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אפריל 2012 April | גיליון מס' 24 .No
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חברי מערכת
רשימת גליונות קודמים
שער הגליון

The paradoxical phenomenon of opioid induced hyperalgesia


Erica Dolnikov MSc a,c, Dorit Pud PhD b Elon Eisenberg MD a,c aThe Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel; bFaculty of Social Welfare and Health Sciences, University of Haifa, Israel; cInstitute of Pain Medicine, Rambam Health Care Campus, Haifa, Israel.


Abstract
Exploring the response to opioid treatment is of a significant clinical importance. Better understanding of the mechanisms underlying this phenomenon and identifying predictors of its development will enable physicians to assemble an individualized treatment for each patient according to his unique profile and to avoid the "trial and error" method. This is particularly important for opioids because chronic use often leads to adverse events, some of which are not without considerable morbidity and risks. This paper will describe the meaning of opioid induced hyperalgesia, will review the current literature that explored this phenomenon both in animal and in human studies, will highlight the possible mechanisms of its development and finally will address the clinical importance. 

Background
Opioids are the cornerstone therapy for the treatment of moderate to severe pain and are one the most commonly prescribed medications for the treatment of chronic non-cancer pain in the US- according to recent studies, as many as 25-44% of patients with chronic pain who use prescription medications, consume opioids. (1). Indeed, the high efficacy of opioids is reflected by statistical analyses which show that the number needed to treat (NNT) for achieving 50% pain reduction by using opioids for neuropathic pain is ~ 2. That is, 1 of 2 patients with neuropathic pain will report 50% pain relief with the use of an opioid (2). Although these statistics provide evidence for the overall efficacy of opioids for long-term treatment, there is still huge inter-individual variability in the magnitude of response to these drugs: while some patients report dramatic pain relief with an opioid, others, who have similar pain syndromes, fail to benefit from the same drug. The reason for this variability in response to opioid treatment remains unknown. Furthermore, so far in a given patient population, there is no way of predicting who will respond or not respond to prolonged opioid treatment. Although common concerns regarding the use and effectiveness of opioids include potential side effects, tolerance and addiction, growing body of evidence suggests that opioids may cause another problem, often referred to as opioid-induced hyperalgesia (OIH) (3).
OIH is defined as a state of nociceptive sensitization caused by exposure to opioids. The condition is characterized by a paradoxical response whereby a patient receiving opioids for the treatment of pain could actually become more sensitive to pain.
That is, the use of opioids may act as a double-edged sword: initially they provide straight analgesic and antihyperalgesic effects, but afterwards may be associated with hyperalgesia, likely due to upregulation of compensatory pronociceptive pathways (3). 

Evidence from animal studies
Dozens of animal studies conducted since the early 1970s triggered the renewed interest in OIH by suggesting that administration of opioids may paradoxically increase the sensitivity to pain and may potentially aggravate preexisting pain.
In 1971, Kayan and colleagues first described hyperalgesia in rats after acute morphine injection using the hot plate test (4). A later study found that hyperalgesia might develop after a sudden withdrawal following an injection of an opioid antagonist and during spontaneous withdrawal after cessation of opioid administration (5). Another study found that chronic administration of opioids causes hyperalgesia which is reflected by lower pain thresholds compared to baseline and showed that this phenomenon depends both on opioid dose and on the experimental pain model (ie, thermal, mechanical, electrical, or chemical (6). In a study conducted by Celerier et al (2000), rats received systemic fentanyl over a short time period (four doses in 1 h, every 15 min). As expected, initially fentanyl produced acute antinociception to a noxious stimulus, an effect that lasted for 2-5 h. But a later response was associated with sustained lowering of the nociceptive threshold (5 days for the longest effect) below the basal value (30% of decrease for the maximal effect), indicative of hyperalgesia. Furthermore, the higher the fentanyl dose was used, the more evident was the fentanyl-induced hyperalgesia (7). Mao (2002) showed that hyperalgesia might not only develop after opioid exposure cessasion, but might also develop during opioid repeated or continuous administration thus suggesting that OIH may develop independently from withdrawal (8).
Lastly, another study worth noting suggested that OIH paradoxically may not even require opioid receptors: Knockout mice lacking the opioid recpetors (μ-, δ-, or κ-) developed thermal hyperalgesia after acute and chronic exposure to fentanyl (9). 

Evidence from human studies
The accumulating evidence regarding the possible development of OIH in animals triggered a series of controlled clinical trials examining this phenomenon, its expression and clinical impact in humans. Unlike animal studies, the evidence regarding both the existence and the importance of this phenomenon in humans is less obvious. A structured evidence-based review published in 2009 examined all levels of evidence (all studies and case reports) on OIH in humans in order to determine their consistency. The authors' concluded that the strongest evidence for OIH in humans comes from opioid infusion studies in normal volunteers as measured by secondary hyperalgesia area and that overall, there is not sufficient evidence to support or refute the existence of OIH in humans (10).
Despite of this controversy, and the lack of findings regarding the clinical prevalence of OIH, several clinical reports provide hints that hyperalgesia may occur in the context of acute and chronic opioid administration. 

Perioperative exposure to opioids in patients undergoing surgery
Guignard (2000) found that large-dose of intraoperative remifentanil in 50 males who underwent major abdominal surgery increased postoperative pain scores and morphine consumption nearly by twice during the first 24 postoperative hours compared to patients that received low dose of intraoperative remifentanil (11). Another randomized, double-blind clinical trial which compared the postoperative analgesic effect and dose consumption of fentanyl after intraoperative high / low dose of fentanyl in 60 female patients who underwent total abdominal hysterectomy, found that patients in the high dose group had higher pain intensity at 4 and 8 hours postoperatively and a greater fentanyl consumption in the postoperative period of 16 hr than those in the low dose group (12). On the other hand, a prospective study conducted on 60 patients who had an elective gynaecological, non-laparoscopic surgery, assessed whether remifentanil-based anesthesia is associated with greater postoperative pain scores and morphine consumption, found that cumulative morphine consumption during the first 24 postoperative hours was similar between the group that received remifentanil (n=30) and the group that received sevoflurane (n=30). Pain scores were also similar between both groups during this period (13). 

Healthy volunteers exposed to opioids
Koopert (2003) found electrical and mechanical hyperalgesia after acute remifentanil infusion to 13 healthy volunteers in a randomized double-blind, placebo controlled, cross-over study (14). Angst (2003) found mechanical hyperalgesia after a short-term infusion of remifentanil in a double blind, randomized, crossover placebo-controlled study conducted on 10 opioid-na??ve, healthy human volunteers (15). 

Former opioid addicts on methadone maintenance therapy
Pud (2006) found OIH in chronic opioid addicts using the cold pressor test (CPT) and showed that detoxification from opioids does not retune their pain perception for at least one month (16). Hay et al (2009) also found hyperalgesia in methadone- maintained patients using the CPT and showed that the nociceptive profile associated with methadone administration is also observed in morphine-treated patients with chronic pain, thus demonstrating that hyperalgesia is not associated with a particular population but with the long-term administration of opioids (17). 

Patients with chronic pain who receive opioid treatment
Evidence regarding hyperalgesia in patients with chronic pain who receive chronic opioid treatment is perhaps the most controversial. A study conducted on 224 chronic pain patients (both with malignant and non-malignant pain) included a group of 142 opioid-treated patients and 82 non-opioid-treated patients did not find significant differences in experimental pain measurements (punctuate pain threshold, pressure pain threshold, heat pain threshold, tonic heat pain intensity), suggesting that oral opioid administration does not result in abnormal pain sensitivity beyond that of patients receiving non-opioid analgesia (18). A study conducted by Chen (2009) compared pain threshold, pain tolerance, and the degree of temporal summation of the second pain in response to thermal stimulation among three groups of subjects: those with neither pain nor opioid therapy (Group 1, n=41), those with chronic pain but without opioid therapy (Group 2, n=41), and subjects with both chronic pain and opioid therapy (Group 3, n=58). As compared with subjects in groups 1 and 2, subjects in group 3 displayed both decreased heat pain threshold and aggravated temporal summation. In contrast, no differences were detected in cold or warm sensation among the groups. The study also found that daily opioid dose correlated with decreased heat pain threshold and aggravated temporal summation of subjects in group 3 (19). A preliminary study (Chu, 2006) conducted on six chronic low back pain patients who were opioid naïve at study entry, examined analgesic tolerance and hyperalgesia before and after 1 month of oral morphine treatment. The researchers found that hyperalgesia to cold (but not to heat pain) occurs within 1 month of morphine treatment. Considering the paucity of data supporting the notion that OIH occurs over time with opioid therapy, this study presented a methodology which allowed the investigation of OIH development over time (20). 

Possible mechanisms underlying OIH
Nearly 100 publications of animal studies demonstrated the existence of OIH following administration of intrathecal morphine treatment or repeated subcutaneous fentanyl and heroin. Based on these findings OIH should be considered as a neurobiological multi-factorial process which may be mediated by several suggested mechanisms that related to different special levels:
(1) Peripheral level - sensitization of primary afferent neurons. Since the µ-opioid receptors are expressed on both central and peripheral terminals of the primary afferent neurons, the peripheral injection of selective opioid agonists might cause functional changes in the neurons by increasing the levels of the pro-nociceptive peptides calcitonin gene-related peptide (CGRP) and substance P (SP) within the dorsal root ganglion (21).
(2) Spinal level - enhanced production and release of excitatory neurotransmitters and diminished reuptake of neurotransmitters. Both intraspinal and systemic administration of opioids has shown that spinal cord plasticity, at least partially underlies OIH development. One of the early studies in this field displayed a thermal hyperalgesia following daily bolus administration of intrathecal morphine to rats for more than 1 week. It was largely confirmed by subsequent investigation that showed that N-methyl-D-aspartate (NMDA) excitatory amino acid receptors and phosphokinase C (PKC) mediate this phenomenon by causing spinal neurons sensitization. It was also shown that spinal blockade of the NMDA receptor (by MK-801 or ketamine) may reduce or reverse OIH (21).
(3) Supraspinal level - higher CNS areas (more specifically, the rostral ventromedial medulla, RVM) may participate in supporting OIH through enhanced descending facilitation to the dorsal horn of the spinal cord. Discontinuation of neuronal discharge from the RVM (which carries descending nerve fibers from the dorsal horn) by microinjection of local anesthetic, was able to prevent or reverse OIH. Furthermore, increased activity of the excitatory peptide neurotransmitter cholecystokinin (CCK) in the RVM causes the activation of spinal pathways that up-regulate spinal dynorphin and thus enhances nociceptive inputs at the spinal level (21). 

Conclusions and clinical implications
1. The phenomenon of opioid-induced hyperalgesia has been well-documented in animals.
2. In the clinical setting, patient reports' of increased pain require a systematic approach in the consideration of possible etiologies.
3. Physicians should be aware to the fact that elevation of opioid dosage may not always result in pain reduction but may cause the opposite effect.
4. It is important to understand the impact of OIH both in the acute post surgical setting and in the management of chronic pain. Development of algorithms or diagnostic tests will allow the identification of patients at risk for developing OIH, and to determine if its expression can be attenuated or even reversed through pharmacological modulation.
5. Future high quality prospective trials need to further explore the conditions under which OIH develops and to clarify its clinical significance through a direct documentation of OIH development by using appropriate assessments of pain sensitivity. 

References
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3. Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology.2006;104(3):570-87.
4. Kayan S, Woods LA, Mitchell CL. Morphine-induced hyperalgesia in rats tested on the hot plate. J Pharmacol Exp Ther.1971;177:509–513.
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6. Celerier E, Laulin JP, Corcuff JB, Le Moal M, Simonnet G. Progressive enhancement of delayed hyperalgesia induced by repeated heroin administration: a sensitization process. J Neurosci.2001;21:4074–4080.
7. Célèrier E, Rivat C, Jun Y, Laulin JP, Larcher A, Reynier P, Simonnet G. Long-lasting hyperalgesia induced by fentanyl in rats: preventive effect of ketamine. Anesthesiology.2000;92(2):465-72.
8. Mao J, Sung B, Ji RR, Lim G. Chronic morphine induces downregulation of spinal glutamate transporters: implications in morphine tolerance and abnormal pain sensitivity. J Neurosci. 2002;22(18):8312-23.
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14. Koppert W, Angst M, Alsheimer M, Sittl R, Albrecht S, Schüttler J, Schmelz M. Naloxone provokes similar pain facilitation as observed after short-term infusion of remifentanil in humans. Pain.2003;106(1-2):91-9.
15. Angst MS, Koppert W, Pahl I, Clark DJ, Schmelz M. Short-term infusion of the mu-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal. Pain.2003;106(1-2):49-57.
16. Pud D, Cohen D, Lawental E, Eisenberg E. Opioids and abnormal pain perception: New evidence from a study of chronic opioid addicts and healthy patients. Drug Alcohol Depend.2006;82(3):218-
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21. Martin S, Angst J, David Clark. Opioid-induced Hyperalgesia. Qualitative Systematic Review. Anesthesiology.2006;104:570–87












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