Opioid-Induced Hyperalgesia was often observed in patients taking high dosage of opioid. Symptoms of Opioid induced hyperalgesia were thought to be more common in long-term opioid therapy. Recent studies and experience has indicated hyperalgesia is also observed in fibromyalgia and short-term opioid therapy.


Facts About Hyperalgesia

  • Hyperalgesia is also recognized as "Medication Overuse Pain".
  • Hyperalgesia caused by opioid medications is generally observed when a medical condition like chronic headache or pain is treated with high doses of opioids.1,2
  • Recent evidence points to the fact that use of chronic opioids is solely responsible for activating pain receptor-IV of the glial cells,1 which leads to pain receptors getting into an inflammatory state resulting in amplification of pain impulse resulting in hyperalgesia.
  • The opioids have been proved to cause chronic hyperalgesia after chronic opioid treatment.
  • Acute hyperalgesia is seen during postoperative pain management with opioids in patients following surgery performed under general anesthesia.3, 4
  • Fibromyalgia causes chronic neuropathic pain, which results in increased sensitivity to pain known as hyperalgesia.

Opioid Induced Hyperalgesia-

  • Past research and studies were mostly focused on side effects of high dosage of long-term opioid therapy.
  • Opioid induced hyperalgesia or OIH is also seen following short-term opioid therapy during postoperative recovery period when treated with opioid for post op pain.
  • Opioid induced hyperalgesia or OIH is occasionally diagnosed as neuropathic pain.

Hyperalgesia in Fibromyalgia: Neuropathic Pain

  • If one is to describe neuropathic pain, it can be done so as both hyperalgesia as well as allodynia.
  • Fibromyalgia causes neuropathic pain.
  • Hyperalgesia is totally different from allodynia. Hyperalgesia is heightened sense of pain after painful stimuli where as allodynia is heightened sense of pain induced by non-painful stimuli like simple palpation on skin.
  • Hyperalgesia induced by opioids is different than hyperalgesia caused by of fibromyalgia.
  • Hyperalgesia caused by fibromyalgia is significantly heightened sense of pain to noxious as well as non-noxious stimuli.

Hyperalgesia and Tolerance:

  • A major side effect of opioid is tolerance. By tolerance, one means developing resistance to positive effects of the opioids, often observed in individuals who have been on chronic opioid treatment.
  • Individuals have a sensation of continuous pain of same intensity even after taking the medication, which in turn results in the individual taking more medication for relief.
  • Similarly an individual suffering with opioid induced hyperalgesia also frequently asks for opioid medication for pain relief.
  • Opioid induced hyperalgesia suggests inadequate pain relief after opioid treatment and is indicative of opioid tolerance.
  • Opioid hyperalgesia is generally misunderstood for increase of tolerance to opioid medications.5
  • The microbiological contrast between Opioid Induced Hyperalgesia and tolerance to opioids is found at the level of the receptors.
  • The receptors of an individual with Opioid Induced Hyperalgesia become oversensitive to noxious as well as nonnoxious stimuli whereas receptors of individuals who develop tolerance to opioids become unresponsive to opioids.

Hyperalgesia and Opioid Withdrawal

  • Opioids are prescribed as analgesics for chronic pain patient.
  • Few chronic pain patients are either dependent or addicted to opioids.
  • Few addicted or dependent patients often consume either all or most of the prescribed opioids during first few days after possession of opioid medications.
  • Opioid withdrawal symptoms are seen when patient takes less amounts of opioids than prescribed amount or stops taking opioids.
  • Most common withdrawal symptoms are increased intensity of pain, nausea, abdominal pain and running nose.
  • During withdrawal period patients feel return of severe intensity of pain characterized as allodynia and hyperalgesia.
  • Withdrawal symptoms are most often seen in individuals on high doses of opioid.
  • Symptoms disappear after ingesting of opioids.
  • Patients taking very high dosage of opioids may suffer through withdrawal symptoms when level of opioids falls below threshold level.
  • Patient taking high therapeutic dosage of opioids may suffer through frequent opioid withdrawal symptoms during 24 hours and may need to take frequent high follow up dosage to treat and prevent symptoms of withdrawal.
  • During several occasions patient may consume more pills a day than prescribed dosage and eventually run out of pills before end of month. In this situation patient will be going through withdrawal symptoms until he receives his next prescription or he may purchase opioid on the street.
  • Patient going through withdrawal symptoms and OIH (Opioid induced hyperalgesia) very often visits physician clinic for early refill.
  • Patient suffering with OIH (Opioid induced hyperalgesia) are often diagnosed as suffering with opioid withdrawal and diagnosed as opioid dependent or addict.1

Hyperalgesia and Addiction:

  • Addiction is a disorder which is seen in people who take opioids for recreational reasons and occasionally in people who are being treated for chronic pain.
  • Patient suffering with chronic intractable pain respond to opioids with adequate relief of pain at first but after prolonged treatment may develop addiction to the medications or hyperalgesia.
  • Chronic pain patients who get addicted to opioid medications tend to ask for additional pain medications and often need early refills of medications.
  • Patient may suggest increased tolerance and resistance to analgesic effect of opioid medications demanding increase in dosages.5
  • Similarly requirement for increased doses of opioid is also seen in individuals with Opioid Induced Hyperalgesia (OIH).
  • Addiction and Opioid induced hyperalgesia are both leading causes for increasing demand for opioid medications.
  • Opioid induced hyperalgesia generally is not completely understood by physicians.
  • Opioid induced hyperalgesia (OIH) can also develop with smaller doses of opioids and within a short period of time.6
  • Opioid induced hyperalgesia (OIH) also may be seen following administration of opioids in a perfectly healthy individual and in individual abusing opioids.8
  • OIH is often misunderstood to be addiction.

Hyperalgesia In Patients With Fibromyalgia:

  • Patient with chronic diseases like fibromyalgia occasional suffer with hyper responsiveness of central nervous system causing hyperalgesia.2
  • One of the study involving 34 patients were divided into two groups of seventeen patients, group consisted of seventeen fibromyalgia patients and seventeen normal control groups.
  • Scientific study was performed by Burgmer M et al. and published in 2012. Each patient in both groups had experimental incision in the right volar forearm. Primary and secondary hyperalgesia were assessed and recorded. Changes in hyperalgesia were correlated to brain activation (functional magnetic resonance imaging). Test results suggest alteration of pain transmission at the central level (brain) in patients suffering with fibromyalgia. Similar changes in MRI were not observed in normal patients. These findings were related to changes in cerebral-midbrain-spinal mechanisms of pain inhibition.
  • Hyperalgesia is a common symptom in-patient suffering with fibromyalgia.
  • Symptom of fibromyalgia often triggers the diagnosis of opioid addiction, tolerance or dependence.
  • Hyperalgesia is a predominant symptom in large population of fibromyalgia patients who are not taking opioids for chronic pain.

Hyperalgesia Following Short-Term Exposure To Opioids:

  • Hyperalgesia is often seen after intravenous opioid treatment for postoperative pain.
  • Opioid Induced Hyperalgesia (OIH) is seen in recovery room after surgery following acute opioid exposure.
  • Intravenous opioid treatment during surgery and in recovery room causes acute hyperalgesia in few patients.9
  • Unidentified hyperalgesia may results in diagnosis of inadequate post op pain relief.
  • Patients are often given large dosage of intravenous opioids to achieve adequate pain relief.
  • Large dose of intravenous opioid may result in complications such as respiratory apnea.

Hyperalgesia and Administrative Route:

  • In the past hyperalgesia was often diagnosed following long-term oral opioid medications.
  • Recent studies indicates Opioid Induced Hyperalgesia (OIH) is observed after oral, intravenous, epidural and intrathecal opioid administration.10

Prevention of Hyperalgesia:

  • Hyperalgesia can be prevented by rotation of different opioids in approximately six month interval.12,15
  • Addition of NMDA receptor antagonists like dextromethorphan, methadone or ketamine with opioids also helps to prevent hyperalgesis.13,15

Treatment of Hyperalgesia

Opioid Rotation-

  • Patients who have hyperalgesia symptoms are treated by rotating opioids.
  • Change of opioids helps to prevent hyperalgesia.

Addition of Adjuvant Medication-

  • Hyperalgesia may not respond to opioid rotation. In such cases following medication are prescriibed with opioids-
    • NSAIDs
    • Muscle Relaxants: Baclofen, Flexeril or Skemaxin
    • Ketamine local application
    • Neurontin or Lyrica
    • Cymbalta

Replace Opioids With Buprenorphine-

  • Opioids are discontinued
  • Buprenorphine is prescribed instead opioids

Treat Hyperalgesia With Non-Opioid Medications-

  • Treat hyperalgesia pain with following non opioid analgesics-
    • Antiepileptic Analgesia- Neurontin or Lyrica
    • Antidepressant Analgesics- Cymbalta and Elavil


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Johnson JL, Hutchinson MR, Williams DB, Rolan P., Cephalalgia. 2013 Jan;33(1):52-64. doi: 10.1177/0333102412467512.

Discipline of Pharmacology, University of Adelaide, Australia.

2. Cerebral mechanisms of experimental hyperalgesia in fibromyalgia.

Burgmer M, Pfleiderer B, Maihöfner C, Gaubitz M, Wessolleck E, Heuft G, Pogatzki-Zahn E., Eur J Pain. 2012 May;16(5):636-47. doi: 10.1002/j.1532-2149.2011.00058.x.

Department of Psychosomatics and Psychotherapy, University Hospital Münster, Münster, Germany.

3. Opioid-induced hyperalgesia:aqualitativesystematic review.

Angst MS, Clark JD

Anesthesiology 2006; 104:570-587.

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Koppert W, Schmelz M.

Best Pract Res Clin Anaesthesiol 2007; 21:65-83.

5. Pain tolerance and narcotic addiction.

Martin JE, Inglis J., Br J Soc Clin Psychol 1965; 4:224-9.

6. Opioid-induced hyperalgesia may be more frequent than previously thought.

ZyliczZ,TwycrossR., J Clin Oncol 2008; 26:1564; author reply 1565.

7. Withdrawal hyperalgesia after acute opioid physical dependence in non-addicted humans: a preliminary study.

ComptonP,AthanasosP,ElashoffD., J Pain 2003; 4:511-9.

8. Methadone maintenance patients are cross-tolerant to the anti-nociceptive effects of morphine.

Doverty M, Somogyi AA, White JM, et al., Pain 2001; 93:155-63.

9. Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine.

Joly V, Richebe P, Guignard B, et al. Anesthesiology 2005; 103:147-55.

10. Colvin LA, Fallon MT. Opioid-induced hyperalgesia: a clinical challenge.

Colvin LA, Fallon MT. , Br J Anaesth 2010; 104:125-7

11. Oral opioid use alters DNIC but not cold pain perception in patients with chronic pain - new perspective of opioid-induced hyperalgesia.

Ram KC, Eisenberg E, Haddad M, et al. Pain 2008; 139:431-8.

12. Hyperalgesia and opioid switching.

Mercadante S, Arcuri E. Am J Hosp Palliat Care 2005; 22:291-4.

13. Using methadone to treat opioid-induced hyperalgesia and refractory pain.

Axelrod DJ, Reville B., J Opioid Manag 2007; 3:113-4.

14. Pharmacological treatment of opioid-induced hyperalgesia: a review of the evidence.

Ramasubbu C, Gupta A., J Pain Palliat Care Pharmacother. 2011;25(3):219-30.

Department of Anesthesiology and Critical Care, Penn Pain Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia PA 19104, USA.

15. A comprehensive review of opioid-induced hyperalgesia.

Lee M, Silverman SM, Hansen H, Patel VB, Manchikanti L., Pain Physician. 2011 Mar-Apr;14(2):145-61.

Centers for Pain Management, Tifton, GA 31794, USA.

16. Opioid-induced hyperalgesia and tolerance.

Bekhit MH., 10.1097/MJT.

Department of Anesthesiology, David Geffen School of Medicine at UCLA, Ronald Reagan UCLA Medical Center, Los Angeles, CA 90095, USA.

Written, Edited or Reviewed By:


Last Modified On: March 18, 2015

Pain Assist Inc.

Pramod Kerkar
  Note: Information provided is not a substitute for physician, hospital or any form of medical care. Examination and Investigation is necessary for correct diagnosis.

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