Background: Opioid analgesics are the most effective pharmacological agents for moderate and severe pain. However, opioid use has several limitations such as opioid-induced hyperalgesia (OIH), which refers to the increased pain sensitivity that occurs once analgesia wears off after opioid administration. Several pharmacological interventions have been suggested for OIH, but the current literature does not provide guidelines on which interventions are the most effective and whether they differ depending on the opioid that induces hyperalgesia. This scoping review aimed to identify and describe all the preclinical trials investigating pharmacological interventions for OIH caused by remifentanil, fentanyl, or morphine as the first step towards evaluating whether the most effective OIH interventions are different for different opioids. Methods: Electronic database searches were carried out in Embase, PubMed, and Web of Science. Detailed data extraction was conducted on the eligible trials. Results: 72 trials were eligible for the review. Of these, 27 trials investigated remifentanil, 14 trials investigated fentanyl, and 31 trials investigated morphine. A total of 82 interventions were identified. The most studied interventions were ketamine (eight trials) and gabapentin (four trials). The majority of the interventions were studied in only one trial. The most common mechanism suggested for the interventions was inhibition of N-methyl-D-aspartate (NMDA) receptors. Conclusion: This scoping review identified plenty of preclinical trials investigating pharmacological interventions for OIH. Using the current literature, it is not possible to directly compare the effectiveness of the interventions. Hence, to identify the most effective interventions for each opioid, the interventions must be indirectly compared in a meta-analysis.
Opioid analgesics are the most effective pharmacological agents for moderate and severe pain. However, opioid use has several limitations such as the build-up of tolerance and a high risk for the development of addiction. One of the lesser-known limitations is opioid-induced hyperalgesia (OIH), which refers to the increased pain sensitivity that occurs once analgesia wears off after opioid administration. OIH is commonly measured by quantitative sensory testing (QST), where mechanical or thermal stimuli are used to assess the subject’s pain threshold. OIH has been mostly studied with surgical patients that have been administered remifentanil. A few trials have observed OIH in chronic pain patients and addiction patients, but it is still unclear whether OIH is clinically significant in non-surgical patient groups. To improve pain management with opioids, plenty of research has been carried out to identify interventions for OIH. Most of the interventions are pharmacological, but non-pharmacological interventions have also been investigated such as exercise, polyamine-deficient diet, and electroacupuncture therapy. Current reviews of the pharmacological OIH interventions are qualitative and lack statistical analysis of effectiveness. Additionally, there are two unpublished reviews registered in PROSPERO that aim to rank the effectiveness of pharmacological interventions for remifentanil-induced hyperalgesia (RIH) in surgical patients. According to our preliminary searches, not enough randomised controlled trials (RCTs) have been carried out in other patient groups or using other opioids to evaluate the effectiveness of different interventions in these perspectives. Therefore, the current literature has a significant knowledge gap, as it is not known whether OIH in different contexts or caused by different opioids is attenuated most effectively by the same interventions. According to Heinl et al., fentanyl-induced hyperalgesia (FIH) and morphine-induced hyperalgesia (MIH) occur via a distinct mechanism to RIH, which suggests that their most effective interventions may differ. Preliminary searches have shown that several preclinical trials have been conducted to investigate pharmacological interventions for OIH caused by remifentanil, fentanyl, or morphine. Hence, this scoping review aimed to identify all the preclinical trials investigating pharmacological interventions for OIH caused by remifentanil, fentanyl, or morphine as the first step towards evaluating whether the most effective OIH interventions are different for different opioids.
The aim of this scoping review was to identify and describe all the preclinical trials investigating pharmacological interventions for OIH caused by remifentanil, fentanyl, or morphine. Analysis of these trials will be carried out as the first step towards evaluating whether the most effective OIH interventions are different for different opioids. Hence, this review will qualitatively review the trials to (1) map the existing literature, (2) describe the trial characteristics, (3) identify gaps and limitations in the current research, and (4) make recommendations for future trials.
This scoping review was planned according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis Extension for Scoping Reviews (PRISMA-ScR) checklist developed by Tricco et al. See Appendix A for a summary of the checklist. A protocol to fulfil the requirements was planned as the first step of the review. The protocol included (1) preliminary searches into OIH intervention research to identify a knowledge gap and a suitable research question, (2) defining the eligibility criteria for including and excluding trials, (3) electronic database searches to gather potentially relevant research, (4) selecting eligible articles, (5) data extraction and description of the trials, and (6) summarising the findings and providing recommendations for future research. It should be noted that the protocol had a few minor deviations from the PRISMA-ScR checklist. The checklist includes a step for “review registration”, but since scoping reviews cannot be registered in the PROSPERO database, this step was skipped. Similarly, the methods subsection “critical appraisal of individual sources of evidence” and the results subsection “critical appraisal within sources of evidence” were skipped, as the assessment of the methodological quality of the included articles is not typically included in scoping reviews.
For a trial to be eligible in the review, it had to (1) investigate pharmacological intervention(s) for OIH, (2) investigate OIH caused by remifentanil, fentanyl, or morphine, (3) use an in vivo animal model, (4) measure hyperalgesia via QST, (5) be an original full research paper, and (6) be written in English. Pharmacological interventions with all timings, frequencies, dosages and administration methods were included. No time period restrictions were set.
The databases were selected for the search according to Bramer et al.’s analysis of the “optimal database combinations for literature searches in systematic reviews”. Hence, to identify potentially relevant trials, electronic database searches were carried out in Embase, PubMed, and Web of Science. Reference lists of the eligible articles were scanned to find trials that may have been missed in the search. All searches were carried out in January 2022.
The search strategy was created according to Leenaars et al.’s “step-by-step guide to systematically identify all relevant animal studies” that combines search items for the disease of interest, interventions, and animal trials. In this review, the disease of interest words included, for example, “opioid-induced hyperalgesia” and “remifentanil-induced hyperalgesia”. The intervention search items included generic intervention words such as “drug therapy” and “pharmacological intervention”, as well as specific intervention words identified during preliminary searches such as “ketamine”. To identify all the available animal trials, the most recently developed animal filters were used. The full search strategies for each database are shown in Appendix B.
The articles obtained in the final search of each database were exported to EndNote. Duplicate articles were removed and the titles and abstracts were checked for eligibility. Full-text articles were evaluated in the next step if the eligibility was unclear. The process was repeated for the articles identified from the references of eligible articles.
Data from eligible trials were charted onto a Microsoft Excel sheet. Data items extracted included the following categories: general, opioid, intervention, study design, QST, and animal model. The general information included the first author and year of publication. The type of opioid investigated was used to place the trial in the right category, and the dose, administration method, and regimen type were noted. The opioid regimen was categorised as “acute” if the opioid was given for less than 1 day and “chronic” if the opioid was given for several days. Intervention data items included the pharmacological agent used and its dose, administration method, administration time in comparison to opioid administration, and mechanism to attenuate OIH. In addition, intervention effectiveness was noted for each experimental group. Intervention in an experimental group was categorised as “effective” if statistical difference to the opioid-only group could be shown at any point with any type of QST. For the study design, the type and size of experimental and control groups were extracted, as well as the experimental injury model used and the length of the trial. In the trial lengths, catheterization procedures or baseline days were not taken into account. QST data items were the type of QST used, units of measurement, type of behaviour recorded (e.g., withdrawal or vocalisation), body area used for QST, and timing of measurements compared to opioid administration. Data items extracted about the animal model used included the species, strain, and sex of the animals.
For simplicity and relevance, not all of the study groups discussed in the articles were recorded. Groups exposed to the intervention without an opioid were excluded, since the analgesic property or the lack of it does not determine the intervention’s antihyperalgesic property. Similarly, groups that were exposed to the injury model without an opioid were excluded, as the research question specifically focuses on OIH and not other types of hyperalgesia. Groups that only provided additional information on the mechanism of the intervention were not included in the study groups. However, the information was used in data extraction to classify the intervention under the right mechanism. If a trial used several control groups, only the most relevant was included. For example, if both saline only and vehicle only groups were used, the vehicle group was selected. Moreover, whether the opioid only group received saline or other control injections (compared to the opioid and intervention group) was not recorded. Likewise, additional control exposures in other groups were not recorded.
The electronic database search results and the article screening process are summarised as a flow diagram in Figure 1. To be able to present the data extraction results without a supplementary materials section, three tables with only the main characteristics of each type of opioid trials were created (Table 1, Table 2.
