Opioid Induced Hyperalgesia

Dr. Sanford Silverman
Pain Week Journal
Q2 2014

Opioid Induced Hyperalgesia

As early as the nineteenth century, OIH was observed in patients receiving morphine for pain. It was recognized that a potent analgesic such as morphine could actually result in an increase in pain, as observed by Albutt in 1870:

“At such times I have certainly felt it a great responsibility to say that pain, which I know is an evil, is less injurious than morphia, which may be an evil. Here experience is needed. Does morphia tend to encourage the very pain it pretends to relieve? ... in the cases in question, I have much reason to suspect that a reliance upon hypodermic morphia only ended in that curious state of perpetuated pain.”

*Sir Thomas Clifford Albutt (1836–1925): a British physician, researcher, and the author of Medical Thermometry.1

abstract: In the United States there is an epidemic of chronic pain that parallels the ever increasing utilization of opioids. This increase in opioid use has led to misuse and abuse and has left in its wake thousands of fatalities. Yearly, there are greater than 15,000 deaths.2 Although the general consensus is that opioids can be prescribed safely and effectively with prudent risk mitigation strategies, certain side effects/complications can be difficult
to treat. Addiction, abuse, and diversion are usually the focus of such efforts, and become relatively straightforward when investigated. However, other side effects to opioid therapy can be somewhat difficult to assess and even more so to treat. Opioid-induced hyperalgesia (OIH), related to but different from tolerance, is one such complication of opioid therapy. There is preclinical and clinical evidence for such, as well as the clinical implications for the pain practitioner.3

Tolerance is a pharmacologic concept. It occurs when there is a progressive lack of response to a drug thus requiring increased dosing. Tolerance can occur with a variety of drugs including opioids.4.5 Tolerance may not only develop to the analgesia provided by opioids but also to the undesirable side effects which are seen with opioid
administration, such as pruritus, nausea, sedation, and respiratory depression.

Sensitization to pain occurs in several areas of the nervous system involving the transmission of pain. Peripheral mechanisms have been well documented with respect to neural injury involving mediators of inflammation. This is known as primary hyperalgesia and is seen clinically with peripheral nerve injuries. Secondary hyperalgesia, on the other hand, occurs “downstream” from the initiating nociceptive stimulus and peripheral injury. In the spinal cord, wide dynamic range neurons become sensitized through a variety of mechanisms that may be mediated by neurotransmitters, such as calcitonin gene-related peptide, vasoactive intestinal peptide, dynorphin, cholecystokinin, neuropeptide Y, and N-methyl-D-aspartate (NMDA).6

Since tolerance is characterized by decreasing efficacy of a drug, it can be overcome by increasing the dose. Unlike tolerance, OIH cannot be overcome by increasing dosage, however, because OIH is a form of pain sensitization induced by the drug, which occurs within the central nerve system (CNS). It is a pro-nociceptive process that is related to, but different from, tolerance. Pain is worsened with increased opioid dosing and is improved by reducing or eliminating the opioid. Tolerance is a necessary condition for OIH, but the converse is not true. Clinically this is an important distinction that has obvious ramifications with respect to continued use of opioids in a given patient.

“Significant pain reduction has been demonstrated in patients who have been detoxified from high-dose opioids.”

Laboratory (preclinical) evidence exists for OIH. In several animal studies, a progressive reduction in baseline pain threshold has been seen following administration of opioids through both intravenous and intrathecal routes.7-10 Supporting evidence has shown that OIH occurs clinically outside the laboratory, and is seen after intraoperative
remifentanil infusion, resulting in decreased opioid efficacy.11 Significant pain reduction has been demonstrated in patients who have been detoxified from high-dose opioids.12 When challenged with cold pressor tests, opioid addicts maintained on methadone demonstrated increased pain sensitivity.13

There are several proposed mechanisms, many of them overlapping, that may explain the phenomenon of OIH. The 3 most commonly proposed are:

  1. 1. The central glutamate system
  2. 2. Elevated spinal dynorphin levels
  3. 3. Descending facilitation

Glutamate is an excitatory neurotransmitter that plays a central role in several disease states including chronic pain and chemical dependency. The excitatory neurotransmitter NMDA binds to receptors throughout the CNS. With prolonged opioid administration, NMDA receptors become activated. This activation can be inhibited with NMDA receptor antagonists and has been demonstrated to prevent the development of tolerance and OIH.14,15

Spinal dynorphin levels may increase with continued infusion of μ-receptor agonists. This in turn leads to increased levels and the release of spinal excitatory neuropeptides, such as calcitonin gene-related peptide from primary afferents.16

Descending facilitation may influence OIH through subsets of neurons (on and off cells) in the rostral ventromedial medulla, which have the unique response to opioids.17,18 In addition, lesioning of these descending pathways in animals has been shown to prevent increases seen in excitatory neuropeptides.19

When a chronic pain patient demonstrates lack of efficacy to a given medication, the most common response is to increase the dose of that medication. The presumed mechanism is tolerance. With opioids, however, does the lack of efficacy equal tolerance or OIH? Clinicians more often than not initially increase the dose of opioid to offset what they believe is tolerance. If the patient responds positively to such an increase, and sustains this over a period of time, then the diagnosis of tolerance is likely. However, if there is no improvement or it is transient, then the clinician must consider OIH.

There are other signs and symptoms that may be helpful in diagnosing OIH. Typically, the pre-existing pain condition will be exacerbated. The pain pattern will become more diffuse and less localized. The clinician must rule out further progression of the disease or increased demand, which is perceived by the patient as increased need for medication (often referred to as pseudotolerance).

In fact, most patients who are utilizing chronic opioid therapy are mildly hyperalgesic, particularly to acute pain. For example, a scenario with which most interventional pain physicians are familiar is when a patient on chronic opioid therapy presents for a procedure. Very often they do not tolerate even the local anesthetic and are less tolerant of the acute pain experienced during the procedure. They often present with intolerance to acute surgical pain. Many surgeons have discovered that these patients often require more opioid for a longer time postoperatively then the typical opioid naïve patient.

However, if a patient on chronic opioid therapy (often at moderate to high doses) presents with diffuse pain, then OIH should be considered. If an increase in opioid fails to address the problem, then OIH should be considered. If a reduction in opioid produces concomitant reduction in pain, then certainly OIH is likely.

When treating a chronic pain patient, it is important to recognize that multimodal therapy produces the best results. Rational polypharmacy to include nonopioid medications should be utilized, particularly in treating neuropathic pain. This in turn provides an opioid sparing effect, reducing the total opioid dose and the concomitant opioid side effects. Interventional pain medicine along with behavioral therapy can accomplish similar goals in reducing pharmacotherapy. If these options are not feasible, then the clinician may consider the following approaches:

  1. 1. Opioid rotation to a different chemical class of opioid
  2. 2. Utilize NMDA receptor antagonists (ketamine, mematine)
  3. 3. Reduce or eliminate the opioid and evaluate change in pain
  4. 4. Utilize opioids with unique properties that may mitigate OIH

Methadone is often utilized to treat chronic pain. It is a racemic mixture in which the D isomer is an NMDA receptor antagonist. Methadone displays incomplete cross tolerance unique from other μ-receptor agonists, which may create a niche role for it in the treatment of OIH and other forms of intractable pain, particularly neuropathic pain. Incomplete cross tolerance of methadone has also led to its association with multiple overdose deaths due to inappropriate escalation of the dose or combining it with other opioids and CNS depressants.20

Buprenorphine has been used to treat chronic pain and has been available in the US since the early 1980s. Commercially available forms for chronic pain include a parenteral form (Buprenex®) and a transdermal delivery system (Butrans®).

Buprenorphine has shown to be intermediate in its ability to induce pain sensitivity in opioid addicts maintained on methadone and control patients not utilizing opioids.13 Buprenorphine is a partial agonist at the μ-receptor but an antagonist at the k-receptor. Spinal dynorphin is a known k-receptor agonist that has been implicated in OIH. Thus, buprenorphine may be unique in its ability to treat chronic pain and OIH via k antagonism.

Weaning patients from high-dose opioid medications can be time-consuming and sometimes impractical. For example, patients often will experience more pain during the weaning process until eventually they break through the hyperalgesic barrier. Physicians will often have to adjust combinations of extended-release and short-acting opioids during the weaning process. Patients may become frustrated and eventually give up.

Breaking the cycle of pain and hyperalgesia is an attractive option for the pain practitioner. Medically supervised withdrawal from highdose opioids utilizing sublingual buprenorphine is rapid and effective. Sublingual buprenorphine is approved for the treatment of opioid dependence. It requires a waiver from the Substance Abuse Mental Health Administration and the Drug Enforcement Administration. Patients who suffer from OIH can be transitioned to sublingual buprenorphine just as patients suffering from opioid addiction are. The buprenorphine can then be weaned accordingly.

Opioid therapy can be very effective for chronic nonmalignant pain. However, like any other therapy, side effects and complications can occur. The physician should have an exit strategy when initiating opioids for the treatment of chronic pain. The potential for dealing with complications such as opioid dependence, addiction, abuse, and OIH are very real, and the pain practitioner must be prepared for these challenges. As the number of patients treated with chronic opioids increases, so do the complications. OIH should be considered in the differential diagnosis when patients fail to respond to opioid therapy, as part of a comprehensive assessment and informed consent/

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