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Opioid-Induced Pain Sensitivity


Try saying this to the patient who comes in to the office complaining of pain that is unrelieved by his or her current regimen of opioid analgesics: "We need to reduce your pain medicine." How well will most patients accept the explanation that their medication is actually increasing their pain?

Opioids are often the analgesics of choice for treating severe acute and chronic pain. But pain relief may not be the only effect of opioids. Exposure to opioids can result in 2 dissimilar processes: the development of opioid tolerance and the development of opioid-induced pain sensitivity, or hyperalgesia.[1] Sensitization and desensitization are both taking place.[2]

Opioid-induced pain sensitivity is a phenomenon that we are only beginning to understand, according to Jianren Mao, MD, PhD, of the Massachusetts General Hospital Center for Translational Pain Research.[3] Many studies have reported that opioid administration causes an unanticipated hyperalgesia (enhanced pain response to noxious stimuli) and allodynia (pain elicited by innocuous stimuli) in both animals and humans.[1]

Preclinical research suggests that abnormal pain sensitivity such as hyperalgesia or allodynia occurs in the absence of overt opioid withdrawal in animals that have been administered opioid drugs. Opioid-induced hyperalgesia can occur with both acute and chronic opioid administration.[3] A paradoxic opioid-induced pain sensitivity may contribute to apparent opioid tolerance in humans because the individual must increase the analgesic dose to maintain the same effect or the duration of action of the opioid will decrease.[4] Both continuous infusion and bolus injections of opioids shift the analgesic dose-response curve to the right so that progressively higher opioid doses are required for the same analgesic effect.

A reduction of the baseline nociceptive threshold following repeated opioid administration is the presumed mechanism of increased pain sensitivity in animals. Intrathecal morphine sulfate, administered twice daily, progressively lowers the baseline nociceptive threshold in rats, as does the administration of subcutaneous fentanyl or heroin boluses. Similar findings occur with continuous opioid infusion.

The relationship between abnormal pain sensitivity and opioid withdrawal is known. Dr. Mao proposes that the lower baseline nociceptive threshold observed in animals is a miniwithdrawal of sorts and precedes the more recognizable withdrawal signs such as diarrhea, wet-dog shake, and jumping. Signs of withdrawal in humans include nausea, ataxia, vomiting, diarrhea, and altered sense of smell.

Cellular Mechanisms of Opioid-Induced Pain Sensitivity

Opioid-induced pain sensitivity is an active process within the central nervous system, mediated through distinct neural mechanisms, including the endogenous dynorphin system, the glutamatergic system, and descending facilitation. These neural mechanisms are similar to those involved in neuropathic pain and involve the NMDA receptor and associated cascades.[5]

Peripheral nerve injury and repeated opioid administration similarly activate the central glutamatergic system. Hyperalgesia from tissue injury and inflammation is caused by prolonged excitation of spinal cord amino acid receptors and second messenger systems. Phosphorylation and sensitization of NMDA receptors follow. Hyperalgesia caused by fentanyl or heroin can be blocked by NMDA receptor antagonists.

Pain sensitization is believed to be mediated by tonic nociceptive afferent input from tissue injury or inflammation, causing:

  • Toxic effect of opioid metabolites (morphine-3-glucuronide (M3G) or hydromorphone-3-glucronide (H3G);

  • Central sensitization as a result of opioid-related activation of NMDA receptors in the central nervous system;

  • Increase in spinal dynorphin activity;

  • Enhanced descending facilitation from the rostral ventromedial medulla; and

  • Activation of intracellular protein kinase C.

There is not yet any direct evidence for opioid-induced heightened pain sensitivity in humans. Self-reports of pain scores cannot distinguish pharmacologic tolerance from increased pain sensitivity. Similarly, observations documenting reduced postoperative analgesic efficacy following intraoperative opioid infusion suggest opioid tolerance but do not make a distinction between pharmacologic tolerance and opioid-induced pain sensitivity or both. In support of the theory of increased pain sensitivity is the finding that patients treated intraoperatively with opioids reported more postoperative pain than matched non-opioid controls.[6,7]

Pain sensitivity also differs between subjects with opioid addiction and normal subjects, with increased pain sensitivity to an experimental pain stimulus in those with opioid addiction. Moreover, pain sensitivity is altered in patients undergoing methadone maintenance. In these individuals, pain sensitivity is increased beyond that of former opioid addicts who are not receiving methadone.[8]

In patients with cancer or other types of chronic pain, it is difficult to separate increased pain sensitivity from increases in disease-related pain. Although anecdotal reports suggest that opioid-induced pain sensitivity does occur in patients with cancer pain, controlled studies of pain sensitivity in these patients are lacking. In a small prospective study of patients with nonmalignant chronic pain, patients were evaluated for opioid tolerance and opioid-induced hyperalgesia. Quantitative sensory testing was performed in 6 patients with chronic low back pain before and 1 month after starting morphine treatment. Pain sensitivity to experimental cold and heat pain was measured during administration of a short-acting mu-opioid agonist. Hyperalgesia and tolerance developed with cold pain but not with heat pain.[9]

Clinical Implications

The patient without apparent disease progression who reports diminishing analgesic efficacy during opioid therapy presents a dilemma. Traditionally, we have assumed that an increased opioid requirement for the same analgesic effect was primarily a sign of pharmacologic tolerance, or possibly a worsening disease state. The usual approach to this situation is to increase the dose of opioid to overcome tolerance or more effectively treat pain. The paradox of opioid-induced pain sensitivity compels us to rethink this approach. Rather than escalating opioid dosages, opioid tolerance caused by increased pain sensitivity is managed by lowering opioid dosages.

How does the clinician determine whether reported pain is preexisting or opioid induced? Dr. Mao suggests 4 tests that can be used to differentiate between the two:

  1. Pain intensity is increased above the level of preexisting pain in the absence of apparent disease progression;

  2. Opioid-induced pain is diffuse, less defined in quality, and beyond the distribution of the preexisting pain state;

  3. Quantitative sensory testing (eg, tolerance to cold and heat pain) may reveal changes in pain threshold, tolerability, and distribution patterns; and

  4. Undertreatment of preexisting pain or development of pharmacologic tolerance may be overcome by a trial of opioid dose escalation. In contrast, opioid-induced pain could be worsened by an increase in opioid dose. Opioid-induced hyperalgesia will improve after supervised opioid tapering.[2]

Clinical evidence suggests that the degree of opioid-induced hyperalgesia varies with different opioids. Morphine, for instance, is more likely to produce hyperalgesia than methadone. Duration of treatment may also influence the development of opioid-induced hyperalgesia, although this phenomenon has been noted in patients receiving short-term opioid therapy. It is not yet known whether switching opioids interrupts this process.


Pharmacologic tolerance or worsening disease state are not the sole explanations for a decrease in analgesic efficacy. When presented with the patient who reports increasing pain or failure of current therapy to provide adequate analgesia, the clinician should consider the possibility of opioid-induced hyperalgesia. Under some circumstances, a trial of opioid tapering might achieve pain reduction.

Supported by an independent educational grant from Ortho-McNeil.



  1. Chang G, Chen L, Mao J. Opioid tolerance and hyperalgesia. Med Clin North Am. 2007;91:199-211. Abstract
  2. Mao J. Opioid-induced hyperalgesia. Pain Clinical Updates. 2008;16:1-4.
  3. Mao J. Opioid-induced pain sensitivity: is it clinically relevant? Paper presented at: the 24th Annual Meeting of the American Academy of Pain Medicine; February 12-16, 2008; Orlando, Florida.
  4. Joranson DE, Gilson AM. A much-needed window on opioid diversion. Pain Med. 2007;8:128-129. Abstract
  5. Mayer DJ, Mao J, Holt J, Price DD. Cellular mechanisms of neuropathic pain, morphine tolerance, and their interactions. PNAS. 1999;96:7731-7736. Abstract
  6. Crawford MW, Hickey C, Zaarour C, et al. Development of acute opioid tolerance during infusion of remifentanil for pediatric scoliosis surgery. Anesth Analg. 2006;102:1662-1667. Abstract
  7. Guignard B, Bossard AE, Coste C, et al. Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology. 2000;93:409-417. Abstract
  8. Compton P, Charuvastra VC, Kintaudi K, et al. Pain responses in methadone-maintained opioid abusers. J Pain Symptom Manage. 2000;20:237-245. Abstract
  9. Chu LF, Clark DJ, Angst MS. Opioid tolerance and hyperalgesia in chronic pain patients: a preliminary prospective study. J Pain. 2006;7:43-48. Abstract
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