia, or dysesthesia. Faulty identification and localization of the stimulus, delay, radiating sensation, and after-sensation may be present, and the pain is often explosive in character. The changes in this note are the specification of allodynia and the inclusion of hyperalgesia explicitly. Previously hyperalgesia was implied, since hyperesthesia was mentioned in the previous note and hyperalgesia is a special case of hyperesthesia".

Feline hyperesthesia syndrome is an uncommon but recognized condition in cats, particularly Siamese, Burmese, Himalayan, and Abyssinian cats. It can affect cats of all ages, though it is most prevalent in mature animals. The disease can be somewhat difficult to detect as it is characterized by brief bursts of abnormal behavior, lasting around a minute or two. One of its symptoms is also found in dogs that have canine distemper disease (CD) caused by canine distemper virus (CDV).

Hyperesthesia (or hyperaesthesia) is a condition that involves an abnormal increase in sensitivity to stimuli of the sense. "When a non-noxious stimulus causes the sensation of pain the area will be termed hyperaesthetic". Stimuli of the senses can include sound that one hears, foods that one tastes, textures that one feels, and so forth. Increased touch sensitivity is referred to as "tactile hyperesthesia", and increased sound sensitivity is called "auditory hyperesthesia". Tactile hyperesthesia may be a common symptom of many neurologic disorders such as herpes zoster, peripheral neuropathy and radiculopathies. In 1979, and then in 1994, Merskey, Bogduk, Noordenbos, Devor and others (a subcommittee of International Association for the Study of Pain) proposed, instead of hyperaesthesia, the concept of allodynia, meaning "other pain", defined as a pain resulting from a stimulus that does not normally provoke pain.

In psychology, Jeanne Siaud-Facchin uses the term by defining it as an "exacerbation des sens" that characterizes gifted children (and adults): for them, the sensory information reaches the brain much faster than the average, and the information is processed in a significantly shorter time.

There is no specific treatment for NDPH. Often they are treated similar to migraines.

A number of medications have been used including amitriptyline, gabapentin, pregabalin, propranolol, and topiramate. There are no prospective placebo controlled trials of preventive treatment. In those with migrainous features treatment may be similar to migraines.

Opiates, or narcotics, tend to be avoided because of their side effects, including the development of medication overuse headaches and potential for dependency. NDPH is often associated with medication overuse. To avoid the development of medication overuse headaches, it is advised not to use pain relievers for more than nine days a month.

NDPH, like other primary headaches, has been linked to comorbid psychiatric conditions, mainly mood and anxiety and panic disorders. The spectrum of anxiety disorders, particularly panic disorder, should be considered in NDPH patients presenting with psychiatric symptoms. Simultaneous treatment of both disorders may lead to good outcomes.

Medications within the tetracycline family, mexiletine, corticosteroids and nerve blocks are being studied. Occipital nerve block have been reported to be helpful for some people. 23/71 people had undergone a nerve block for their severe headache. The NDPH-ICHD group responded to the nerve block much more often (88.9%) than the NDPH with migraine features (42.9% responded to nerve block).

Expensive and invasive, the above treatments are not guaranteed to work, and are not meeting the needs of patients. There is a need for a new, less expensive, less invasive form of treatment, two of which are postulated below.

- Spinal cord stimulation has been studied in the last couple of years. In a long case study, 8 patients were given spinal cord stimulation via insertion of a percutaneous lead at the appropriate level of the cervical or thoracic spine. Between 36 and 149 months after the stimulations, the patients were interviewed. 6 of the 8 had received initial pain relief, and three experienced long-term pain relief. Spinal cord stimulation is cheaper than brain stimulation and less invasive, and is thus a more promising option for pain treatment.

- In 2007, Dr. V. S. Ramachandran and his lab proposed that caloric stimulation might be effective in treating Dejerine–Roussy syndrome. They hypothesized that if cold water was streamed into the ear down the auditory canal, the symptoms associated with Dejerine–Roussy syndrome would be alleviated. Ramachandran stated that he had carried out provisional experiments on two patients and believed that their reactions supported his theory.

Many chemical medications have been used for a broad range of neuropathic pain including Dejerine–Roussy syndrome. Symptoms are generally not treatable with ordinary analgesics. Traditional chemicals include opiates and anti-depressants. Newer pharmaceuticals include anti-convulsants and Kampo medicine. Pain treatments are most commonly administered via oral medication or periodic injections. Topical In addition, physical therapy has traditionally been used alongside a medication regimen. More recently, electrical stimulation of the brain and spinal cord and caloric stimulation have been explored as treatments.

The most common treatment plans involve a schedule of physical therapy with a medication regimen. Because the pain is mostly unchanging after development, many patients test different medications and eventually choose the regimen that best adapts to their lifestyle, the most common of which are orally and intravenously administered.

Most patients have persistent headaches, although about 15% will remit, and 8% will have a relapsing-remitting type. It is not infrequent for NDPH to be an intractable headache disorder that is unresponsive to standard headache therapies.

Research suggests that people with AFP are not helped greatly by health care professionals. One study reported that on average, individuals had consulted 7.5 different doctors. 91% had seen dentists, 80% physicians, 66% neurologists, 63% ear, nose and throat surgeons, 31% orthopedic and maxillofacial surgeons, 23% psychiatrists, 14% neurosurgeons and 6% ophalmologists and dermatologists. In this study, the individuals had been subjected to a wide variety of different treatments, from surgery, antidepressants, analgesics and physical therapies. None of the persons reported that surgery was beneficial, and in many cases the pain was worsened by surgery. The article sited as the source of this information was withdrawn from publication, saying the information was out of date and not meeting Cochrane methodological standards.

It has been suggested that the onset of chronic facial will likely be a life changing development for those affected.

Psychosocial interventions for AFP include cognitive behavioral therapy and biofeedback. A systematic review reported that there was weak evidence to support the use of these treatments to improve long-term outcomes in chronic orofacial pain, however these results were based primarily upon temporomandibular joint dysfunction and burning mouth syndrome rather than ATP and AO.

Psychosocial interventions assume 2 models of chronic facial pain, namely "inactivity" and "over activity". The former is where people with pain become conditioned to avoid physical activity as a result of exacerbating their pain. These negative thoughts and behaviors in fact prolong and intensify their symptoms. Some psychosocial interventions work on this fear-avoidance behaviour to improve functioning and thereby alleviate symptoms. The over activity model involves factors such as anxiety, depression or anger acting to increase pain by triggering autonomic, visceral and skeletal activity.

A range of medications that act on the central nervous system has been found to be useful in managing neuropathic pain. Commonly used treatments include tricyclic antidepressants (such as nortriptyline or amitriptyline), the serotonin-norepinephrine reuptake inhibitor (SNRI) medication duloxetine, and antiepileptic therapies such as gabapentin, pregabalin, or sodium valproate. Few studies have examined whether nonsteroidal anti-inflammatory drugs are effective in treating peripheral neuropathy.

Symptomatic relief for the pain of peripheral neuropathy may be obtained by application of topical capsaicin. Capsaicin is the factor that causes heat in chili peppers. The evidence suggesting that capsaicin applied to the skin reduces pain for peripheral neuropathy is of moderate to low quality and should be interpreted carefully before using this treatment option. Local anesthesia often is used to counteract the initial discomfort of the capsaicin. Some current research in animal models has shown that depleting neurotrophin-3 may oppose the demyelination present in some peripheral neuropathies by increasing myelin formation.

High-quality evidence supports the use of cannabis for neuropathic pain.

The treatment of peripheral neuropathy varies based on the cause of the condition, and treating the underlying condition can aid in the management of neuropathy. When peripheral neuropathy results from diabetes mellitus or prediabetes, blood sugar management is key to treatment. In prediabetes in particular, strict blood sugar control can significantly alter the course of neuropathy. In peripheral neuropathy that stems from immune-mediated diseases, the underlying condition is treated with intravenous immunoglobulin or steroids. When peripheral neuropathy results from vitamin deficiencies or other disorders, those are treated as well.

Investigational medications include cannabinoids and the 5-HT3 receptor antagonist tropisetron. Low quality evidence found an improvement in symptoms with a gluten free diet among those without celiac disease. A controlled study of guaifenesin failed to demonstrate any benefits from this treatment.

Health Canada and the US Food and Drug Administration (FDA) have approved pregabalin and duloxetine, for the management of fibromyalgia. The FDA also approved milnacipran, but the European Medicines Agency refused marketing authority.

Antidepressants are mostly ineffective in treating CFS. Antiviral and immunological therapies have provided some benefit, but are limited by their side effects.

Steroid replacement therapy is not effective.

There is some preliminary evidence that the immunomodulatory medication rintatolimod improves exercise capacity, as well as cognitive function and quality of life, based on two trials. The US FDA has repeatedly denied commercial approval, citing numerous deficiencies in both trials, and concluding that the available evidence is insufficient to demonstrate its safety or efficacy in CFS.

In 2017, the U.S. Centers for Disease Control and Prevention recommended light exercises and stretching but not in the four hours before bed to help with sleep. Stretching and movement therapies are also recommended for pain. Previously, a 2014 National Institutes of Health report concluded that while GET could produce benefits, it may not yield improvement in quality of life and that because of this limitation, GET should not be considered as a primary treatment, but instead be used only as one component of a broader approach. The report also noted that a focus on exercise programs had discouraged patient participation in other types of physical activity, due to concerns of precipitating increased symptoms. A July 2016 addendum to this report recommended that the Oxford criteria not be used when studying ME/CFS. If studies based on the Oxford criteria were excluded, there would be insufficient evidence of the effectiveness of GET on any outcome.

A 2016 Cochrane review stated that exercise therapy could contribute to alleviation of some symptoms of CFS, especially fatigue. The Cochrane review also noted that research was inconclusive as to which, if any, type of exercise therapy was superior, and concluded that no evidence had been found suggesting that exercise therapy worsened outcomes. A 2015 review article determined that serious adverse effects, or harms, from exercise therapy were poorly reported in most studies, and determined there was insufficient evidence for a conclusion.

As with CBT, patient organisations have long criticised the use of exercise therapy, most notably GET, as a treatment for CFS. In 2012 the MEA commenced an extensive opinion survey of patients who had received GET. Based on the findings of this survey, in 2015 the MEA concluded that GET in its current delivered form should not be recommended as a primary intervention for persons with CFS.