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Treatment of Neuropathic Pain: The Role of Unique Opioid Agents

Agents that work against central nervous system receptors may be the key to successful pain management in patients with nerve damage or injury.
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Neuropathic pain often is defined as pain caused by a lesion to or dysfunction of the central or peripheral nervous systems.1 Neuropathic pain often is chronic in nature, with a complex pathophysiology.2

Postherpetic neuralgia and diabetic neuropathy are the two most commonly studied and described types of neuropathic pain. In addition to diabetes and the herpes zoster virus, other triggers of neuropathic pain include toxins, trauma, infection, chemotherapy, surgery, tumor infiltration, and immunologic disorders.3,4

Differing from nociceptive pain, neuropathic pain is usually described as “burning,” “electric,” “tingling,” and/or “shooting”; it presents as both continuous background pain and spontaneous pain, and it can be impervious to conventional analgesic medications.4-7

Nonetheless, several agents have shown substantial evidence for efficacy in the treatment of neuropathic pain. Selected agents that are most commonly used and studied for the treatment of neuropathic pain can be seen in Table 1.7-12

Table 1. Select Medications for the Treatment of Neuropathic Pain

Table 1. Select Medications for the Treatment of Neuropathic Pain


Although there is limited data in published guidelines on the use of opioids to treat neuropathic pain, 4,5,8,9,13 several reports suggest that certain unique opioids might be useful in this setting.14-18

Pathophysiology of Nerve Pain

To demonstrate why specific opioids might be beneficial, it is essential to understand the pathophysiology of neuropathic pain and the receptors with which the opioids interact. To facilitate this understanding and draw parallels between the mechanisms of action of older and newer prospective therapies, this article reviews currently approved treatments and off-label treatment options.

Location, Location, Location

Based on lesion location in the nervous system, the pain originates centrally, peripherally, or may be mixed. Peripherally, a local inflammatory response will occur after direct damage to a nerve. This inflammation causes nociceptors to become more sensitive to normal stimuli, to undergo a lengthened response when stimulated, and to discharge spontaneously.

More specifically, calcium channels that regulate the release of neurotransmitters from terminals of sensory neurons become altered. Overactivity of these channels causes a decrease in neurotransmitter release and, subsequently, abnormal firing at the nerve ending.13

Normally, when a person experiences a painful stimulus, excitatory amino acids such as glutamate are released. Glutamate can interact with the N-methyl-d-aspartate (NMDA) receptor in the central nervous system. Prolonged and repeated activation by glutamate on the NMDA receptor leads to an increase in neuronal signal transduction to the central nervous system and strengthened synapses between neurons.

This sensitization of spinal cord neurons causes a heightened responsiveness to certain signal inputs that are received.19 Further changes in nerve function, chemistry, and structure can occur, triggering the spontaneous pain and allodynia that are characteristic of neuropathic pain.13

It is known that opioids act primarily as agonists at endogenous opioid receptors. The various opioid receptors include delta, kappa, and mu, with mu playing the largest role in analgesia. The physiological effects that opioids have when binding to these receptors generally are well understood. Depending on the receptor and the opioid-binding affinity, varying levels of analgesia and adverse effects can occur.

Opioids do not act by altering pain threshold, or transduction, rather they change the way pain is perceived in the afferent pathway of the central nervous system.20 The aforementioned changes to the pain-transmitting system that occur in neuropathic pain are likely what makes treatment so challenging.

In spite of an opioid’s ability to alter nociceptive signals, neuronal excitation still occurs. Failure of most opioids, especially as single agents, to treat neuropathic pain, happens all too often.

There are, however, distinctive opioids that bind to receptors other than the mu-opioid receptor and have non-opioid properties that are relevant to the pathophysiology of neuropathic pain.14 Although a recent meta-analysis indicates possible efficacy of various opioids without these unique mechanisms, the usefulness of these medications, such as oxycodone or morphine, in neuropathic pain remains equivocal,21

This review will focus on those opioids with nonopioid properties and unique mechanisms of action.

Unique Mechanism

Methadone and levorphanol are two opioids that have unique mechanisms in addition to their conventional opioid receptor actions. Both of these opioids additionally work by antagonizing NMDA receptors and inhibiting the reuptake of norepinephrine, the latter being the mechanism by which certain antidepressants purportedly work to treat neuropathic pain.22,23

Levorphanol also has additional unique qualities, in that it has a high affinity for the kappa-opioid receptor, possibly adding to its analgesic activity.24

These properties have provided an incentive to design clinical trials that assess the treatment efficacy of methadone and levorphanol. In one double-blinded, randomized, controlled crossover trial, a low dose of methadone was used to demonstrate its efficacy in patients with chronic nonmalignant neuropathic pain.14 Compared with the placebo group, the group receiving 20 mg of methadone daily experienced statistically significant improvements in subjective scale ratings of maximum pain intensity, average pain intensity, and pain relief. The improvements in all three outcomes extended for more than 48 hours and demonstrated a significant analgesic effect of methadone in neuropathic pain.14

A small study assessing allodynia and spontaneous pain in 18 patients with neuropathic pain also revealed similar results. Pretreatment pain scores were significantly lowered with methadone therapy, from 7.7 to 1.4. Patients who experienced “shooting pain” reported a complete response, and 9 of 13 patients with allodynia reported complete resolution.15 A retrospective review of 13 patients over a 12-month study period suggested that methadone is also effective. Although four patients discontinued methadone before the 12-month study period ended, the remaining nine patients reported, on average, a 47% improvement in quality of life, a 43% increase in pain relief, and a 30% improvement in sleep.16

The Forgotten Opioid

Although methadone often is considered a stigmatized opioid, it still is more commonly prescribed than levorphanol, which is sometimes referred to as “the forgotten opioid.”22-24 Because levorphanol shares the unique non-opioid properties of methadone, it also, theoretically, should be useful in the treatment of neuropathic pain.

This commentary is the sole opinion of the authors and does not reflect the opinion of, nor was it reviewed by, any government agency. It was not prepared as a part of Dr. Fudin’s official government duty as Clinical Pharmacy Specialist.
Last updated on: January 6, 2016
First published on: May 1, 2011