Opioid Induced Hyperalgesia Pdf File

Opioid induced hyperalgesia pdf file

Chronic pain patients receiving opioid drugs are at risk for opioid-induced hyperalgesia OIH , wherein opioid pain medication leads to a paradoxical pain state. OIH involves central sensitization of primary and secondary afferent neurons in the dorsal horn and dorsal root ganglion, similar to neuropathic pain.

Hyperalgesia and allodynia pdf files

Gabapentin, a gamma-aminobutyric acid GABA analog anticonvulsant used to treat neuropathic pain, has been shown in animal models to reduce fentanyl hyperalgesia without compromising analgesic effect. Chronic pain patients have also exhibited lower opioid consumption and improved pain response when given gabapentin. However, few human studies investigating gabapentin use in OIH have been performed in recent years. In this review, we discuss the potential mechanisms that underlie OIH and provide a critical overview of interventional therapeutic strategies, especially the clinically-successful drug gabapentin, which may reduce OIH.

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Effective attenuation of pain is of the utmost importance in patient care. Opioid medications are commonly used in perioperative pain management in addition to providing relief for back Chu et al. Paradoxically, increased use of these medications has revealed side effects including opioid dependence, tolerance, and opioid-induced hyperalgesia OIH.

Opioid induced hyperalgesia pdf file

OIH is characterized by a paradoxical state of heightened pain sensation in which both pain threshold and pain tolerance decrease Kim et al. Moreover, this effect is seen not only in the chronic user but also surgical populations receiving opioids intraoperatively Ballantyne, ; Akbari, ; Lee et al.

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OIH is similar to opioid tolerance in that opioid drugs exhibit diminished efficacy with time, such that increasing dosage is required to provide a consistent level of analgesic effect Chu et al. However, OIH differs from opioid tolerance in that dose increases are accompanied by an increase in pain sensitivity and higher pain scores Ballantyne, ; Compton et al. OIH is also accompanied by allodynia, pain caused by a stimulus that does not normally provoke pain Fishbain et al.

It is thought that the analgesic and hyperalgesic effects of opioids exist at the same time, but the analgesic effects normally predominate, masking the hyperalgesia that is present Ballantyne, Human studies have revealed that several commonly used opioid drugs including fentanyl, remifentanil, and morphine have the ability to induce OIH Lenz et al. An infusion of remifentanil 0.

Human patients receiving higher intraoperative doses of remifentanil 0. In particular, the study saw higher visual analog scale scores in the remifentanil group as compared to the placebo group; however this difference was no longer significant 2—24 h after surgery.


In this review, we focus on gabapentin as a method for treatment of remifentanil and fentanyl induced-hyperalgesia.

OIH is comparable to neuropathic pain in both its neuro-inflammatory qualities and central sensitization processes. In neuropathic pain and OIH alike, there is ascending central hyperexcitability and diminished descending supraspinal inhibition, causing increased sensitivity to nociceptive inputs Compton et al. NMDA receptor activity has quickly gathered attention as one of the mechanisms involved in the propagation of hyperalgesia.

This NMDAR increase leads in turn to an upregulation of the NO synthase cascade and negative functional regulation of morphine algesia, as well as to protein kinase C-mediated phosphorylation of opioid receptors Koppert and Schmelz, ; da Cunha Leal et al. Increased NMDAR activation may also downregulate glutamate reuptake mechanisms, leading to central sensitization Vorobeychik et al. This enhanced NMDAR activity leads in turn to an upregulation of the nitric oxide synthase cascade-a negative functional regulator of morphine algesia, as well as to protein kinase C-mediated phosphorylation of opioid receptors and downregulation of glutamate reuptake mechanisms.

Together, these changes bring about central sensitization to pain and an increased need for opioid medications, sustaining the cycle.

Opioid-Induced Hyperalgesia

However, other classical studies have shown nitric oxide to inhibit rather than potentiate NMDARs in cortical neurons. These seemingly disparate results are partially explained in studies of the frequency at which presynaptic neurons are stimulated. Frequent neuronal stimulation leads to potentiation of the NMDA receptors while a lesser frequency leads to opposing inhibition and nitrosation of NMDA receptors. Opioid-associated pain may also result from neuroplastic changes in the rostral ventromedial medulla RVM.

Opioid induced hyperalgesia pdf file

A study by Gardell et al. The injection abolished tactile and thermal hypersensitivity, indicating the RVM modulates nociceptive input. The same study correlated chronic morphine exposure with upregulation of immune reactivity for calcintonin gene-related peptides and spinal dynorphin Gardell et al. The role of spinal dynorphin in attenuating pain is not yet clear, however, a recent study correlates activation of spinal bradykinin receptors by elevated spinal dynorphin with maintenance of inflammatory hyperalgesia Bannister et al.

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Gabapentin, a GABA analog commonly used as an anticonvulsant, has also been used in the treatment of neuropathic pain caused by diabetes, chronic illness, and a wide variety of surgeries, to great effect. When given prior to and after surgery, gabapentin has been shown to significantly decrease postoperative pain scores. Gabapentin has also proven effective against postoperative nausea and vomiting within the first 24 h when given alongside dexamethasone, and significantly reduced the rate of postoperative sore throat in another study.

Perioperative use of gabapentin was also correlated with a reduction in opioid consumption and the associated side effects while contributing few side effects of its own, namely nausea and dizziness. The side effects of gabapentin were seen most commonly in the chronic user, and were of concern mainly for elderly populations where such side effects might increase the risk of falling.

Gabapentin's side effects were not increased in opioid-abusing patients on concurrent methadone use and at risk for OIH Compton et al. Such a drug which effectively and more safely attenuates nociceptive pain is of great interest to those searching for an effective method for treating and reducing OIH. While several studies have demonstrated the efficacy of gabapentin in reducing postoperative hyperalgesia and allodynia, the exact mechanism by which it alleviates pain is poorly understood.

Central sensitization resulting from increased activity of afferent nociceptive neurons has been shown to be a key contributing factor in heightened pain sensitivity. Gabapentin reduces central sensitization through attenuating lesion-induced hyperexcitability of posterior horn neurons. Once bound, gabapentin inhibits the post-Golgi forward trafficking of the subunit to the surface of the cell, thus reducing VGCC expression Zoidis et al.

Such variance in VGCC reduction suggests a possible reason for gabapentin's low overall efficacy as well as its success in attenuating nociceptive pain in certain patients Li et al. In successful cases, the downregulated VGCC activity and reduced excitatory glutamate release led to decreased activity of the 4-isoxazolepropionic acid AMPA receptor and decreased norepinephrine release within the brain Chang et al.

AMPA receptors facilitate synaptic transmission in the central nervous system and the locus coeruleus LC. In the study conducted by Suto et al. The researchers were particularly interested in the effect of gabapentin on the LC, suspecting the importance of the LC in activating descending inhibition. Specifically, the study found that neurons providing descending inhibition within this area were excited by gabapentin's action on astrocytes which increased glutamate tone within the LC.

This increase in glutamate was induced via glutamate transporter-1 GLT-1 -dependent mechanisms. This increase in glutamate was not seen within the spinal cord Bao et al. Also of note, gabapentin was found to decrease GABA within the LC, a major site of descending pain inhibition, rather than the spinal dorsal horn Pertovaara, ; Yoshizumi et al.

N-type Ca v 2. A second derivative of gabapentin, 2- aminomethyl adamantanecarboxylic acid GZ4 , had similar effects on N-type Ca v 2. Administration of AdGABA and GZ4 resulted in the inhibition of excitatory neurotransmitters such as glutamate and reduced the presence of hyperalgesia and allodynia Zoidis et al.

Opioid induced hyperalgesia pdf file

Recent studies have shown that the analgesic qualities of gabapentin may not be limited to the interaction at voltage gated calcium channels, but may also include interactions with the interleukin IL heme oxygenase-1 HO-1 signaling pathway. IL is a key immunoregulatory cytokine with anti-inflammatory properties.

IL induces heme oxygenase-1 in macrophages through an activated protein kinase cascade Zoidis et al. The action of the heme oxygenase system is to induce the heme catabolic pathway. The HO system plays an important role in controlling tissue homeostasis during inflammation by inhibiting pro-inflammatory cytokine synthesis and prompting anti-apoptotic processes Asadullah et al.

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Several studies have shown the importance of the HO system in the attenuation of neuropathic pain. CO-releasing and HO-inducing molecules were utilized due to their demonstrated ability to activate the cyclic guanosine monophosphate-PKG pathway, which is responsible for morphine's local antinociceptive effects Abraham and Kappas, Gabapentin has been shown to positively influence interactions between both the IL and HO-1 pathways Compton et al.

Gabapentin used in conjunction with morphine has been shown to enhance the anti-nociceptive effect of IL and HO-1 signal transduction pathway through inhibition of spinal inflammation in a preclinical neuropathic pain model. Significantly increased IL levels were present with the co-administration of gabapentin and morphine as compared to morphine alone, supporting the role of gabapentin in this pathway. Furthermore, the use of anti-IL antibody or zinc protoporphyrin, an HO-1 inhibitor, partially blocked the effect of gabapentin on morphine.

These results implicate neuro-inflammation as a common mechanism in both neuropathy-induced and opioid-induced glial activation See Footnote 1.

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Although the mechanisms of gabapentin as well as opioid—induced hyperalgesia are not completely understood, the efficacy of gabapentin in attenuating OIH has been documented in several case studies. Compton et al.

Opioid induced hyperalgesia pdf file

A mg PO dose was administered daily over a 1-week period, and pain was evaluated using a standardized CP test. The experimental group showed statistically significant improvements in pain threshold and tolerance compared to the control group at peak as well as trough methadone levels.

The study concluded that when used in clinically tolerated doses, gabapentin significantly improved CP pain responses in methadone-maintained patients Compton et al.

This experiment provided evidence supporting the use of gabapentin in treating OIH. Another study by Cuignet et al.

opioid induced hyperalgesia

Patients were treated with mg of gabapentin three times per day for 21 days. Pain levels were evaluated using a visual analog scale. In the earlier stages of the study, both experimental and control groups had similar pain scores. However, during the rest of the treatment phase, the pain scores became significantly smaller in the gabapentin group as did the required opioid dosage Hervera et al. A reduction in opioid dosage with the use of gabapentin would also mean a reduced risk of developing OIH and allodynia.

Hauer et al.

Opioid-induced hyperalgesia in chronic pain patients and the mitigating effects of gabapentin

These case reports identified pain sources as nociceptive, peripheral neuropathic, central neuropathic, and visceral hyperalgesic in nature. Significant improvement in apnea following empiric treatment with gabapentin was observed.

In both cases, the initial gabapentin dose was 2. The reports proved gabapentin's role in the treatment and attenuation of hyperalgesia under altered neurologic states and amongst different age groups.

OIH will remain an important issue so long as chronic opioid usage remains prevalent in pain control.

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As such, clinicians should exercise caution in prescribing opioids, and may consider prescribing alternative therapies for pain relief if available. As discussed in prior studies, the use of adjunctive therapies such as gabapentin may be applicable if OIH is suspected. Gabapentin also leads to increased IL and HO-1 pathway activation, promoting anti-inflammatory activity at sites of spinal neuron insult.

At this time, the efficacy of gabapentin in mitigating OIH has been demonstrated in animal models and some human case studies.

However, few large scale standardized patient studies have been performed to corroborate these findings. We propose the design and implementation of standardized studies investigating gabapentin use in pain patients receiving opioid medications to further elucidate mechanisms underlying OIH as well as to establish a statistical basis for gabapentin use as an adjuvant therapy.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. National Center for Biotechnology Information , U.

Opioid induced hyperalgesia pdf file

Journal List Front Pharmacol v. Front Pharmacol. Published online May