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Withdrawal-Induced Hyperalgesia (WIH)

Opioid Withdrawal-Induced Hyperalgesia (WIH) can be defined as “an increased response to a painful stimulus caused by precipitating opioid withdrawal.” It can be experienced when withdrawing from use of prescription opioids for chronic pain or by illicit use of opioids related to substance abuse or addiction.



Hyperalgesia is an exaggerated, increased painful response to a stimulus which is normally painful.


Also see:


Opioid Tolerance

Opioid-Induced Hyperalgesia (OIH)

Opioid Withdrawal

Withdrawal-Induced Hyperalgesia (WIH)

Neurobiology of Pain

Neuropathic Pain

Gabapentin (Neurontin) & Pregabalin (Lyrica)

TLR-4 Antagonists



Definitions and Terms Related to Pain

Key to Links:

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Blue text – Journal publication



Withdrawal-Induced Hyperalgesa (WIH)

The syndrome of symptoms associated with abruptly stopping or markedly reducing one’s chronic dose of opioids is referred to as Opioid Withdrawal (OW) syndrome. It is characterized by muscle aches (myalgias), joint paints (arthralgias), nausea, vomiting, abdominal cramps, diarrhea, sweating, malaise, fatigue, headaches and other symptoms. Withdrawal-induced hyperalgesia (WIH) is a distinct entity that may accompany the OW syndrome which is  an increased sensitivity to pain,  characterized by a magnified perception of pain as well as a lower threshold for a stimulus to be perceived as painful.


WIH is commonly experienced when someone stops taking opioids, whether it is related to prescription opioid use for chronic pain or illicit opioid use related to substance abuse or addiction. Ii is a phenomenon apparently associated with all opioids such as opioids commonly prescribed for pain, including buprenorphine and methadone. While research is lacking, it may not be unexpected to also find WIH as a consequence of non-opioid medication withdrawal including benzodiazepines, alcohol and cannabis (marijuana).


Risks for WIH

There are few studies that investigate risk factors that may influence the occurence or severity of WIH. Clinical observations identify the severity of WIH to be related to the dosing and duration of opioid use, with higher doses and longer duration of use associated with greater severity of WIH. Anecdotal reports suggest that some opioids may provide greater severity than others, including buprenorphine to possibly offer less severity, but no definitive studies are available.


A recent study assessed the severity of WIH in heroin withdrawal patients and reported greater severity in those with negative affect states, in other words those with negative emotions including unhappiness, anger, contempt, disgust, guilt, and fear, and nervousness. These emotions are related to depression, stress, anxiety, PTSD and other psychiatric disturbances. The caveat here would suggest that it is important to treat emotional and psychatric conditions that would impact withdrawal states.


Manifestations of WIH

There are different manifestations of opioid WIH.


Nonspecific Hyperalgesia

Abruptly discontinuing opioids leads to generalized hypersensitivity to pain that may include not only any underlying chronic pain for which the opioids were prescribed, but also other types of pain. Though not well studied, it is believed to be worse the higher the doses of opioids discontinued and the longer the opioids were taken. The hypersensitivity to pain has mostly been studied for pain related to cold exposure as studied in cold pressor testing in which pain is measured after immersing a subject’s arm in ice water while an inflated blood pressure cuff restricts blood flow to the arm.


Withdrawal-Induced Injury Site Pain (WIISP)

It has also been found that many people may experience re-activation of a pain related to a remote injury or trauma that had previously resolved and become pain-free prior to initiating opioid therapy, even injuries from childhood (Withdrawal Induced Injury Site Pain or WIISP).  Pain sensitivity in areas of previous trauma can also be experienced differently from the original pain. Patients describe their WIISP as distinct from other OW symptoms. WIISP appears to occur mostly in patients that abruptly discontinue opioids as opposed to those slowly tapering down. This experience of recurrence of old pains is temporary and resolves as the OW syndrome resolves.

While anecdotal eports of WIISP are not uncommon, WIISP appears to be avaluated by only one study of 58 patients, published in 2016. In this study 47 of the 58 patients described symptoms consistent with WIISP. Their experiences were generally reported as intense and aversive, both physically and emotionally. In another study not yet published, the author evaluated 685 people who injected opioids as part of their addiction and discovered a 40% prevalence of WIISP in this population. Of interest in this group it was noted that the presence of chronic neuropathic pain actually had a negative association compared with other types of pain, although there may have been medication confounders in the interpretation of this association including the use of buprenorphine/naloxone which may reduce the symptoms of neuropathic pain and/or reduce the symptoms of WIISP.

While most people experienced resolution of their WIISP symptoms within 2 weeks of stopping their opioids and 82% experienced resolution within one month, one patient described continued symptoms for one year. In contrast, the average duration of withdrawal is the population studied was 13 days. Most patients described the WIISP symptoms as severe (averaging 8/10) and worse than other OW related pain. While the majority of people described their WIISP pain as equal or less severe than the pain associated with the original condition, 35% experienced the WIISP pain as more severe than the original.

Prior to discontinuing opioids, those who had rotated to a different opioid, especially buprenorphine (i.e Suboxone), experienced less severe pain with their WIISP. There did not appear to be any one opioid that demonstrated significantly more, or less, risk for WIISP. The most commonly reported medications that were identified by study participants as reducing their pain of WIISP included NSAIDs, gabapentin (Neurontin) and pregabalin (Lyrica).

Of significance, a number of subjects indicated that calming techniques including meditation and deep relaxation techniques offered significant benefit. Coupled with the finding that emotional disturbances similar to the original experience were often re-experienced with WIISP, it is evident that the emotional centers of the brain are involved as well as pain centers. This strongly suggests a role for medical hypnosis and guided imagery techniques along with other mindful exercises in the management of WIISP.

Prevention of WIH

Studies suggest that rather than abruptly stopping opioids, tapering down slowly will reduce the risk and/or severity of WIH. Additionally, rotating to an alternative opioid prior to tapering may also be effective. Anecdotal reports indicate that rotating to buprenorphine may be especially helpful.

 See: Tapering off Opioids


Treatment of WIH

WIH treatment is not well studied and it is recommended that a multi-modal approach is more likely to be effective. The following classes of medications may offer relief.

NMDA Antagonists

Since the main proposed mechanism for OIH involves the NMDA receptors (see Education – Pain), there is some research to support the benefit of NMDA blockers such as ketamine (see Compounded Topical medications) and dextromethorphan in suppressing WIH.


Activation of NMDA receptors by glutamate is implicated in the mechanism of OIH and WIH. The increase in the release of glutamate in the dorsal horn of the spinal cord and the sustained increase in the response of NMDA receptors through protein kinase-C -mediated manganese removal, seem to be the main mechanisms implicated in OIH. NMDA receptors can be activated by most opioids although two opioids, methadone and levorphanol, have been found to antagonize NMDA activity which is why they are believed to be associated with less development of opioid analgesic tolerance. However, methadone possesses only weak NMDA antagonism and is still associated with significant WIH.


Depending on the source of pain, there may be an argument for the use of topical ketamine. Recent research showed that oral ketamine at low, slowly increasing doses may prove effective in neuropathic pain and would likely benefit WIH as well.  MgSo4 (epsom salts) are thought to be an NMDA antagonist and may offer benefit. Dextromethorphan, a cough suppressant found in OTC cough medications such as Delsym, may also be a treatment option.


Memantine, a prescription NMDA antagonist, in doses of 30-60mg/day has been shwn to reduce the severity of opioid withdrawal and may be effective in treating WIH.

See: Ketamine and Dextromethorphan

Gabapentinoids (Gabapentin (Neurontin) and Pregabalin (Lyrica)

There is growing evidence that adding gabapentin (Neurontin), pregabalin (Lyrica) may be effective against both OID and WIH. Current research indicates that the gabapentinoids, gabapentin and pregabalin, have multiple mechanisms by which they reduce hyperalgesia and some of these mechanisms suggest potential benefit in reducing WIH. In one study of OIH, gabapentin acted synergistically to prevent OIH when combined with ketamine.

See: Gabapentin (Neurontin) & Pregabalin (Lyrica)



NSAIDs (ibuprofen, Aleve, Naproxen)

Activation of COX-2 receptors in the spinal cord likely play a role in WIH and prostaglandins are involved in NMDA activity and the development of hyperalgesia. Studies suggest the benefit of  the Cox-2 inhibitor, celecoxib (Celebrex), in suppressing the development of OIH and NSAIDs that inhibit Cox-1 receptors including ibuprofen and naproxen have been shown to alleviate WIH.



Ondansetron (Zofran)

Ondansetron (Zofran), commonly used to treat nausea and vomiting, has been showing promise in recent studies to be effective against OW and OIH through its action as a 5-HT3 receptor antagonist.

See: Withdrawal Induced Hyperalgesia


Microglial Inhibitors & TLR-4 Antagonists

There may be a WIH treatment role for microglial inhibitors, drugs that suppress the activity of microglia, the cells in the nervous system that are thought to activate neuro-inflammation, an underlying mechanism for hyperalgesia and central sensitization. There is a great deal of research interest in medications that may modify microglial activity but little is known that is very useful clinically yet. Some research suggests that minocycline, an antibiotic, may inhibit microglial activity by mechanims unrelated to antibiotic activity. Animal studies have shown that minocycline inhibits heat-related hyperalgesia.


Another group of medications, TLR-4 antagonists, also holds promise in the management of WIH as well as for OIH and opioid tolerance. Toll-like receptors (TLR) are a class of receptors found in glial cells which make up the matrix of cells surrounding and communicating with nerve cells in both the peripheral and central nervous systems.  Toll-like receptors, especially toll-like receptors 4 (TLR-4) are relatively recently discovered players in the complex cascade of nerve activity related to pain and, in particular, opioids. Agents that block, or antagonize, TLR-4 receptors such PEA (palmitoylethanolamide), naloxone and naltrexone may be useful in managing WIH, OIH, opioid analgesic tolerance and some types of pain.

 See: Toll-Like Receptor (TLR-4) Antagonists


Antioxidants and NRF2 Activators

Animal studies have identified a role of reactive oxidative species (ROS) – free radicals – in the development of neuropathic and inflammatory pain, hyperalgesia and central sensitization. The role of ROS species in the dorsal horn neurons including the superoxide free radical produced in mitochondria and superoxide dismutase, the antioxidant manufactured in mitochondria have been implicated in neuropathic pain, hyperalgesia and central sensitization.


Furthermore, mitochondrial dysfunction has also been identified as a likely contributor to neuropathic pain as well as the hyperalgesia, allodynia and central sensitization associated with fibromyalgia.


Based on this preliminary research, it would appear prudent to minimize oxidative stress as a means of reducing or reversing neuropathic pain, OIH and central sensitization as well possibly reducing risk for developing atherosclerosis or Alzheimer disease. Supplements including various antioxidants, NRF2 activators and nicotinamide riboside (NR) have growing evidence for their potential benefit in these conditions.

See: Antioxidants, NRF2 Activators, Nicotinamide Riboside, and Mitochondrial Dysfunction.


Neurobiology of WIH

Multiple factors and mechanisms may be theorized to contribute for WIH, such as: changes in NMDA and TLR-4 receptors, intracellular messengers, spinal COX activation, release of excitatory amino acids and reduction of inhibitory neurotransmitters and activity of descending nerve pathways. With chronic pain and/or opioid use, changes can be seen in the central and peripheral nervous system, with sensitization of pro-nociceptive (pro-pain) pathways. Cellular changes are seen in several anatomical sites, such as afferent neurons and spinal cord, glia, the brain, and descending nerve pathways. Changes can be seen in receptors and nerve channels, as well as peripheral and central sensitization. The endogenous opioid system is altered as well and may contribute to the hyperalgesia.

See: Neurobiology of Pain


Withdrawal Induced Hyperalgesa (WIH)

Reference Articles:


WIH – Overviews

  1. Reduced Cold Pain Tolerance in Chronic Pain Patients Following Opioid Detoxification – 2008
  2. Negative Affect Heightens Opiate Withdrawal-Induced Hyperalgesia in Heroin Dependent Individuals – 2011


WIH – Treatment, Gabapentin

  1. Role of gabapentin in preventing fentanyl- and morphine-withdrawal-induced hyperalgesia in rats. – PubMed – NCBI
  2. Gabapentin Effect on Pain Associated with Heroin Withdrawal in Iranian Crack – 2012


WIH – Treatment, Ketamine

  1. Experience of the use of Ketamine to manage opioid withdrawal in an addicted woman – a case report – 2016
  2. The role of ketamine in preventing fentanyl-induced hyperalgesia and subsequent acute morphine tolerance. – PubMed – NCBI

WIH – Treatment: Memantine

  1. memantine-produces-modest-reductions-in-heroin-induced-subjective-responses-in-human-research-volunteers-pubmed-ncbi
  2. a-placebo-controlled-trial-of-memantine-as-an-adjunct-to-injectable-extendedrelease-naltrexone-for-opioid-dependence-2014
  3. memantine-improves-buprenorphinenaloxone-treatment-for-opioid-dependent-young-adults-2015
  4. ondansetron-an-effective-treatment-for-the-withdrawal-symptoms-of-opioids
  5. From mouse to man – the 5-HT3 receptor modulates physical dependence on opioid narcotics – 2009


WIH – Treatment: Minocycline

  1. Minocycline blocks lipopolysaccharide induced hyperalgesia by suppression of microglia but not astrocytes – 2015
  2. Minocycline, a microglial inhibitor, blocks spinal CCL2-induced heat hyperalgesia and augmentation of glutamatergic transmission in substantia gelatinosa neurons – 2014


WIH – Treatment: Ondanstron

  1. ondansetron-an-effective-treatment-for-the-withdrawal-symptoms-of-opioids
  2. From mouse to man – the 5-HT3 receptor modulates physical dependence on opioid narcotics – 2009


WIH – Treatment, Complementary and Alternative (CAM)

  1. Acetyl-L-carnitine in the management of pain during methadone withdrawal syndrome. – 2009


Withdrawal-induced Injury Site Pain (WISP) – Overviews

  1. Withdrawal-associated injury site pain (WISP – a descriptive case series of an opioid cessation phenomenon – 2016

Emphasis on Education


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