Opioid-induced hyperalgesia
Encyclopedia
Opioid-induced hyperalgesia or opioid-induced abnormal pain sensitivity is a phenomenon associated with the long term use of opioid
s such as morphine
, hydrocodone
, oxycodone
, and methadone
. Over time, individuals taking opioids can develop an increasing sensitivity to noxious stimuli, even evolving a painful response to previously non-noxious stimuli (allodynia
). Some studies on animals have also demonstrated this effect occurring after only a single high dose of opioids.
Although tolerance and opioid-induced hyperalgesia both result in a similar need for dose escalation, they are nevertheless caused by two distinct mechanisms. The similar net effect makes the two phenomena difficult to distinguish in a clinical setting. Under chronic opioid treatment, a particular individual's requirement for dose escalation may be due to tolerance
(desensitization of antinociceptive mechanisms), opioid-induced hyperalgesia (sensitization of pronociceptive mechanisms), or a combination of both. Identifying the development of hyperalgesia is of great clinical importance since patients receiving opioids to relieve pain
may paradoxically experience more pain as a result of treatment. Whereas increasing the dose of opioid can be an effective way to overcome tolerance, doing so to compensate for opioid-induced hyperalgesia may worsen the patient's condition by increasing sensitivity to pain while escalating physical dependence
.
If an individual is taking opioids for a chronic non-cancer pain condition, and cannot achieve effective pain relief despite increases in dose, they may be experiencing opioid-induced hyperalgesia. In this case, they may benefit from complete withdrawal from opioid therapy. Many individuals report reduced pain levels when opioids are withdrawn.
The precise mechanisms underlying opioid-induced hyperalgesia are poorly understood. The sensitization of pronociceptive pathways in response to opioid treatment appears to involve several pathways. Research thus far has primarily implicated the abnormal activation of NMDA receptors in the CNS, and long-term potentiation of synapses between nociceptive C fibers and neurons in the spinal dorsal horn. One possible strategy for treating hyperalgesia involves blocking activation of these receptors with NMDAR antagonists such as ketamine
, dextromethorphan
, or methadone
(which has NMDAR antagonist properties in addition to being an opioid analgesic). Human studies examining the benefit of combining opioid treatment with NMDAR antagonism have yielded mixed results, and few conclusions can be drawn until larger studies are conducted. Targeting the NMDA receptors in areas of potential pathology (such as the dorsal horn of the spinal cord) is a challenge considering their widespread presence throughout the spinal cord and brain, and the profound psychotomimetic
side effects associated with known NMDAR antagonists may limit their clinical potential as adjuvants to the treatment of pain.
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
s such as morphine
Morphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
, hydrocodone
Hydrocodone
Hydrocodone or dihydrocodeinone is a semi-synthetic opioid derived from either of two naturally occurring opiates: codeine and thebaine. It is an orally active narcotic analgesic and antitussive...
, oxycodone
Oxycodone
Oxycodone is an opioid analgesic medication synthesized from opium-derived thebaine. It was developed in 1916 in Germany, as one of several new semi-synthetic opioids in an attempt to improve on the existing opioids: morphine, diacetylmorphine , and codeine.Oxycodone oral medications are generally...
, and methadone
Methadone
Methadone is a synthetic opioid, used medically as an analgesic and a maintenance anti-addictive for use in patients with opioid dependency. It was developed in Germany in 1937...
. Over time, individuals taking opioids can develop an increasing sensitivity to noxious stimuli, even evolving a painful response to previously non-noxious stimuli (allodynia
Allodynia
Allodynia is a pain due to a stimulus which does not normally provoke pain. Temperature or physical stimuli can provoke allodynia, and it often occurs after injury to a site...
). Some studies on animals have also demonstrated this effect occurring after only a single high dose of opioids.
Although tolerance and opioid-induced hyperalgesia both result in a similar need for dose escalation, they are nevertheless caused by two distinct mechanisms. The similar net effect makes the two phenomena difficult to distinguish in a clinical setting. Under chronic opioid treatment, a particular individual's requirement for dose escalation may be due to tolerance
Tachyphylaxis
Tachyphylaxis is a medical term describing a decrease in the response to a drug due to previous exposure to that drug. Increasing the dose of the drug may be able to restore the original response. In this context tachyphylaxis is a synonym for drug tolerance...
(desensitization of antinociceptive mechanisms), opioid-induced hyperalgesia (sensitization of pronociceptive mechanisms), or a combination of both. Identifying the development of hyperalgesia is of great clinical importance since patients receiving opioids to relieve pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
may paradoxically experience more pain as a result of treatment. Whereas increasing the dose of opioid can be an effective way to overcome tolerance, doing so to compensate for opioid-induced hyperalgesia may worsen the patient's condition by increasing sensitivity to pain while escalating physical dependence
Physical dependence
Physical dependence refers to a state resulting from chronic use of a drug that has produced tolerance and where negative physical symptoms of withdrawal result from abrupt discontinuation or dosage reduction...
.
If an individual is taking opioids for a chronic non-cancer pain condition, and cannot achieve effective pain relief despite increases in dose, they may be experiencing opioid-induced hyperalgesia. In this case, they may benefit from complete withdrawal from opioid therapy. Many individuals report reduced pain levels when opioids are withdrawn.
The precise mechanisms underlying opioid-induced hyperalgesia are poorly understood. The sensitization of pronociceptive pathways in response to opioid treatment appears to involve several pathways. Research thus far has primarily implicated the abnormal activation of NMDA receptors in the CNS, and long-term potentiation of synapses between nociceptive C fibers and neurons in the spinal dorsal horn. One possible strategy for treating hyperalgesia involves blocking activation of these receptors with NMDAR antagonists such as ketamine
Ketamine
Ketamine is a drug used in human and veterinary medicine. Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Pharmacologically, ketamine is classified as an NMDA receptor antagonist...
, dextromethorphan
Dextromethorphan
Dextromethorphan is an antitussive drug. It is one of the active ingredients in many over-the-counter cold and cough medicines, such as Robitussin, NyQuil, Dimetapp, Vicks, Coricidin, Delsym, and others, including generic labels. Dextromethorphan has also found other uses in medicine, ranging...
, or methadone
Methadone
Methadone is a synthetic opioid, used medically as an analgesic and a maintenance anti-addictive for use in patients with opioid dependency. It was developed in Germany in 1937...
(which has NMDAR antagonist properties in addition to being an opioid analgesic). Human studies examining the benefit of combining opioid treatment with NMDAR antagonism have yielded mixed results, and few conclusions can be drawn until larger studies are conducted. Targeting the NMDA receptors in areas of potential pathology (such as the dorsal horn of the spinal cord) is a challenge considering their widespread presence throughout the spinal cord and brain, and the profound psychotomimetic
Psychotomimetic
A drug with psychotomimetic actions mimics the symptoms of psychosis, including delusions and/or delirium, as opposed to just hallucinations. Some drugs of the opioid class have psychotomimetic effects, such as pentazocine and butorphanol....
side effects associated with known NMDAR antagonists may limit their clinical potential as adjuvants to the treatment of pain.