Opioid-induced hyperalgesia is a clinical syndrome whereby patients on long-term opioids become more sensitive to pain while taking opioids. Opioid-induced hyperalgesia is characterized by increased pain intensity over time, spreading of pain to other locations, and increased pain sensation to external stimuli. To characterize opioid-induced hyperalgesia, laboratory methods to measure hyperalgesia have been developed. To determine the performance of these methods, the authors conducted a systematic review of clinical studies that incorporate measures of hyperalgesia in chronic pain patients on long-term opioids.
PubMed and Cochrane databases were searched (terms: opioid induced hyperalgesia, study or trial, and long-term or chronic). Studies published in English were selected if they were conducted in chronic pain patients on long-term opioids and incorporated measures of hyperalgesia; acute/single-dose studies and/or conducted in healthy volunteers were excluded.
Fourteen articles made the final selection (11 were selected from the search and 3 others were found from additional sources); there was one randomized controlled trial, one prospective controlled study, three prospective uncontrolled studies, and nine cross-sectional observation studies. Hyperalgesia measurement paradigms used included cold pain, heat pain, pressure pain, electrical pain, ischemic pain, and injection pain. Although none of the stimuli were capable of detecting patients’ hyperalgesia, heat pain sensitivity showed some promising results.
None of the measures reviewed herein met the criteria of a definitive standard for the measurement of hyperalgesia. Additional studies that use improved study design should be conducted.
In a systematic review of 14 studies of opioid-induced hyperalgesia, most sensory modalities tested failed to demonstrate hypersensitivity to test stimuli, and additional work with stronger study designs is needed.
Opioid-induced hyperalgesia is a clinical concept associated with increased pain sensitivity and decreased efficacy at the same dose of opioids with ongoing opioid use
The most appropriate sensory testing for opioid-induced hyperalgesia is not clear
In a systematic review of 14 studies of opioid-induced hyperalgesia, most sensory modalities tested failed to demonstrate hypersensitivity to test stimuli, and additional work with stronger study designs is needed
FOR many decades, physicians have expressed concerns about the manifestation of tolerance to opioids with long-term use. Tolerance to opioid analgesia can manifest either as loss of pain relief while receiving fixed doses of opioids or as the need for dose escalation to maintain the same degree of pain relief. Clinically, such patients end up on high doses of opioid therapy, with persistent high pain intensity, and poor physical and psychosocial function. There are a variety of reasons why relief from pain might be lost (or opioid doses escalated) in these patients, including worsening in pain intensity over time, worsening of underlying disease, a desire for hedonistic effects, the emergence of tolerance, or the emergence of opioid-induced hyperalgesia (OIH). OIH is defined as a clinical syndrome in which patients on long-term opioids become more sensitive to pain as a result of taking opioids. Clinically, OIH is characterized by a triad of symptoms: (1) an increase in pain intensity over time, (2) the spreading of pain to other location than the initial painful site, and (3) an increase in pain sensation to external stimuli. Whether clinical OIH truly exists is controversial. OIH has been reliably demonstrated in animal models and there is some clinical evidence to support its occurrence in humans.1,2 Although opioid tolerance and OIH can be measured in behavioral models in rodents and human experimental pain models, the relevance of these models to patients on long-term opioid therapy for chronic pain is unclear.1,3 Recent reviews and meta-analyses have documented remifentanil-associated increases in pain, postoperative opioid requirements, and hyperalgesia at or near the surgical site.4 Although the effects of short-acting intraoperative opioids on acute postoperative outcomes is interesting, this topic is beyond the scope of this review which focuses on patients who are maintained on long-term opioid therapy.
To determine whether clinical OIH exists and to characterize it, researchers have aimed at developing laboratory methods to measure hyperalgesia (i.e., the increase in pain sensitivity, as a proxy to clinical OIH) in chronic pain patients on long-term opioids, outside of the patient’s primary clinical pain syndrome. To this end, laboratory methods have been developed that consist of evaluating patients’ pain threshold and tolerance to external experimental stimuli such as mechanical (pressure, touch, or injection), thermal (cold/heat), electrical, or other stimuli (e.g., ischemia). Two possible study designs have been typically used (1) patients with chronic pain on long-term opioids are cross-sectionally compared with patients with the same chronic pain syndrome not taking opioids, or (2) patients with chronic pain on long-term opioids are evaluated before and after an intervention such as discontinuing opioid therapy. However, none of these experimental approaches have been validated or is considered the definitive standard for measuring hyperalgesia in clinical trials of pain patients on chronic opioids. A suitable method for evaluating hyperalgesia would be reliable and responsive, that is, able to discriminate groups of patients known to have different levels of pain sensitivity that may be associated with opioid therapy. Therefore, we conducted a systematic review of clinical studies that incorporated measures of hyperalgesia in chronic pain patients on long-term opioids to determine and compare the performance of each method to measure hyperalgesia. Because responsiveness requires reliability, we have focused on responsiveness as the key performance characteristic for this review. Finding adequate experimental methods to measure hyperalgesia in chronic pain patients will help determine whether clinical OIH exist, to characterize it, and to prevent or treat it.
Materials and Methods
To find human studies that measure hyperalgesia in patients on long-term opioids for chronic pain, a search in PubMed and Cochrane databases was performed using terms (“all terms” search) such as “opioid induced hyperalgesia,” “study or trial,” and “long-term or chronic,” and rejecting the terms “mice or rodent.” A first screening of the retrieved articles was performed based on the title and abstract; the screened articles were then retrieved in their full version and carefully read to be included in the final selection. In order for an article to be selected, the study had to meet the following criteria: (1) be a randomized controlled trial, a prospective study, or a cross-sectional comparative study; (2) be conducted in patients on long-term opioids for chronic pain (single-dose/acute studies and studies conducted only in healthy volunteers were excluded); (3) include assessments or measures of hyperalgesia as part of the study; and (4) be published in English. The search included articles up to May 2014 (no date limit was used).
The methods used to measure hyperalgesia in the articles retrieved from the main search were compiled. To ensure that all possible original articles were found, a secondary literature search was conducted using the terms “opioid induced hyperalgesia” and the name of the test used to measure hyperalgesia (e.g., cold pressor test, thermal sensory analyzer, lidocaine injection, electrical stimulation, etc.).
Data extracted from the articles included the type of study (studies were categorized into randomized controlled trials, prospective controlled studies, prospective uncontrolled studies, and cross-sectional comparative studies), the patient population, the measure(s)/test(s) used to assess hyperalgesia, available results (difference between pre- and posttreatment, difference between groups, dose-related data, and any other relevant data), and P values (when available).
The article screening and selection process is illustrated in figure 1. The PubMed Library search retrieved 62 articles and the Cochrane database search retrieved 22; a search of our personal records retrieved 1 article. After elimination of duplicates, 68 articles were screened for relevance. A total of 11 articles made the final selection (from most to least recent): Suzan et al.,5 Chu et al.,6 Krishnan et al.,7 Edwards et al.,8 Wang et al.,9 Hooten et al.,10 Chen et al.,11 Ram et al.12 Hay et al.,13 Cohen et al.,14 and Chu et al.15 Searching the references of these articles retrieved two other articles (Reznikov et al.16 [cited in Suzan et al.5 ]; Doverty et al.17 [cited in Chu et al.6 ]). Another original article was found via the secondary search for OIH and lidocaine injection (Kim et al.18 ). Thus, a total of 14 original studies that measured hyperalgesia in patients on long-term opioids for chronic pain were found.
Description of Studies
Of the 14 selected studies, 1 was a randomized controlled trial,6 1 was a prospective controlled study,5 3 were prospective uncontrolled studies,9,10,15 and 9 were cross-sectional observation studies.7,8,11–14,16–18 Six hyperalgesia measurement paradigms were used in these studies: cold pain, heat pain, pressure pain, electrical pain, ischemic pain, and injection pain; these methods are described in table 1. The design, patient population, and results of each study are summarized in table 2.
Summary of Findings
The ideal measure would be able to differentiate pain sensitivity in patients randomly exposed prospectively to opioids compared with a cohort randomly assigned to a control condition. Only one study6 used such a design (randomized controlled trial), and the two experimental methods used in that study (cold pain threshold and tolerance using ice water immersion and heat pain threshold and tolerance using the Medoc TSA; Medoc Ltd. Advanced Medical Systems, Ramat Yishai, Israel) both failed to differentiate the two groups. It is unclear whether these approaches failed because of the measures, because the patients did not in fact develop hyperalgesia, or because treatment was short term and used relatively low doses. Thus, no measure of hyperalgesia can claim definitive standard status.
Table 3 summarizes the test results by indicating which measures were used in each study, and whether the P value for the between-group difference tested was greater than 0.05 (−) or less than 0.05 (+). The major methods that have been used are (1) cold pain threshold and tolerance using ice water immersion, and (2) heat pain threshold, tolerance, or intensity at suprathreshold stimulus levels using computer-controlled thermode devices. The summary results in table 3 suggest that, on average, none of the stimuli were capable of detecting hyperalgesia in chronic pain patients on long-term opioids. However, some specific findings merit attention. For instance, two controlled prospective studies5,6 and one uncontrolled prospective study10 found a significant difference in heat pain sensitivity between pre- and postopioid treatment.
This systematic review was conducted to determine and compare the responsiveness of methods to measure hyperalgesia in clinical studies of chronic pain patients on long-term opioids. Fourteen articles reporting original studies measuring hyperalgesia in those patients were retrieved. Because clinical OIH has not yet been definitively demonstrated, it is not possible to directly determine the responsiveness of measures of this phenomenon. Furthermore, the studies performed in this area tend to have small sample sizes, different experimental designs, and different testing protocols, thereby precluding formal meta-analytic methods. The summary results in table 3 suggest that, on average, none of the stimuli have sufficient power to detect hyperalgesia in chronic pain patients on long-term opioids. However, some specific findings merit attention. For instance, it is notable that three prospective studies that assessed heat pain ratings reported heat hyperalgesia when patients were on opioid therapy (compared with when they were off opioids).5,6,10 Although a larger number of studies have been performed with ice water immersion, a substantial proportion of these studies failed to discriminate “known” groups, and the aversive nature of the test should be considered. Mechanical testing approaches (algometry or von Frey filaments) have been used several times, never successfully.7,8,11,13,16 Other approaches (conditioned pain modulation, ischemia, injection pain) have been unsuccessful, inconsistent, or have been used too rarely to conclude.7,8,12,14,18
Thus, this review failed to identify a definitive standard for hyperalgesia measures. This is mainly due to the fact that the measurements failed to detect a change because the measures are not sensitive enough, the sample is too small for the measure to detect change, the studies use suboptimal study designs (most being cross-sectional), and/or the timing of opioid dosing was not controlled for. Moreover, all these studies provide averages of hyperalgesia variables over the entire group of opioid-treated patients, which may obliterate the phenomenon if the development of hyperalgesia is a rare occurrence in patients on opioids. Therefore, clinicians who wish to conduct a clinical trial to measure hyperalgesia in opioid-treated patients should choose a randomized controlled trial design and report the proportion of patients on opioids who develop hyperalgesia during the treatment. Finally, although most studies focused on measure responsiveness, assessing reliability and other forms of validity would also be informative. This review identified heat stimuli (using the Medoc TSA; Medoc Ltd. Advanced Medical Systems) as a potentially good candidate for further testing in future studies. More data should also be generated with injection pain to determine whether this method holds true potential.
Importantly, clinicians should be cautious not to take the increase in pain sensitivity (hyperalgesia) to experimental stimuli as a proof of OIH in opioid-treated patients. Indeed, clinical OIH is a syndrome that has three main symptoms: one of them being an increase in pain sensitivity to external stimuli and the other two being an increase in pain intensity over time and the spreading of pain to other locations. To conclude that a patient experiences OIH should rely on additional evaluation of the patient’s clinical data and medical history to determine whether all characteristics of clinical OIH are present. To this end, Chen et al.11 provides a list of clinical factors that should be taken into account in the diagnosis of clinical OIH.
This study was funded by Campbell Alliance, Raleigh, North Carolina.
The authors declare no competing interests.